The Landscape of Early Phase Research

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landscape-for-web

As Jonathan is fond of saying: Drugs are poisons. It is only through an arduous process of testing and refinement that a drug is eventually transformed into a therapy. Much of this transformative work falls to the early phases of clinical testing. In early phase studies, researchers are looking to identify the optimal values for the various parameters that make up a medical intervention. These parameters are things like dose, schedule, mode of administration, co-interventions, and so on. Once these have been locked down, the “intervention ensemble” (as we call it) is ready for the second phase of testing, where its clinical utility is either confirmed or disconfirmed in randomized controlled trials.

In our piece from this latest issue of the Kennedy Institute of Ethics Journal, Jonathan and I present a novel conceptual tool for thinking about the early phases of drug testing. As suggested in the image above, we represent this process as an exploration of a 3-dimensional “ensemble space.” Each x-y point on the landscape corresponds to some combination of parameters–a particular dose and delivery site, say. The z-axis is then the risk/benefit profile of that combination. This model allows us to re-frame the goal of early phase testing as an exploration of the intervention landscape–a systematic search through the space of possible parameters, looking for peaks that have promise of clinical utility.

We then go on to show how the concept of ensemble space can also be used to analyze the comparative advantages of alternative research strategies. For example, given that the landscape is initially unknown, where should researchers begin their search? Should they jump out into the deep end, to so speak, in the hopes of hitting the peak on the first try? Or should they proceed more cautiously–methodologically working their way out from the least-risky regions, mapping the overall landscape as they go?

I won’t give away the ending here, because you should go read the article! Although readers familiar with Jonathan’s and my work can probably infer which of those options we would support. (Hint: Early phase research must be justified on the basis of knowledge-value, not direct patient-subject benefit.)

UPDATE: I’m very happy to report that this paper has been selected as the editor’s pick for the KIEJ this quarter!

BibTeX

@Manual{stream2014-567,
    title = {The Landscape of Early Phase Research},
    journal = {STREAM research},
    author = {Spencer Phillips Hey},
    address = {Montreal, Canada},
    date = 2014,
    month = jul,
    day = 4,
    url = {http://www.translationalethics.com/2014/07/04/the-landscape-of-early-phase-research/}
}

MLA

Spencer Phillips Hey. "The Landscape of Early Phase Research" Web blog post. STREAM research. 04 Jul 2014. Web. 21 Jul 2017. <http://www.translationalethics.com/2014/07/04/the-landscape-of-early-phase-research/>

APA

Spencer Phillips Hey. (2014, Jul 04). The Landscape of Early Phase Research [Web log post]. Retrieved from http://www.translationalethics.com/2014/07/04/the-landscape-of-early-phase-research/


Stems and Blossoms (part 2): Really Informed Consent

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There is a strain within the clinical and bioethics community that takes a minimal view of informed consent: investigators are supposed to provide requisite information to volunteers; if research subjects fail to comprehend this information, pity for them. This view brings to mind a memorable exchange between Inspector Clouseau and a hotel clerk (Clouseau: “does your dog bite?” Clerk: “No.”  Clouseau then extends a hand; the dog lunges at him.  “I thought you said your dog doesn’t bite.” Clerk: “Zat is not my dog.”)


The ISSCR guidelines take a bold stand on informed consent. “Investigators involved in clinical research must carefully assess whether participants understand the essential aspects of the study.”  The guidelines go on to state “ideally, the subject’s comprehension of information should be assessed through a written test or an oral quiz during the time of obtaining consent.” Once again, ISSCR shows vision here in going well beyond the legalistic conception of informed consent described above.

The ISSCR guidelines also urge researchers to:
• explain possible irreversibility of some toxicities
• describe the sources of stem cells
• inform patients that researchers “do not know whether they will work as hoped”

These laudable recommendations aside, I might have hoped for more guarded language about the therapeutic value of early phase studies. For one, the guidelines use mostly “therapeutic” language, for example, using the aspirational term “cell therapy” instead of the neutral term “cell transfer.” Second, the third item above logically means that the probability of benefit is less than 100%; experience tells us, however, that when interventions are highly novel, major therapeutic benefits for early phase trials are very improbable. (photo credit: Helen K, Stems, 2008)

BibTeX

@Manual{stream2008-114,
    title = {Stems and Blossoms (part 2): Really Informed Consent},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2008,
    month = dec,
    day = 30,
    url = {http://www.translationalethics.com/2008/12/30/stems-and-blossoms-part-2-really-informed-consent/}
}

