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 Sep 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/


Tea Leaves: Predicting Risk and Benefit in Translation

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Every early phase trial begins with a series of predictions: that a new drug will show clinical utility down to road, that risks to study volunteers will be manageable, and perhaps, that patients in trials will benefit. Make a bad prediction here, and people potentially get hurt and resources wasted. So how good a job do we do with these predictions?


Hard to know, but given the high rate of failure in clinical translation, there are grounds for believing that various stakeholders go into early phase trials with an excess of optimism. In the current issue of PLoS Medicine, Alex London and I posit two problems with the way decision-makers make predictions in early phase trials. First, they underattend frequent and systematic flaws in the preclinical evidence base. Secondly, they draw on an overly narrow evidence base (what we call “evidential conservatism”) that obscures an assessment of whether preclinical studies in a given research area are a reliable indicator of agent promise.

As an open access journal, readers are invited to view our article here. The article has garnered a decent amount of press- digestible summaries can also be found at the Scientist and Pittsburgh Gazette. Also check out a commentary commissioned by the journal editors. (photo credit: canopic 2010)

BibTeX

@Manual{stream2011-54,
    title = {Tea Leaves: Predicting Risk and Benefit in Translation},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2011,
    month = mar,
    day = 21,
    url = {http://www.translationalethics.com/2011/03/21/tea-leaves-predicting-risk-and-benefit-in-translation/}
}

MLA

Jonathan Kimmelman. "Tea Leaves: Predicting Risk and Benefit in Translation" Web blog post. STREAM research. 21 Mar 2011. Web. 21 Sep 2017. <http://www.translationalethics.com/2011/03/21/tea-leaves-predicting-risk-and-benefit-in-translation/>

APA

Jonathan Kimmelman. (2011, Mar 21). Tea Leaves: Predicting Risk and Benefit in Translation [Web log post]. Retrieved from http://www.translationalethics.com/2011/03/21/tea-leaves-predicting-risk-and-benefit-in-translation/


Conditions of Collaboration: Protecting the Integrity of the Scientific Enterprise

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So what does it take to keep medical research a well-oiled enterprise that efficiently and effectively delivers cures? Lots of cooperation–or so I argue, along with co-authors Alex John London and Marina Emborg in a piece appearing in Science [a publicly accessible version of the essay is available at Science Progress]. Unfortunately, we argue, the way or system of drug development currently thinks about the ethics of clinical research does not presently place sufficient emphasis on the conditions necessary to sustain this cooperation.


Right now, oversight of clinical research is focused almost exclusively on protecting the personal interests of human subjects by obtaining valid informed consent and ensuring that risks are reasonable in relation to benefits. We suggest that this ostensibly private transaction between investigators and patient-volunteers has a public dimension in at least three ways. First, such private transactions inevitably draw on public resources. Second, such transactions have externalities- adverse events occurring on one trial have potential to disrupt collaborations elsewhere in the research system. Third, lax oversight of such private transactions creates conditions where consumers have difficulty identifying (and hence rewarding) producers of high quality goods (namely, trials that are well designed).

We suggest that, when considering whether to initiate highly innovative clinical trials that draw on such public goods, proper oversight and analysis must take into consideration factors that lie beyond the personal interests of human volunteers. (photo credit: McKillaboy, Cataglyphis velox 22, 2009)

BibTeX

@Manual{stream2010-65,
    title = {Conditions of Collaboration: Protecting the Integrity of the Scientific Enterprise},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2010,
    month = may,
    day = 18,
    url = {http://www.translationalethics.com/2010/05/18/conditions-of-collaboration-protecting-the-integrity-of-the-scientific-enterprise/}
}

MLA

Jonathan Kimmelman. "Conditions of Collaboration: Protecting the Integrity of the Scientific Enterprise" Web blog post. STREAM research. 18 May 2010. Web. 21 Sep 2017. <http://www.translationalethics.com/2010/05/18/conditions-of-collaboration-protecting-the-integrity-of-the-scientific-enterprise/>

APA

Jonathan Kimmelman. (2010, May 18). Conditions of Collaboration: Protecting the Integrity of the Scientific Enterprise [Web log post]. Retrieved from http://www.translationalethics.com/2010/05/18/conditions-of-collaboration-protecting-the-integrity-of-the-scientific-enterprise/


California Dreamin: CIRM Announces New Stem Cell Awards

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California’s Institute for Regenerative Medicine just announced a series of large funding awards to fund translational research initiatives involving (mostly) stem cells. The projects funded are telling with respect to what was funded, and what they will attempt to achieve.


