Uncaging Validity in Preclinical Research

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High attrition rates in drug development bedevil drug developers, ethicists, health care professionals, and patients alike.  Increasingly, many commentators are suggesting the attrition problem partly relates to prevalent methodological flaws in the conduct and reporting of preclinical studies.

Preclinical efficacy studies involve administering a putative drug to animals (usually mice or rats) that model the disease experienced by humans.  The outcome sought in these laboratory experiments is efficacy, making them analogous to Phase 2 or 3 clinical trials.

However, that’s where the similarities end.  Unlike trials, preclinical efficacy studies employ a limited repertoire of methodological practices aimed at reducing threats to clinical generalization.  These quality-control measures, including randomization, blinding and the performance of a power calculation, are standard in the clinical realm.

This mismatch in scientific rigor hasn’t gone unnoticed, and numerous commentators have urged better design and reporting of preclinical studies.   With this in mind, the STREAM research group sought to systematize current initiatives aimed at improving the conduct of preclinical studies.  The results of this effort are reported in the July issue of PLoS Medicine.

In brief, we identified 26 guideline documents, extracted their recommendations, and classified each according to the particular validity type – internal, construct, or external – that the recommendation was aimed at addressing.   We also identified practices that were most commonly recommended, and used these to create a STREAM checklist for designing and reviewing preclinical studies.

We found that guidelines mainly focused on practices aimed at shoring up internal validity and, to a lesser extent, construct validity.  Relatively few guidelines addressed threats to external validity.  Additionally, we noted a preponderance of guidance on preclinical neurological and cerebrovascular research; oddly, none addressed cancer drug development, an area with perhaps the highest rate of attrition.

So what’s next?  We believe the consensus recommendations identified in our review provide a starting point for developing preclinical guidelines in realms like cancer drug development.  We also think our paper identifies some gaps in the guidance literature – for example, a relative paucity of guidelines on the conduct of preclinical systematic reviews.  Finally, we suggest our checklist may be helpful for investigators, IRB members, and funding bodies charged with designing, executing, and evaluating preclinical evidence.

Commentaries and lay accounts of our findings can be found in PLoS Medicine, CBC News, McGill Newsroom and Genetic Engineering & Biotechnology News.

BibTeX

@Manual{stream2013-300,
    title = {Uncaging Validity in Preclinical Research},
    journal = {STREAM research},
    author = {Valerie Henderson},
    address = {Montreal, Canada},
    date = 2013,
    month = aug,
    day = 5,
    url = {http://www.translationalethics.com/2013/08/05/uncaging-validity-in-preclinical-research/}
}

MLA

Valerie Henderson. "Uncaging Validity in Preclinical Research" Web blog post. STREAM research. 05 Aug 2013. Web. 21 Sep 2017. <http://www.translationalethics.com/2013/08/05/uncaging-validity-in-preclinical-research/>

APA

Valerie Henderson. (2013, Aug 05). Uncaging Validity in Preclinical Research [Web log post]. Retrieved from http://www.translationalethics.com/2013/08/05/uncaging-validity-in-preclinical-research/


Icarus, again: Adversity in another Gene Transfer Trial

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Two weeks ago brought good news and bad news for gene transfer. First the good news. New England Journal of Medicine beatified a new gene transfer strategy for Wiskott-Aldrich Syndrome (WAS). WAS is a primary immunodeficiency that primarily affects boys. It is thus in the same family of disorders that have been, in varying degrees, successfully addressed using retroviral gene transfer. Like other immunodeficiencies, this represents relatively low hanging fruit for an approach like gene transfer, because scientists can access and target stem cells, and because corrected cells should be at a selective advantage for survival compared with uncorrected cells.

The NEJM article reported clinical, functional, and molecular outcomes for two boys in a trial based in Germany. Briefly the two boys were given a type of chemotherapy (in order to make space for genetically corrected cells), and then transplanted with “corrected” blood stem cells. The corrected blood stem cells contained a viral vector similar to those used in previous gene transfer trials of primary immune deficiency. The team saw: 1) stable levels of genetically corrected stem cells that expressed the WAS protein (indicating the genetically modified cells “took,” and produced WAS; 2) recovery of the function of a variety of immune cells; 3) reduction of disease symptoms, including improvement of eczema, and reduced severity of infections.

The article exhaustively ruled out events that have occurred in other, similar gene transfer trials in which children developed leukemias from the vector. Now the bad news. The same day NEJM published the results, American Society of Gene and Cell Therapy (the largest professional society devoted to gene transfer) released a statement saying that the German team just announceda serious adverse event in a gene therapy trial for Wiskott-Aldrich syndrome (WAS)”- one of the ten children in the German trial developed a leukemia.

