Before testing new drugs in human beings, drug developers must first perform a series of safety tests in animals. Unfortunately, these preclinical toxicology studies are typically protected as trade secrets. In fact, many countries have laws that specifically bar drug regulators from releasing preclinical toxicology data submitted by drug developers.
Unless you take the extreme view that animal experimentation raises no ethical concerns, this represents a terrible waste of animals and a failure of researchers to enable the sacrifice of animals to enrich the bank of human knowledge. As an afterthought, it’s worth mentioning that this also comes with certain opportunity costs for human beings, since such nondisclosure potentially 1-frustrates efforts by researchers to improve their knowledge about drug safety, 2- results in duplicative expenditure of human resources.
It needn’t be this way, and the field of gene transfer shows one modest way toxicology data could be published and pooled. Since it was established, the National Gene Vector Laboratories, at Indiana University, have invited gene transfer researchers to submit summary data on toxicology studies to their database (the laboratory recently was eliminated and replaced with the National Gene Vector Biorepository– NGVB for short). As described by NGVB director Ken Cornetta and project coordinator Lorraine Matheson in Molecular Therapy (April 2009), the database is intended to provide a resource for researchers so that they can cross-reference toxicology experiments in their FDA filings and avoid duplicative studies. The authors also envision the database as a resource for grant reviewers.
The database contains 27 toxicology studies in all. This number seems small when you consider the volume of gene transfer studies pursued since the database was established. The fact that every institution that has contributed to the database is a nonprofit suggests that the private sector has not taken an interest in this worthy resource. One question I have is how many private companies have used data contained in this databank in their FDA filings (this should be easy to determine).
These questions aside, other fields should create similar resources to pool data and create opportunities for data linkage. I would go so far as to say that ethics policies should require that, at a minimum, such summary data be published on a public database. The failure to do so seem a toxic waste for animals, scientists, funders, and patients alike. (photo credit: drp, Waste Not, 2004)
@Manual{stream2009-104,
title = {Toxic Waste?},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2009,
month = apr,
day = 27,
url = {http://www.translationalethics.com/2009/04/27/toxic-waste/}
}
MLA
Jonathan Kimmelman. "Toxic Waste?" Web blog post. STREAM research. 27 Apr 2009. Web. 09 Jan 2025. <http://www.translationalethics.com/2009/04/27/toxic-waste/>
APA
Jonathan Kimmelman. (2009, Apr 27). Toxic Waste? [Web log post]. Retrieved from http://www.translationalethics.com/2009/04/27/toxic-waste/
In the most recent issue of Molecular Therapy, U Penn researcher Hildegrund Ertl provides a strong and eloquent defense of the Recombinant DNA Advisory Committee (RAC). RAC was initially formed to evaluate the safety of studies involving recombinant DNA. In the last decade, however, its most visible function has been to provide advise to researchers pursuing novel gene transfer protocols in human beings.
Many researchers resent RAC, viewing it as yet another layer of oversight for their clinical studies. Understandably, they question whether it makes sense to have a separate review track for gene transfer. Other scientists and ethicists might question whether gene transfer is so exceptional as to be singled out for separate review, but would nevertheless argue that the RAC model should be extended to other ethically contentious areas of medical research. Nevertheless, the RAC model of centralized review of trial protocols has yet to be extended to comparably novel and contentious human clinical research areas like cell transfer, embryonic stem cell research, or tissue engineering.
Ertl provides a clear and persuasive description of RAC’s role in improving gene transfer trial safety, enhancing scientific value of studies, and ensuring appropriate informed consent practices. But the structure of her argument embeds three assumptions that, in my view, need to be questioned.
1- Why demand solid preclinical evidence? Ertl answers “if such data are not available, the risk outweighs the potential benefit for human volunteers– and that is not acceptable.” I would argue that preclinical evidence is of greater use in improving the scientific value of clinical studies.
2- How are risks justified in early phase studies? In the above quote, Ertl seems to suggest the answer is therapeutic benefit for the volunteer. In my view, risks in first-in-human trials are justified by the potential for scientific gain, not direct medical benefit.