First, notwithstanding a press release containing the words “bringing stem cell therapies to the clinic,” several projects are really dressed up gene transfer studies. Thus, one team will use gene transfer in hematopoietic stem cells for sickle cell anemia; another two will use gene transfer to stem cells for treating brain malignancies; another RNAi for HIV. All this is only further evidence that the field of stem cells is devouring gene transfer. Other projects are aimed more at getting “stem cells out of the clinic” by using small molecules or monoclonal antibodies to destroy stem cells causing malignancies.

Second is the sweeping ambition. As it stands today, only one clinical trial involving embryonic stem cell-derived tissues has been initiated. The projects funded under these awards are “explicitly expected to result in a filing with the FDA to begin a clinical trial.” Given that these projects are funded for four years, CIRM seems to be banking on the prospect of at least a few of these initiating phase 1 trials within five years. Four of these proposals involve goals of implanting embryo-derived tissues, and two of these involve non-lethal conditions–macular degeneration and type I diabetes (technically, other awarded projects involve nonlethal, though extremely morbid conditions). Another involves implantation of embryo-derived tissues for Amyotrophic Lateral Sclerosis. It will be interesting to see how many of these meet their translational objectives, and how investigators will navigate the ethical, regulatory, and social complexity of initiating clinical testing. (photo credit: Michael Ransburg, 2008)

BibTeX

@Manual{stream2009-80,
    title = {California Dreamin: CIRM Announces New Stem Cell Awards},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2009,
    month = nov,
    day = 5,
    url = {http://www.translationalethics.com/2009/11/05/california-dreamin-cirm-announces-new-stem-cell-awards/}
}

MLA

Jonathan Kimmelman. "California Dreamin: CIRM Announces New Stem Cell Awards" Web blog post. STREAM research. 05 Nov 2009. Web. 21 Sep 2017. <http://www.translationalethics.com/2009/11/05/california-dreamin-cirm-announces-new-stem-cell-awards/>

APA

Jonathan Kimmelman. (2009, Nov 05). California Dreamin: CIRM Announces New Stem Cell Awards [Web log post]. Retrieved from http://www.translationalethics.com/2009/11/05/california-dreamin-cirm-announces-new-stem-cell-awards/


Mice- Three Different Ones: Towards More Robust Preclinical Experiments

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One of the most exciting and intellectually compelling talks thus far at the American Society of Gene Therapy meeting was Pedro Lowenstein’s.  A preclinical researcher who works on gene transfer approaches to brain malignancies (among other things), Lowenstein asked the question: why do so many gene transfer interventions that look promising in the laboratory fail during clinical testing? His answer: preclinical studies lack “robustness.”


In short,  first-in-human trials are typically launched on the basis of a pivotal laboratory study showing statistically significant differences between treatment and control arms. In addition to decrying the “p-value” fetish- in which researchers, journal editors, and granting agencies view “statistical significance” as having magical qualities- Lowenstein also urged preclinical researchers to test the “nuances” and “robustness” of their systems before moving into human studies.

He provided numerous provocative examples where a single preclinical study showed very impressive, “significant” effects on treating cancer in mice. When the identical intervention was tried with seemingly small variations (e.g. different mouse strains used, different gene promotors tried, etc.), the “significant effects” vanished.  In short, Lowenstein’s answer to the question of why so many human trials fail to recapitulate major effects seen in laboratory studies is: we aren’t designing and reviewing preclinical studies properly. Anyone (is there one?) who has followed this blog knows: I completely agree. This is an ethical issue in scientific clothing. (photo credit: Rick Eh, 2008)

BibTeX

@Manual{stream2009-98,
    title = {Mice- Three Different Ones: Towards More Robust Preclinical Experiments},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2009,
    month = may,
    day = 29,
    url = {http://www.translationalethics.com/2009/05/29/mice-three-different-ones-towards-more-robust-preclinical-experiments/}
}

MLA

Jonathan Kimmelman. "Mice- Three Different Ones: Towards More Robust Preclinical Experiments" Web blog post. STREAM research. 29 May 2009. Web. 21 Sep 2017. <http://www.translationalethics.com/2009/05/29/mice-three-different-ones-towards-more-robust-preclinical-experiments/>

APA

Jonathan Kimmelman. (2009, May 29). Mice- Three Different Ones: Towards More Robust Preclinical Experiments [Web log post]. Retrieved from http://www.translationalethics.com/2009/05/29/mice-three-different-ones-towards-more-robust-preclinical-experiments/


Prime Time for Embryonic Stem Cells?

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According to a recent report in the Washington Post, researchers at Geron have received approval from FDA to initiate the first ever human trial involving stem cells derived from human embryos.  A story in the most recent issue of Nature provides more background.


Briefly, the study will involve transplanting tissues derived from human embryonic stem cells into patients who have recently suffered severe spinal cord injury. The principle behind the study is that the embryo-derived oligodendrocytes might repair myelin and restore the ability for nerves to transmit impulses.  According to the Nature report, Geron, submitted 22,000 pages of material to FDA, including data from 24 studies involving over 2000 animals.

