What’s the difference between testing a typical small molecule drug, and testing a novel cell therapy strategy? And where might the latter raise ethical challenges that the former doesn’t? These questions are extensively discussed in my book, and given human drama in a recent story by Jennifer Couzin-Frankel in the Feb 12, 2010 issue of Science (“Replacing an Immune System Gone Haywire“).
Couzin-Frankel describes the numerous difficulties that researchers have faced in attempting to validate autologous bone marrow transplantation for the treatment of (often nonlethal but highly debilitating) autoimmune disorders like type 1 diabetes, Crohn’s disease, and multiple sclerosis. The idea of this procedure is to “reset” the immune system by purging patients of their bone marrow cells, and then returning healthy bone marrow to them. The approach has shown some promise for certain autoimmune disorders. However, response is highly variable and unpredictable, and validating and applying bone marrow transplantation for autoimmune disorders is beset by numerous ethical and logistical difficulties.
A major one is the risk-benefit balance: bone marrow transplantation requires exposing patients to the dangers of the transplantation procedure (6.6% mortality in one report of lupus patients). And yet, the procedures appear to work better in patients whose disease is not yet advanced. Testing the procedure therefore requires recruiting more or less healthy, at risk patients (sometimes children) into studies that expose them to serious risk of mortality. Clinicians understandably balk at referring their patients to such studies, making recruitment very difficult.
A second challenge is funding: many of these approaches involve using the patient’s own bone marrow cells. There is nothing to patent– and hence, little commercial interest in bone marrow transplantation for autoimmune disorders. This deprives this promising line of research needed resources.
And all this creates the perfect storm for a series of ethical challenges not directly addressed in this article (but covered in my book and articles): the siting of such studies in low and middle-income settings. Prohibitive costs, plus extreme difficulty recruiting patients who are otherwise eligible for somewhat effective and extremely expensive monoclonal antibody therapies, makes the siting of such trials in economically disadvantaged settings very attractive. This gives rise to what I have elsewhere called “expedient” justification for recruitment. Not surprisingly, then, one of the first trials of the procedure was performed in Brazil, and the article closes by mentioning that ongoing trials involving high-income country researchers are recruiting from São Paulo, Prague, China, and Argentina. This is good news if people in those settings have a reasonable prospect of having widespread and affordable access to bone marrow transplantation once it becomes validated. But it is troubling indeed if people in these countries will be bearing considerable burdens for the sake of knowledge benefits that will primarily (or most expeditiously) accrue to patients in high-income settings. (photo credit: Wellcome Images, Compact Bone, 2009)
Jonathan Kimmelman. "Transplanting Autoimmune Research" Web blog post. STREAM research. 26 Feb 2010. Web. 22 Oct 2024. <http://www.translationalethics.com/2010/02/26/transplanting-autoimmune-research/>
APA
Jonathan Kimmelman. (2010, Feb 26). Transplanting Autoimmune Research [Web log post]. Retrieved from http://www.translationalethics.com/2010/02/26/transplanting-autoimmune-research/
What can the biotechnology industry do for neglected diseases (infectious diseases that, because they primarily afflict low-income countries, are not heavily researched in the public or private sector)? Biotechnology enthusiasts might answer “everything,” ignoring the dearth of research and development incentives for small biotechnology firms, much less the major challenges presented by the manufacture, distribution, purchase, and administration of biotechnology products. Critics might answer “nothing,” drawing attention to the existing availability of simple, low cost interventions against diarrheal diseases, tuberculosis, etc..
A recent article puts forward a series of proposals on the biotechnology sector and neglected disease. In the April 2009 issue of Nature Biotechnology (Leveraging biotech’s drug discovery expertise for neglected diseases), authors Joanna Lowell and Christopher Earl (of BIO Ventures for Global Health) argue that biotechnology companies can play a “pivotal role” in developing small-molecule drugs against neglected diseases. Noting that many neglected diseases involve drug targets that are similar to those for high-income country diseases, Lowell and Earl suggest that companies can simultaneously advance their primary objectives while supporting development of drugs for neglected diseases.