And so continues the saga of gene transfer: three steps forward, one back. (photo credit: vk-red 2009)

BibTeX

@Manual{stream2010-58,
    title = {Icarus, again: Adversity in another Gene Transfer Trial},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2010,
    month = nov,
    day = 29,
    url = {http://www.translationalethics.com/2010/11/29/icarus-again-adversity-in-another-gene-transfer-trial/}
}

MLA

Jonathan Kimmelman. "Icarus, again: Adversity in another Gene Transfer Trial" Web blog post. STREAM research. 29 Nov 2010. Web. 21 Sep 2017. <http://www.translationalethics.com/2010/11/29/icarus-again-adversity-in-another-gene-transfer-trial/>

APA

Jonathan Kimmelman. (2010, Nov 29). Icarus, again: Adversity in another Gene Transfer Trial [Web log post]. Retrieved from http://www.translationalethics.com/2010/11/29/icarus-again-adversity-in-another-gene-transfer-trial/


Accelerated Approval: Safe at Any Speed?

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Drug regulatory authorities like the FDA have a mandate to protect public health by requiring and evaluating evidence of safety and efficacy before licensing new drugs for commercial sale. But for decades now, patient advocates have argued that FDA bureaucracy kills by keeping promising drugs from the IV’s of terminal patients. In response to these criticisms, FDA and others have created new pathways for drug approval whereby drugs can be partially approved for sale on the basis of smaller, Phase 2 trials using surrogate endpoints (tumor shrinkage) instead of survival– provided drug companies confirm efficacy in subsequent trials.


This pathway, called “accelerated approval,” is controversial because it allows companies to sell drugs whose efficacy and safety is not yet well established. True- the companies are obliged to run confirmatory studies, but a) how will confirmatory trials enroll enough subjects if patients know they might be randomized to standard, ineffective drugs, and they can get the drug outside a clinical trial? b) drug companies will not have sufficient incentive to run confirmatory studies once their drug is provisionally approved. c) drug companies stand to make lots of money selling unproven drugs to desperate patients in search of a cure.

In the most recent issue of Journal of Clinical Oncology, Elizabeth Richey and coauthors put these concerns to the test in an analysis “Accelerated Approval of Cancer Drugs: Improved Access to Therapeutic Breakthroughs or Early Release of Unsafe and Ineffective Drugs.” They find that:

• a very large percentage of new cancer drugs are initially approved under “accelerated approval.” (37% approvals between 1995 and 2008)

• 63% of drugs receiving accelerated approval have their clinical benefit confirmed in subsequent studies

• drugs involving very rare cancers are often not subjected to confirmatory testing (42%); drugs for more common cancers are tested in confirmatory studies typically (71%– though the percentage I calculated from their figures is actually higher- 86%)

• drugs receiving accelerated approval are twice as likely to receive black box warnings compared with drugs approved by the standard mechanism (21% vs. 10%)

• about half of non-orphan drugs approved under accelerated approval (47%) become first line treatment regimens in the National Comprehensive Cancer Network.

The authors see the glass half full on accelerated approval: to the title question of their article, the authors answer “Improved Access to Therapeutic Breakthroughs.” (photo credit: Marxpix 2008)

BibTeX

@Manual{stream2009-85,
    title = {Accelerated Approval: Safe at Any Speed?},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2009,
    month = sep,
    day = 9,
    url = {http://www.translationalethics.com/2009/09/09/accelerated-approval-safe-at-any-speed/}
}

MLA

Jonathan Kimmelman. "Accelerated Approval: Safe at Any Speed?" Web blog post. STREAM research. 09 Sep 2009. Web. 21 Sep 2017. <http://www.translationalethics.com/2009/09/09/accelerated-approval-safe-at-any-speed/>

APA

Jonathan Kimmelman. (2009, Sep 09). Accelerated Approval: Safe at Any Speed? [Web log post]. Retrieved from http://www.translationalethics.com/2009/09/09/accelerated-approval-safe-at-any-speed/


Help Wanted, Part 2

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So, what are some of the intriguing ethical questions of Kolata’s August 2d article? Here is one: when researchers conduct studies and ethics committees review protocols, resource allocation is an important consideration. If, as Kolata alleges, mediocre trials siphon eligible patients away from good trials, then there is a case to be made that IRBs and investigators need to ponder carefully the effects proposed trials will have on other studies- even when proposed trials have a favorable direct benefit-risk balance for volunteers who enter them.