MLA

Jonathan Kimmelman. "Stems and Blossoms (part 2): Really Informed Consent" Web blog post. STREAM research. 30 Dec 2008. Web. 21 Jul 2017. <http://www.translationalethics.com/2008/12/30/stems-and-blossoms-part-2-really-informed-consent/>

APA

Jonathan Kimmelman. (2008, Dec 30). Stems and Blossoms (part 2): Really Informed Consent [Web log post]. Retrieved from http://www.translationalethics.com/2008/12/30/stems-and-blossoms-part-2-really-informed-consent/


Stems and Blossoms (part 1): Justice

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Shortly before I left for holiday, the International Society for Stem Cell Research (ISSCR) issued a policy paper, “Guidelines for the Clinical Translation of Stem Cells,” outlining ethical and scientific considerations for researchers designing translational trials involving stem cells (whether stem cell derived, adult, or embryonic).


In my opinion, the document wins the award for most forward thinking and comprehensive statement on the ethics of a translational enterprise. It shows that the stem cell research leadership has closely studied mistakes made by translational researchers in other highly innovative fields.  But the guidelines do more than look backwards; they proactively contemplate fairness and justice considerations as well.  Here are a few justice-related excerpts:

On responsiveness: “The ISSCR strongly discourages conduct of trials in a foreign country solely to benefit patients in the home country of the sponsoring agency. The test therapy, if approved, should realistically be expected to become available to the population participating in the clinical trial through existing health systems or those developed on a permanent basis in connection with the trial.”

On reasonable availability: “As far as possible, groups or individuals who participate in clinical stem cell research should be in a position to benefit from the results of this research.”

On diversity: “Stem cell collections with genetically diverse sources of cell lines should be established”

On access and licensing: “Commercial companies, subject to their financial capability, should offer affordable therapeutic interventions to persons living in resource-poor countries who would otherwise be wholly excluded from benefiting from that stem cell-based therapy. Academic and other institutions that are licensing stem cell therapeutics and diagnostic inventions should incorporate this requirement in their intellectual property license”

On review: “Regulatory and oversight agencies (local, national, and international) must explicitly include the consideration of social justice principles into their evaluations.”

On trial participation: “… the sponsor and principal investigator have an ethical responsibility to make good faith, reasonable efforts whenever possible to secure sufficient funding so that no person who meets eligibility criteria is prevented from being considered for enrollment because of his or her inability to cover the costs of the experimental treatment.”

In upcoming posts, I will comment on other aspects of the ISSCR guidelines. (photo credit: Helen K, Stems, 2008)

BibTeX

@Manual{stream2008-115,
    title = {Stems and Blossoms (part 1): Justice},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2008,
    month = dec,
    day = 28,
    url = {http://www.translationalethics.com/2008/12/28/stems-and-blossoms-part-1-justice/}
}

MLA

Jonathan Kimmelman. "Stems and Blossoms (part 1): Justice" Web blog post. STREAM research. 28 Dec 2008. Web. 21 Jul 2017. <http://www.translationalethics.com/2008/12/28/stems-and-blossoms-part-1-justice/>

APA

Jonathan Kimmelman. (2008, Dec 28). Stems and Blossoms (part 1): Justice [Web log post]. Retrieved from http://www.translationalethics.com/2008/12/28/stems-and-blossoms-part-1-justice/


Soft Cells and C-Sections

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The American Society of Gene Therapy is renaming itself: “American Society of Gene and Cell Therapy” (membership has yet to finalize the name change.”  The European Society of Gene Therapy has already done so: “European Society of Gene and Cell Therapy.”


Why is gene transfer going cellular? The publicly stated reasons are two fold. First is a recognition that gene transfer has always involved “cell transfer.” For instance, ADA-SCID and X-SCID protocols– for that matter, all ex vivo protocols– involve modifying cells outside the body, and returning them to the volunteer.

A second reason is to have a more “inclusive” society, and an “expanded membership base.” I suspect this partly reflects a concern that cell-types might affiliate with groups like ISCT (International Society of Cell Therapy), which has a “gene therapy” committee, or perhaps also ISSCR (International Society of Stem Cell Research).

