Friday, March 27, 2009

Red Handed: An Independent Review of IRBs

A decade or so ago, the Government Accounting Office published a series of reports faulting human protections at VA hospitals, raising concerns about HHS oversight of human research, and urging continued vigilance in human research

After a seeming pendulum swing toward protections bashing (witness the outpouring of condemnation after OHRP sanctioned a team of researchers investigating ways to cut infection rates in intensive care units, or the Tricouncil draft policy's use of the phrase "over-protection"), a recent GAO report may show a revival of concerns about independent review operations.

In it, GAO reports the result of a "sting" operation in which a sham device study was presented to three private IRBs.  The IRBs were selected on the basis of having "less burdensome initial paperwork requirements."  Two of the IRBs rejected the protocol, describing it as "awful" and "the riskiest thing I've ever seen on this board."  But one– identified in a New York Times article as Coast Independent Review Board (whose webpage lists "speed" as the first selling point), unanimously approved the protocol, characterizing it as "probably very safe." 

Congress, GAO, and press reports are framing this as evidence of flaws in private IRB review. I'm actually impressed that the glass is 2/3 full.  And without suggesting endorsement of the private IRB model, I actually wonder how well academic medical center IRBs-- most of whose members are salaried by an institution with a significant financial and professional stake in seeing research protocols approved-- would have performed.  (photo credit: laughing squid, 2008)

Centralized Revue

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)

Tuesday, March 10, 2009

Departing Milano Stazione? ADA-SCID and Gene Transfer

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)