Second, if resource allocation is a key consideration in realms where patients are scarce, investigators (and IRBs) need reliable criteria for assessing the broader social value of study protocols. They further need some way of being able to compare one protocol against a body of others that are either underway or in the pipeline. The current system provides no straightforward way of doing this.

Third, if 50% of trials fail to recruit sufficient numbers to produce meaningful results, investigators, IRBs, DSMBs, and granting agencies are doing a lousy job ensuring high ethical standards in human research. It is well established that, for any study to redeem the burdens that volunteers endure on enrollment, it must produce valuable findings. It is disturbing, to say the least, that many volunteers enter studies that go nowhere, and that investigators, IRBs, and funding agencies are not realistically projecting recruitment.

Last, Kolata suggests that many cancer trials are merely aimed at “polishing a doctor’s résumé.” It would make a useful contribution to the field of cancer research- and bioethics- to measure the frequency of this practice. Meantime, this inability of IRBs to detect this kind of conduct, and stop it in its tracks, signals an important deficiency in human protections. Which leads me to my next post… (photo credit: ziggy fresh 2006)

BibTeX

@Manual{stream2009-88,
    title = {Help Wanted, Part 2},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2009,
    month = aug,
    day = 9,
    url = {http://www.translationalethics.com/2009/08/09/help-wanted-part-2/}
}

MLA

Jonathan Kimmelman. "Help Wanted, Part 2" Web blog post. STREAM research. 09 Aug 2009. Web. 21 Sep 2017. <http://www.translationalethics.com/2009/08/09/help-wanted-part-2/>

APA

Jonathan Kimmelman. (2009, Aug 09). Help Wanted, Part 2 [Web log post]. Retrieved from http://www.translationalethics.com/2009/08/09/help-wanted-part-2/


Help Wanted- For the War on Cancer

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Earlier this week (Aug 2), Gina Kolata of the NYTimes ran a fascinating story about challenges recruiting patients to cancer clinical trials. The story contains interesting facts, credible claims, analysis, and unfortunately, some misleading conjectures. The problem of patient recruitment also invites some hard headed ethical analysis.


First the facts. According to the article, one in five National Cancer Institute-funded trials fails to enroll a single subject; half fail to recruit enough to produce meaningful results. Now some credible claims: many trials are “aimed at polishing a doctor’s résumé, and produce meaningless results; many oncologists avoid cancer studies because they can be a money loser, and many patients shy away from trial participation- particularly when their cancer is less advanced and they can obtain treatment outside of trials.


The article, however, is swathed in some misleading conjectures. The article makes the suggestion that problems with recruitment are “one reason” and “the biggest barrier” to major strides in the “war on cancer” (hence the recruitment poster in the graphic above). Hard to reconcile this with Kolata’s contention elsewhere that many trials are useless. It’s also hard to square the claim with Kolata’s point, earlier in the article, that trials involving really promising drugs usually have no problems with recruitment. In one famous case, a Phase 1 trial testing endostatin at Harvard received 1000 inquires from patients for 3 slots in the trial (Pop quiz: see if you can guess which New York Times reporter wrote an article on endostatin that many commentators criticized for sensationalizing the drug’s promise?). Third, with only about 1 in 20 cancer drug candidates making it from phase 1 tests to FDA approval, a reasonable question to ask is whether preclinical researchers are validating their drug candidates properly. And finally, the article makes no mention of the fact that many studies have exceedingly narrow eligibility criteria. Many patients may be solicited for trial participation- but only a fraction meet eligibility criteria.

Still, Kolata’s article is enlightening and raises a number of intriguing questions that demand ethical analysis. I’ll discuss some of these in my next posting (photo credits: Joan Thewlis, 1918 Recruitment Poster, 2009).

BibTeX

@Manual{stream2009-90,
    title = {Help Wanted- For the War on Cancer},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2009,
    month = aug,
    day = 6,
    url = {http://www.translationalethics.com/2009/08/06/help-wanted-for-the-war-on-cancer/}
}

MLA

Jonathan Kimmelman. "Help Wanted- For the War on Cancer" Web blog post. STREAM research. 06 Aug 2009. Web. 21 Sep 2017. <http://www.translationalethics.com/2009/08/06/help-wanted-for-the-war-on-cancer/>

APA

Jonathan Kimmelman. (2009, Aug 06). Help Wanted- For the War on Cancer [Web log post]. Retrieved from http://www.translationalethics.com/2009/08/06/help-wanted-for-the-war-on-cancer/


Basic Science and Pharmaceutical Productivity

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One of the great paradoxes of contemporary medicine has been a seeming inverse relationship between investment in basic science and registration of novel new drugs by regulatory agencies. The delay between basic science discoveries and clinical applications can be very long; many promising drug candidates are called on the basis of laboratory discovery, but few are chosen.