They offer several reasons why biotechnology companies might do so. First is “the chance to prove technology platforms.” Companies might “leverage” philanthropic support to test biologic pathways of relevance to drugs targeting more affluent markets (I will note, without comment, that such a proposal would need to think through justice concerns). Second is employee morale: initiating such research is an important way of attracting and retaining talented and idealistic scientists. Third is “sustaining underutilized discovery platforms.” Once companies have discovered a lead compound, drug discovery platforms can potentially languish. Using this dormant capacity helps companies maintain their drug discovery platforms so that they will be available in the future.
I leave it to readers to decide the soundness of the proposals. On the one hand, the idea that biotechnology companies can derive benefits from pursuing neglected disease research seems plausible, as does the notion that the biotechnology sector has much to offer low-income countries (curiously, the article centers on small molecule drugs rather than vaccines). The authors cite a number of examples to support their claims, and BIO Ventures for Global Health has received a “seal of approval” (e.g. generous funding) from the Bill and Melinda Gates Foundation.
On the other hand, are struggling biotechnologies likely to embrace this– especially given today’s credit markets? One can be forgiven for wondering whether this is merely a PR ploy for a biotechnology industry that has sought contentious policies like strong intellectual property protections. BIO Ventures for Global Health is, after all, an arm of the biotechnology trade association, BIO. (photo credit: ViaMoi, Neglect, 2007)
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MLA
Jonathan Kimmelman. "The Biotechnology of Neglect" Web blog post. STREAM research. 13 Apr 2009. Web. 22 Oct 2024. <http://www.translationalethics.com/2009/04/13/the-biotechnology-of-neglect/>
APA
Jonathan Kimmelman. (2009, Apr 13). The Biotechnology of Neglect [Web log post]. Retrieved from http://www.translationalethics.com/2009/04/13/the-biotechnology-of-neglect/
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)
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MLA
Jonathan Kimmelman. "Cancer, Low and Middle-Income Countries, and Translational Research" Web blog post. STREAM research. 21 Oct 2008. Web. 22 Oct 2024. <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/
Surgical innovation has always been a problem for medical ethics. Surgeries are unregulated, and partly as a result, few are introduced to clinical practice having been validated in randomized controlled trials. Moreover, attempts at novel surgeries typically fly beneath the radar of ethical review, because they are viewed as innovative clinical practice rather than research. There are some good–and not so good– reasons for such “surgical exceptionalism.”
On Sunday, the Washington Post ran a story (“Scarless Surgery Uses Body’s Own Openings,” Rob Stein, Sept 21) on a new type of surgery, Natural Orifice Transluminal Endoscopy (NOTES), which avoids skin incisions by accessing organs through the mouth, anus, or vagina. Various teams are testing and/or using NOTES to remove gall bladder stones, to perform appendectomies and cholecystectomies, and to collect tumor tissue for cancer staging.
NOTES has the potential to reduce pain and scarring, and to hasten recovery. But the technique still requires validation in animal models. One major concern is infection: NOTES requires incisions through flora-rich environments like the rectum, stomach, or vagina.
Several U.S. and European medical societies have established initiatives aimed at guiding development of this technique. One example is NOSCAR (www.noscar.org), which maintains an outcome registry and identifies unmet research needs. The group also urges surgeons to seek independent ethics review before attempting NOTES in humans.
However, many first tries at NOTES have been performed outside traditional centers of medical innovation. For instance, the first team to perform a NOTES appendectomy is based in Hyderabad, India; several surgical teams in Brazil are also publishing a disproportionately large volume of human case reports (the prominence of Latin America and Asia is briefly NOTEd in the Washington Post story). One searches far and wide for any commentary on this phenomenon. Why are Brazil and India at the vanguard of surgical innovation? Is this simply one manifestation of the knowledge economy moving overseas? Or does it have something to do with laxer regulations and safety standards? Are there characteristics of NOTES that make it particularly attractive for surgeons working in resource-limited circumstances? (photo credit: photosan0, Pink Floyd album, 2006)
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MLA
Jonathan Kimmelman. "NOTES from the Underground" Web blog post. STREAM research. 22 Sep 2008. Web. 22 Oct 2024. <http://www.translationalethics.com/2008/09/22/notes-from-the-underground/>
APA
Jonathan Kimmelman. (2008, Sep 22). NOTES from the Underground [Web log post]. Retrieved from http://www.translationalethics.com/2008/09/22/notes-from-the-underground/
In the current issue of Bulletin of the World Health Organization, authors Margaret Carrel and Stuart Rennie describe ethical challenges presented by demographic and health surveillance activities performed in low-income countries (“Demographic and Health Surveillance: Longitudinal Ethical Considerations”). What’s the link to translational research and gene transfer?