3- What is the purview of ethics? Ertl, like many others, partitions “technical” concerns like study validity / value / preclinical evidence from “ethical” concerns like informed consent and conflict of interest. But why is the former any less ethical than the latter, given that technical questions implicate problems of risk-benefit balance and the ultimate ends of research. In my view, there is no clear division between the technical and ethical, and few if any decisions in designing and executing clinical protocols are devoid of ethical content. (photo credit: 416style, 2005)
@Manual{stream2009-108,
title = {Centralized Revue},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2009,
month = mar,
day = 27,
url = {http://www.translationalethics.com/2009/03/27/centralized-revue/}
}
MLA
Jonathan Kimmelman. "Centralized Revue" Web blog post. STREAM research. 27 Mar 2009. Web. 09 Jan 2025. <http://www.translationalethics.com/2009/03/27/centralized-revue/>
APA
Jonathan Kimmelman. (2009, Mar 27). Centralized Revue [Web log post]. Retrieved from http://www.translationalethics.com/2009/03/27/centralized-revue/
Greetings after a hiatus for teaching, grants, committees, book deadlines, wiping runny noses, and more. Much has happened since my last posting, and in the next two or three weeks, I hope to catch up.
First item on the agenda is a Jan 29 report in New England Journal of Medicine (NEJM) describing successful reconstitution of immune function in eight of ten children receiving gene transfer for adenosine deaminase severe combined immune deficiency (ADA-SCID). The paper follows on a previous report in Science, 2002, and almost certainly counts as gene transfer’s greatest clinical accomplishment to date.
I have previously argued in Lancet and Developing World Bioethics, as well as in my forthcoming book, that this study raised important justice concerns because it recruited volunteers from economically disadvantaged settings without clearly fulfilling the requirement, articulated in the Declaration of Helinki, of responsiveness. The NEJM article does not say where subsequent volunteers were recruited, though the fact that all but one new volunteer received PEG-ADA (a very expensive standard of care available only in high-income countries) suggests that later patients were not economically disadvantaged.
Rather than dwell on justice, I’d like to focus on the significance of this study. As indicated, eight of ten children with a life threatening immune disorder had their immune systems reconstituted. Five of these children had T-cell counts that were “above the lower limits of normal.” These children were able to enjoy normal social relations parents and other children.
There do not appear to have been any adverse events relating to the gene transfer vector. A major concern was the possibility that gene transfer might trigger a leukemia-like syndrome observed in two X-SCID studies. Blood tests of children in this ADA-SCID study, however, do not evidence of either the leukemia syndrome or its precursors– at least within the time frame of the study (median follow-up of 4 years; range: 1.8-8 years).
So is ADA-SCID gene transfer ready to leave Milan and conquer ADA-SCID? For children lacking haplo-identical bone marrow donors, maybe so given the morbidity associated with marrow transplantation. Still, there are lingering concerns. First, though these results are encouraging, risks of malignancy remain unquantified. Second, this gene transfer regime requires several ancillary treatments- like bone marrow conditioning- that expose patients to risk of infection until the gene transfer intervention kicks in. Several volunteers in this study developed infections and neutropenia, for example. In an accompanying editorial in NEJM, Donald Kohn and Fabio Candotti describe several ways that retroviral gene transfer to blood stem cells might be made safer. Last, it is important to remember that ADA-SCID is a multi-system disorder, with neurological, skeletal, and other effects. Though this approach seems to address what is by far the largest cause of morbidity and mortality in children with ADA-SCID, it does eradicate their condition.
The results of Aiuti et al have been widely celebrated in the gene transfer community. Kohn and Candotti’s editorial, for example, is titled “Gene Therapy Fulfilling its Promise.” More than any single gene transfer study I can think of, this one seems to have earned the vindicating headlines. (photo credit: Paolo Margari, Milano Sazione Centrale Ferrovi, 2008)
@Manual{stream2009-109,
title = {Departing Milano Stazione? ADA-SCID and Gene Transfer},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2009,
month = mar,
day = 10,
url = {http://www.translationalethics.com/2009/03/10/departing-milano-stazione-ada-scid-and-gene-transfer/}
}
MLA
Jonathan Kimmelman. "Departing Milano Stazione? ADA-SCID and Gene Transfer" Web blog post. STREAM research. 10 Mar 2009. Web. 09 Jan 2025. <http://www.translationalethics.com/2009/03/10/departing-milano-stazione-ada-scid-and-gene-transfer/>
APA
Jonathan Kimmelman. (2009, Mar 10). Departing Milano Stazione? ADA-SCID and Gene Transfer [Web log post]. Retrieved from http://www.translationalethics.com/2009/03/10/departing-milano-stazione-ada-scid-and-gene-transfer/
On December 12, the Catholic Church issued what the New York Times called “the most sweeping document on bioethical issues,” its Dignitas Personae. The document– the summary of which is available on the web– is dominated by discussion of in vitro fertilization, embyro research, and stem cells. But there is a section on gene transfer– and following on my previous post, the degree to which gene transfer has receded from the public discussion is striking (for example, gene transfer gets nary a mention in the New York Times coverage on Friday).