Cancer drugs, in particular, have one of the highest rates of failure as measured by the probability that a new drug entering phase 1 clinical testing will prove promising enough to eventually be registered by the FDA. One 2004 report pegged this figure at about 5%.

The question is: will such discouragingly low figures hold for new classes of cancer drugs that are entering clinical testing? According to Ian Walker and Herbie Newell in the January issue of Nature Reviews Drug Discovery, maybe not. Walter and Newell examined pharmaceutical development databases to determine probabilities that a particular class of new cancer drugs– protein kinase inhibitors– will survive from phase 1 testing through to registration (the wonder drug Gleevec is in this class). They found that 53% of new kinase inhibitors that enter phase 1 trials are ultimately licensed. They conclude that their analysis “further demonstrate[s] the benefits of developing molecularly targeted therapeutics for cancer.”

Here are some concerns about their analysis. First, their figures for success from phase 1 to registration for all cancer drugs (not just kinase inhibitors) are roughly three times previous estimates. This bears explaining. A second concern is that this may represent a particularly successful class of molecularly targeted agents. Third and crucially, according to a recent Nature Reviews–Cancer report, there are 11 different kinase inhibitors approved by the FDA. Eleven divided by the sample used in this paper– 137 kinase inhibitor drugs entering phase 1 testing– yields 8%– a number very similar to the 5% success rate that has been quoted elsewhere. Last, some kinase inhibitors are “me-toos” or at least, very closely related (e.g. panitumumab and cetexumab)

Too early, I say, to conclude that the way we are doing basic and preclinical science is beginning to bear fruit in terms of pharmaceutical productivity. (photo credit: Night Heron, Pull Chain, 2007)

BibTeX

@Manual{stream2009-102,
    title = {Basic Science and Pharmaceutical Productivity},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2009,
    month = may,
    day = 13,
    url = {http://www.translationalethics.com/2009/05/13/basic-science-and-pharmaceutical-productivity/}
}

MLA

Jonathan Kimmelman. "Basic Science and Pharmaceutical Productivity" Web blog post. STREAM research. 13 May 2009. Web. 21 Sep 2017. <http://www.translationalethics.com/2009/05/13/basic-science-and-pharmaceutical-productivity/>

APA

Jonathan Kimmelman. (2009, May 13). Basic Science and Pharmaceutical Productivity [Web log post]. Retrieved from http://www.translationalethics.com/2009/05/13/basic-science-and-pharmaceutical-productivity/


Yellow Light on Gene Transfer Studies

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Among the greatest heartbreaks in the field of gene transfer have been problems encountered in trials involving a rare, hereditary immune disorder, X-SCID (known popularly as “Bubble Boy” syndrome).  As is well known, a team of researchers based in Paris– and then in London– successfully reversed severe immunodeficiencies in 20 or so children using retroviral gene transfer starting around year 2000.  Shortly thereafter, however, the Paris team began observing rare leukemic disorders that were causally related to the gene transfer. To date, the Paris team has reported 4 cases of leukemia, with one leading to death. The London team has reported one leukemia.


In response to these events, the U.S. Recombinant DNA Advisory Committee (RAC) recommended that investigators only use retroviral gene transfer in the most severe situations– namely, where patients are ineligible for even high risk alternative care options like haploidentical stem cell transplantation.  RAC’s recommendations were stricter than those in the U.K., which allowed children to enter a study even if they were candidates for haploidentical transplants.  

As reported in the current issue of Molecular Therapy, the RAC recently decided to liberalize its recommendations, allowing retroviral gene transfer in children who are eligible for halploidentical transplantation. RACs recommendations are still somewhat stricter than those of the UK, because the former recommends against retroviral gene transfer in children who are candidates for haploidentical transplantation but under 3.5 years age (children in this category respond better to haploidentical transplants). RAC additionally supported a similar trial involving a different vector that integrates its genome into the host’s (lentiviral vectors, which are derived from HIV).