A number of issues identified in this article represent continuing challenges for fields like gene transfer, and this article offers analysis on these from an entirely different angle and context.
The most prominent example is the problem of distinguishing between research and care. Health surveillance activities inevitably identify health problems that demand intervention. But because surveillance sites are designed to provide information that will predict trends in similar, unmonitored sites, intervening risks diminishing the reliability of information about disease patterns. Some readers of this blog might be aware that I have argued that clear demarcations between research and care are impossible, and ethicists should abandon the project of trying to devise a dichotomous distinction (Hastings Center Report 2007). Health surveillance provides yet another example.
A second parallel is the issue of consent. The authors of this article ask whether new members of a household–children, for example–must provide consent for surveillance activities that their parents agreed to before they were born. This is analogous to issues encountered around germ cell interventions (intentional or otherwise) in gene transfer. Same is true for infertility treatment research.
Finally, a recent entry in this blog describes a paper Alex John London and I published on gene transfer trials in low and middle-income countries. The kinds of surveillance activities described in this article provide the types of information that research sponsors will need to make the case that an intervention they intend to test will be “responsive” to local health needs. Getting the ethics right for this “leg work” will be necessary for getting the ethics right for translational trials. (photo credit: Christian et Cie, 2008).
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MLA
Jonathan Kimmelman. "You are being (ethically) watched!" Web blog post. STREAM research. 06 Aug 2008. Web. 22 Oct 2024. <http://www.translationalethics.com/2008/08/06/you-are-being-ethically-watched/>
APA
Jonathan Kimmelman. (2008, Aug 06). You are being (ethically) watched! [Web log post]. Retrieved from http://www.translationalethics.com/2008/08/06/you-are-being-ethically-watched/
In the next issue of the journal Haemophilia, two researchers, Katherine Ponder and Alok Srivistava, take me to task for an article I recently published on the ethics of hemophilia gene transfer trials. My article discusses the little noticed phenomenon of researchers at elite medical centers in the U.S. recruiting trial subjects in Brazil and India for Phase 1 studies.
Ponder and Srivastava make two basic arguments in defense of the practice: 1- they represent a good therapeutic option for persons living in low and middle-income countries (LMICs) who can’t afford standard of care of high-income countries, and 2- we needn’t worry about exploitation at all, because such studies might produce medical applications that can be used in LMICs.
Could be. But the latter argument strikes me as logical and doubtful as any generic ethical claim, such as “We needn’t worry about safety in gene transfer trials, because gene transfer can be safe.” At any rate, look for a full response to their letter in an upcoming issue of Haemophilia. (photo credit: wallyg 2008– Rothko No.25/28).
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MLA
Jonathan Kimmelman. "Seeing Red" Web blog post. STREAM research. 04 Apr 2008. Web. 22 Oct 2024. <http://www.translationalethics.com/2008/04/04/seeing-red/>
APA
Jonathan Kimmelman. (2008, Apr 04). Seeing Red [Web log post]. Retrieved from http://www.translationalethics.com/2008/04/04/seeing-red/
What’s the difference between testing a typical small molecule drug, and testing a novel cell therapy strategy? And where might the latter raise ethical challenges that the former doesn’t? These questions are extensively discussed in my book, and given human drama in a recent story by Jennifer Couzin-Frankel in the Feb 12, 2010 issue of Science (“Replacing an Immune System Gone Haywire“).
