Toxic Waste?

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)

The Biotechnology of Neglect

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)

Guinea Pig Nation?

Here is an irresistible news headline: "Public Policy That Makes Test Subjects of Us All."(New York Times, April 6, 2009). Then you open to the story only to discover, to your disappointment, that the piece is written by John Tierney, probably the most uninformed and underqualified members of the NYTimes staff.

His argument is ridiculous: that the New York City mayor's initiative to "pressure" the food industry to cut salt amounts to a big experiment that would normally have to undergo IRB review and informed consent (never mind that the initiative is not an experiment designed to further knowledge.  Never mind that the initiative is not aimed at generalizable knowledge, or that public health initiatives grounded in a state-based interest that are enacted by elected leaders have the "consent of the governed").

But in the most recent issue of JAMA, a news story (Bridget M. Kuehn, "Rare Neurological Condition Linked to Newer Monoclonal Antibody Biologics," April 8, 2009) reminds us that, in some small sense, licensure of novel biologics makes guinea pigs of us all.  The report describes how FDA recently issued an advisory on the psoriasis drug efalizumab after reports emerged that it may be associated with a risk of developing a rare and fatal brainwasting disease (progressive multifocal leukoencephalopathy, or PML).  FDA had previously issued warnings on two similar, immunomodulating drugs, and established a restricted distribution system for a third (natalizumab-- for multiple sclerosis).

In the case of natalizumab, cases of PML occurred in pre-marketing clinical trials.  For the other drugs, knowledge of the risk emerged only after drug licensing.  Risk of PML was totally unexpected, and is a reminder of the high degree of uncertainty surrounding interventions directed at the immune system.  

Premarketing clinical trials are statistically powered only to detect common, "signature" adverse events.  As we move into an era of biologics-based pharmaceuticals (and accelerated approval), expect that many adverse events will only be discovered once a drug is in widespread use.  Robust systems of pharmacovigilence will be especially critical (photo credit: Peter Guthrie, 2006).

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)

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)

Found Figures: Picking up the Pieces after an HIV Vaccine Trial Fails

In the November 29, 2008 issue of Lancet, two reports (plus a commentary) report the famously disappointing outcome of a recent placebo-controlled study testing adenoviral vector-based vaccines against HIV. News reports over a year ago reported that the study was halted after an interim analysis failed to show any prospect of proving effective. More troubling, subgroup analysis suggested that vaccine recipients who had high pre-existing immunity to the adenoviral vectors showed higher rates of sero-conversion compared with placebo. As this vaccine was among the most promising and advanced in terms of development, these results were seen as a major setback.

The recent Lancet reports paint a complicated picture: if I read them correctly, the inference that vector might enhance sero-conversion is muddied by the finding that circumcision status might also have played a role in sero-conversion (men with higher rates of adenoviral immunity were also, coincidentally, less likely to be circumcised).

What is clear, from what I gather, is that this is a good example where rigorous preclinical testing, coupled with rigorous trial design, permits meaningful interpretation of (unfortunately) negative human trial results. As Merlin Robb notes in a commentary accompanying the Lancet reports "the predictive value of the non-human SHIV-challenge model is not supported by this experience. The benchmarks for advancing candidate vaccines to efficacy testing and the priorities for vaccine research have been re-examined."

Well-designed studies, supported by rigorous preclinical testing, should always produce valuable, findings– like the unexpected "found figures" in the bark of a tree  (photo credit: Readwalker, Found figures, 2006)