Is this gentle liberalization of standards justified?  Some will argue that the benefits of haploidentical transplantation are variable and undependable, and that since initial leukemias have been reported, researchers have made progress in improving the safety of their vectors. All this might be true, if one were evaluating this as a clinical judgment.

However, the judgment is better viewed through the lens of research rather than therapy. Though laboratory testing indicates that new retroviral and lentiviral vectors are safer than the old ones, there remain substantial uncertainties. For example, current assays for determining the oncogenicity of integrating vectors are not well worked out. Neither the new retroviral vectors nor lentiviral vectors have been used in blood stem cell gene transfer in a pediatric population. The effect of lentiviral vectors on gene sequences near their integrating sites remains poorly understood. In short, the null hypothesis of new trials is that these new vectors are no better than the old ones.

What’s the safest way to refute this null hypothesis and confirm what many think, on laboratory evidence, will be the case? In my view, the safest approach– for patients as well as the field in general, which stands to lose much from another major toxicity– is to begin with the most narrow medical indication possible, which means excluding children who stand a chance of benefiting from standard (albeit suboptimal) care.  (photo credit: Jamelah 2007)

BibTeX

@Manual{stream2009-103,
    title = {Yellow Light on Gene Transfer Studies},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2009,
    month = may,
    day = 12,
    url = {http://www.translationalethics.com/2009/05/12/yellow-light-on-gene-transfer-studies/}
}

MLA

Jonathan Kimmelman. "Yellow Light on Gene Transfer Studies" Web blog post. STREAM research. 12 May 2009. Web. 21 Sep 2017. <http://www.translationalethics.com/2009/05/12/yellow-light-on-gene-transfer-studies/>

APA

Jonathan Kimmelman. (2009, May 12). Yellow Light on Gene Transfer Studies [Web log post]. Retrieved from http://www.translationalethics.com/2009/05/12/yellow-light-on-gene-transfer-studies/


Cancer, Low and Middle-Income Countries, and Translational Research

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In the October 20, 2008 issue of Journal of Clinical Oncology, oncologist Zeba Aziz describes morning rounds in a cancer ward in Lahore, Pakistan. The first patient earns $20 a month and requires a combination therapy costing $10K. In the second case, a father can only pay 15% of the treatment needed by his daughter. The third case involves a single mother, who showed a significant tumor response on the first cycle of treatment but can not afford subsequent rounds.


According to Aziz, only 2% of Pakistan’s population has health insurance; 95% earn $30-100 / month. Aziz’s hospital serves 10K cancer patients annually, and has a medicines budget of around $80K each year. Treatments that wipe out the immune system are especially tricky, because medicines for infection might not be affordable.

Low and middle-income countries (LMICs) are undergoing an epidemiological transition in which chronic diseases replace infection as the main drivers of mortality. According to Franco Cavalli (“The World Cancer Declaration: A Roadmap for Change,” Lancet Oncology, September 2008), cancer kills more people worldwide than AIDS, tuberculosis, and malaria combined. Cavalli describes a “World Cancer Declaration” issued by the Geneva based International Union Against Cancer that calls for improvements in the prevention, detection, reporting, and treatment of cancer in LMICs.

But a serious response to cancer in LMICs will require changes in translational research as well. Clearly, the vast majority of cancer treatment research is directed toward markets in high-income countries. These treatments have properties– costs, side-effect profiles, demand for ancillary services– that make their application in LMIC populations improbable. If, as argued by many commentators, we in HICs have a duty to persons in LMICs, translational researchers and funding agencies should give some thought and effort to the development and testing of treatments that, while perhaps not adding as many weeks of extra median survival, are deployable in settings like Aziz’s clinic. (photo credit: CasaDeQueso 2008)

BibTeX

@Manual{stream2008-128,
    title = {Cancer, Low and Middle-Income Countries, and Translational Research},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2008,
    month = oct,
    day = 21,
    url = {http://www.translationalethics.com/2008/10/21/cancer-low-and-middle-income-countries-and-translational-research/}
}

MLA

Jonathan Kimmelman. "Cancer, Low and Middle-Income Countries, and Translational Research" Web blog post. STREAM research. 21 Oct 2008. Web. 21 Sep 2017. <http://www.translationalethics.com/2008/10/21/cancer-low-and-middle-income-countries-and-translational-research/>

APA

Jonathan Kimmelman. (2008, Oct 21). Cancer, Low and Middle-Income Countries, and Translational Research [Web log post]. Retrieved from http://www.translationalethics.com/2008/10/21/cancer-low-and-middle-income-countries-and-translational-research/


In the Dark?