Of course, this raises the question of what ASGCT means by “CT.” Does the society intend “American Society of Gene AND Cell Therapy,” or is it “OR Cell Therapy (which would include protocols that do not involve genetic modification). I can’t help but wonder what the realignment will mean for gene transfer. Since its founding, “gene transfer” has represented a kind of “invisible college” – an international network of collaborations and co-citations with a common set of concerns. Does renaming represent the demise of the gene transfer invisible college, as “genes” are absorbed under the more powerful social category of “cells?”  Or does it represent a promising extension of the network? Is this simply a reflection that in the first decade of the 21st century, “cells” are, in terms of scientific capital, what “genes” were to the 1990s? (photo credit: I like 2008)

BibTeX

@Manual{stream2008-117,
    title = {Soft Cells and C-Sections},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2008,
    month = dec,
    day = 10,
    url = {http://www.translationalethics.com/2008/12/10/soft-cells-and-c-sections/}
}

MLA

Jonathan Kimmelman. "Soft Cells and C-Sections" Web blog post. STREAM research. 10 Dec 2008. Web. 21 Jul 2017. <http://www.translationalethics.com/2008/12/10/soft-cells-and-c-sections/>

APA

Jonathan Kimmelman. (2008, Dec 10). Soft Cells and C-Sections [Web log post]. Retrieved from http://www.translationalethics.com/2008/12/10/soft-cells-and-c-sections/


Sell Therapy, European Style

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Two side-by-side news reports in the August 21 issue of Nature spell more trouble for cell therapy in Europe. The first story follows on previous reports about Austrian urologist Hannes Strasser (see postings on Jul 23 and May 27, 2008). According to an Austrian government report, Strasser “failed to get appropriate approval for the trial from authorities… failed to adequately inform patients… [and used] poor study design.” Strasser’s university has banned him from seeing patients. Somewhat cryptically, the article mentions that “several of the hundreds of patients who have undergone the procedure by Strasser’s team… claim that they have had serious side effects.”  Are these attributable to the intervention?  We shall see.


About 600 kilometers to the Southeast, a Bulgarian deputy minister resigned after the European Union shut down a Sophia-based clinic that provides non-validated bone marrow therapy treatments for victims of spinal-cord trauma, stroke, and neurodegenerative diseases.  The minister reportedly has family members who “own two private companies” that perform the procedures. (photocredit: Eesti, Central Hali Market in Sophia, 2005)

BibTeX

@Manual{stream2008-139,
    title = {Sell Therapy, European Style},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2008,
    month = aug,
    day = 28,
    url = {http://www.translationalethics.com/2008/08/28/sell-therapy-european-style/}
}

MLA

Jonathan Kimmelman. "Sell Therapy, European Style" Web blog post. STREAM research. 28 Aug 2008. Web. 21 Jul 2017. <http://www.translationalethics.com/2008/08/28/sell-therapy-european-style/>

APA

Jonathan Kimmelman. (2008, Aug 28). Sell Therapy, European Style [Web log post]. Retrieved from http://www.translationalethics.com/2008/08/28/sell-therapy-european-style/


Stemming Medical Tourism (part 1)

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The July 17 issue of Nature reports that a patient participating in a Vienna-based cell transfer study for urinary incontinence won a lawsuit against the University Hospital in Innsbruck for not being “told… the procedure was experimental.”


The case was described in an earlier post in my blog (May 27, 2008: Bladder Trouble at the Frontier).  There are a number of cell transfer strategies that are being applied in clinics, despite absence of reliable data showing efficacy. This should worry conscientious investigators who are trying to shepherd this promising technology platform to clinical application.

Here’s one example: Bankok based company TheraVitae offers cell transfer to advanced heart patients. In future posts, I will explore concerns about an emerging overseas industry in non-validated therapeutics that 1- involve cutting edge therapies, and 2-involve investors, and scientists, whose countries of origin have not yet licensed such therapies for clinical application. (photo credit: Olivander 2006)

BibTeX

@Manual{stream2008-143,
    title = {Stemming Medical Tourism (part 1)},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2008,
    month = jul,
    day = 23,
    url = {http://www.translationalethics.com/2008/07/23/stemming-medical-tourism-part-1/}
}

MLA

Jonathan Kimmelman. "Stemming Medical Tourism (part 1)" Web blog post. STREAM research. 23 Jul 2008. Web. 21 Jul 2017. <http://www.translationalethics.com/2008/07/23/stemming-medical-tourism-part-1/>

APA

Jonathan Kimmelman. (2008, Jul 23). Stemming Medical Tourism (part 1) [Web log post]. Retrieved from http://www.translationalethics.com/2008/07/23/stemming-medical-tourism-part-1/


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