So is the decision to initiate studies at this juncture prudent?  That’s impossible to know without seeing the supporting data. What I can comment on, however, is the recurrence of a rhetoric that glosses trial initiation– rather than trial outcome– as a medical achievement in itself.  Whereas the former is a regulatory event, the latter is a clinical event. In my book about gene transfer, I argue that this sets up a cycle of expectation that is difficult to sustain given the scientific and clinical uncertainties. We saw this in the early days of gene transfer. Some examples of this “trial initiation”=”medical achievement”:

• “This… marks the dawn of a new era in medical therapeutics. This approach is one that reaches beyond pills and scalpels to achieve a new level of healing.” (Thomas Okarma, Geron chief executive)
• “Today’s news… is a milestone in the new era of hope…” (Amy Comstock Rick, Coalition for the Advancement of Medical Research)
• “This is what we’ve all been waiting for” (Robert Lanza, Advanced Cell Technology)
• “The announcement boosted the price of shares in [Geron]… up 56% from the day before the announcement” (Meridith Wadman, Nature, Jan 27, 2009)

I wish Geron, and the patients enrolled in this study, all the best.  But if embryonic stem cell work is anything like practically every other major medical advancement, be prepared for a very long, tough slog with lots of setbacks.  In one of the stories, Sean Tipton from the Coalition for the Advancement of Medical Research, commented  “This is a trial of one particular application, not a trial of all embryonic stem cells.” That sounds just about right. (photo credit: no typographic man, UlamSpiral (negative), 2006)

BibTeX

@Manual{stream2009-111,
    title = {Prime Time for Embryonic Stem Cells?},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2009,
    month = jan,
    day = 30,
    url = {http://www.translationalethics.com/2009/01/30/prime-time-for-embryonic-stem-cells/}
}

MLA

Jonathan Kimmelman. "Prime Time for Embryonic Stem Cells?" Web blog post. STREAM research. 30 Jan 2009. Web. 21 Sep 2017. <http://www.translationalethics.com/2009/01/30/prime-time-for-embryonic-stem-cells/>

APA

Jonathan Kimmelman. (2009, Jan 30). Prime Time for Embryonic Stem Cells? [Web log post]. Retrieved from http://www.translationalethics.com/2009/01/30/prime-time-for-embryonic-stem-cells/


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 Sep 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/


In Brugge: The Cure

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One of the most striking themes at the European Society of Gene and Cell Therapy was the extent to which continental European researchers conceptualize first-in-human gene transfer experiments as therapeutic interventions rather than research protocols.


Perhaps the most extreme and explicit expression of this was view was presented by Bonn internest Thomas Heinemann (he also studied philosophy and serves on several ethics committees in Germany). Heinemann advanced the notion of the “controlled individual therapeutic attempt,” for which the primary objective is therapeutic gain; the scientific dimensions of such studies (e.g. collecting safety data) are necessarily secondary. As he put it, research is only justified “ex post facto.”


I found this argument intriguing for several reasons. First, Heinemann justified this claim largely on grounds of autonomy and instrumentalization of desperately ill patients. In contrast, North American bioethicists typically use autonomy and instrumentalization to argue the opposite: that research is primarily intended to serve the ends of others, hence the paramount importance of obtaining consent from volunteers and their guardians, hence the need to be extremely cautious going into a desperately ill population, where autonomy might be compromised.

Second, I was impressed by the speaker’s conviction that first-in-human trials have therapeutic warrant. After almost twenty years of painstaking and at times discouraging research, we seem to have learned two things:  first, that first-in-human trials rarely go as expected, and second, that such studies often yield important insights about new interventions. I might have expected a more cautious and seasoned view about the therapeutic merits of first-in-human attempts: does it really enhance the autonomy of volunteers to offer so little by means of therapy, but to foreseeably get so much in terms of social good? (photo credit: virtualais //www.77click.it, Brugge, 2008)

BibTeX

@Manual{stream2008-122,
    title = {In Brugge: The Cure},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2008,
    month = nov,
    day = 24,
    url = {http://www.translationalethics.com/2008/11/24/in-brugge-the-cure/}
}

MLA

Jonathan Kimmelman. "In Brugge: The Cure" Web blog post. STREAM research. 24 Nov 2008. Web. 21 Sep 2017. <http://www.translationalethics.com/2008/11/24/in-brugge-the-cure/>

APA

Jonathan Kimmelman. (2008, Nov 24). In Brugge: The Cure [Web log post]. Retrieved from http://www.translationalethics.com/2008/11/24/in-brugge-the-cure/


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