Here is what the document has to say about gene transfer. It defines “gene therapy” in a rather un-(small-‘c’)atholic way, as “techniques of genetic engineering applied to human beings for therapeutic purpses, that is to say, with the aim of curing gentically based diseases.” This excludes lots of what goes on in gene transfer, like cancer and cardiovascular disease gene transfer and gene marking. It also excludes much of what is morally contested about gene transfer– namely, enhancement applications. About “somatic gene therapy,” the statement says that “in order to proceed to a therapeutic intervention, it is necessary to establish beforehand that the person being treated will not be exposed to risks to his health or physical integrity which are excessive or disproportionate to the gravity of the pathology for which a cure is sought. The informed consent of the patient or his legitimate representative is also required.” Nothing startling about this statement. But a careful reading raises interesting questions. What, for example, is meant by “establish beforehand?” What type and degree of evidence is required? Are gene transfer applications not aimed at “therapeutic intervention,” like gene marking or vaccines, exempt? Another question: why the word “cure” given that few if any gene transfer strategies actually cure. Why not the more inclusive “treat?”
The statement on germ line cell therapy is somewhat intriguing. The document stops far short of categorically condemning such practices, and instead advises against them given that “the risks… are considerable and as yet not fully controllable.” In principle, then, the Catholic Church does not oppose germline gene transfer applied surgically to adults, fetuses, gametes, and embryos provided risks are manageable. But it is hard to imagine how these risks could be reduced for embryos without research that destroys embryos. It is also hard to imagine how the safety of gamete gene transfer could be established without the creation of “injured” embryos. If my analysis is correct, embryonic and gamete germline gene transfer are obliquely banned, leaving permissible application of germline gene transfer to fetuses with genetic illness provided benefits outweigh risks.
The document goes on to warn against “genetic engineering… with the presumed aim of improving and strengthening the gene pool.” Such techniques “promote a ‘eugenic mentality’;” many disabilities activists (and medicalsocial constructivists) will be heartened by the admonition that these techniques “introduce an ‘indirect social stigma with regard to people who lack certain qualities, while privileging qualities that happen to be appreciated by a certain culture or society….” Still, one wonders what, exactly, this condemns other than heavy handed state, or large collective efforts, to improve the gene pool (that is, genetic engineering with the aim of creating individuals who can fly, see in the dark, or think more clearly is not explicitly banned).
Somewhat surprisingly, the document contains no language on somatic gene transfer applied towards the ends of enhancement, though the spirit of the prohibition on cosmetic germline alteration would seem to rule out the use of such techniques. (photo credit: Vatican stairs, tintalle* 2007)
@Manual{stream2008-116,
title = {GenetEx Cathedra},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2008,
month = dec,
day = 14,
url = {http://www.translationalethics.com/2008/12/14/genetex-cathedra/}
}
MLA
Jonathan Kimmelman. "GenetEx Cathedra" Web blog post. STREAM research. 14 Dec 2008. Web. 09 Jan 2025. <http://www.translationalethics.com/2008/12/14/genetex-cathedra/>
APA
Jonathan Kimmelman. (2008, Dec 14). GenetEx Cathedra [Web log post]. Retrieved from http://www.translationalethics.com/2008/12/14/genetex-cathedra/
Before testing new drugs in human beings, drug developers must first perform a series of safety tests in animals. Unfortunately, these preclinical toxicology studies are typically protected as trade secrets. In fact, many countries have laws that specifically bar drug regulators from releasing preclinical toxicology data submitted by drug developers.