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Most cancer patients who enter phase 1 clinical trials are motivated by the prospect of controlling their cancer. Increasingly, however, such studies, in the words of one ethicist, “take without giving in return” by involving biopsy procedures in which tissue is collected before and during the study in order to gauge whether a new drug is having intended biological effects. Such procedures are potentially burdensome, and offer no direct benefits for patients.


So is it ethical for clinical investigators to “stick it to” their research subjects? Depends in part on the level of risk. In the August 20, 2008 issue of Journal of Clinical Oncology, Aaron P. Brown and coworkers at NIH performed a literature review examining the complication rate for research biopsies in the context of studies involving radiotherapy (“Performing Nondiagnostic Research Biopsies in Irradiated Tissue: A Review of Scientific, Clinical, and Ethical Considerations”). One might expect to find higher than usual complication rates in this context, because irradiation can interfere with wound healing.

Here is what they found. Of 29 eligible studies, only 3 (!!) actively evaluated adverse events related to biopsy (another 16 reported adverse events– but not specifically related to biopsy) These 3 studies reported a total of 17 adverse events.

Here is what the authors concluded: “Limited data suggest that biopsies can be performed in irradiated tissues without clinically significant excess risk.”

The authors sagely argue that “all clinical trials that perform biopsies in combination with other therapies should actively study and report complications.” But with their specific study question- the complication rate of tissue biopsies- so underexposed, the their conclusions are dodgy. (photo credit: Moominsean 2006)

BibTeX

@Manual{stream2008-137,
    title = {In the Dark?},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2008,
    month = sep,
    day = 11,
    url = {http://www.translationalethics.com/2008/09/11/in-the-dark/}
}

MLA

Jonathan Kimmelman. "In the Dark?" Web blog post. STREAM research. 11 Sep 2008. Web. 21 Sep 2017. <http://www.translationalethics.com/2008/09/11/in-the-dark/>

APA

Jonathan Kimmelman. (2008, Sep 11). In the Dark? [Web log post]. Retrieved from http://www.translationalethics.com/2008/09/11/in-the-dark/


Are Phase 1 Volunteers Vulnerable?

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In the January 2008 issue of Archives of Internal Medicine, an NIH team led by Christine Grady reports the results of a study (Participants in Phase 1 Oncology Research Trials: Are They Vulnerable?) surveying the demographics of patients who participate in phase 1 cancer studies. They report that these volunteers are overwhelmingly white, have pretty good physical functioning, earn above average incomes, have above average educational attainment, and do not lack for health insurance coverage. The authors then suggest that phase 1 volunteers “do not fit into any of the categories of vulnerable populations addressed by specific regulations.”


This is an informative paper, though the results should not surprise anyone who has followed the field of phase 1 cancer research. Their use of National Cancer Institute (NCI) data is clever and comprehensive (though their anemic sample of 11 non-NCI studies is puzzling). And I agree with the tacit message: that regulators and ethicists should avoid infantalizing persons with terminal illness.

On the other hand, the article contains some misleading or debatable statements. The suggestion that phase 1 cancer volunteers “do not fit into any categories of vulnerable populations” is not exactly true: the Belmont Report implicitly categorizes the “very sick” as vulnerable. The World Health Organizations CIOMS policy states quite clearly: “Persons who have serious, potentially disabling or life-threatening diseases are highly vulnerable.”

The view of vulnerability and autonomy espoused in this paper will strike many readers as thin and reductionistic– as if it were a box on a census form rather than an experience. So too is the suggestion that phase 1 study participants are not “in need of special protection.” Nevertheless, this paper does help direct our concerns away from income and demography towardvariables that might really matter, like dependence, fear, and flux. (photo credit: Lutz-R.Frank 2007).

BibTeX

@Manual{stream2008-145,
    title = {Are Phase 1 Volunteers Vulnerable?},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2008,
    month = jul,
    day = 3,
    url = {http://www.translationalethics.com/2008/07/03/are-phase-1-volunteers-vulnerable/}
}

MLA

Jonathan Kimmelman. "Are Phase 1 Volunteers Vulnerable?" Web blog post. STREAM research. 03 Jul 2008. Web. 21 Sep 2017. <http://www.translationalethics.com/2008/07/03/are-phase-1-volunteers-vulnerable/>

APA

Jonathan Kimmelman. (2008, Jul 03). Are Phase 1 Volunteers Vulnerable? [Web log post]. Retrieved from http://www.translationalethics.com/2008/07/03/are-phase-1-volunteers-vulnerable/


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