In Brugge / No Compassion (Part II)

Further to the therapeutic outlook on first-in-human studies at the Brugge meeting was Adrian Thrasher's thoughtful presentation on his own X-SCID study at Great Ormand Street Hospital. Thrasher's study was able to restore immune function in nearly all volunteers. Recently, however, his team reported a lymphoproliferative disorder like those seen in a very similar Paris study.

Thrasher stated clearly "The purpose [of X-SCID protocol] is therapeutic effect; it is not a safety study."  Fair enough: the study was in a pediatric population (standard research ethics requires clear therapeutic warrant for such risky studies), and Thrasher's protocol did not range doses the way typical first-in-human studies do. And I should add, there is some grounds for thinking of the study as having therapeutic warrant, not the least because it was supported several unsuccessful X-SCID human studies and a successful one in Paris). Still, putting the therapy before the learning- this made me somewhat uncomfortable.  Therapy might have been his (and his hospital's) intent, but to describe the study as ontologically "therapeutic" and not "research"?  Intent only gets us so far...

Thrasher revealed some unusual properties about the molecular events leading to this leukemia (see? told you it could be construed as a safety study).  And now, here's the compassion part. Thrasher was circumspect about this particular leukemia, because the patient who developed the leukemia had originally been ineligible for the protocol because he had a matched unrelated bone marrow donor. The regulatory agency made a "one-time" exception to waive the normal risk-benefit balance.

Of course, one should be very careful generalizing from this one case where "compassion" seems to have led authorities astray. And presumably, the boy's parents were thoroughly informed about the risks going in to the protocol. Still, the example is somehow instructive. (photo credit: missinguigga 2008).

No Compassion

"They say compassion is a virtue...." so sang David Byrne of the Talking Heads.  But what about "Compassionate Use?" 

This refers to the practice of giving terminally ill patients who are otherwise ineligible for early phase clinical trials access to investigational agents. At the Brugge ESGCT meeting, Finnish researcher Akseli Hemminki described providing 125 patients compassionate use access to a novel oncolytic gene transfer vector– Ad5/3-Cox2L-D24. Hemminki was not reassuring when asked by an audience member whether a concurrent clinical trial was actually testing the approach, and rumors swirled that he had charged patients for the agent.

Compassionate Use is highly controversial.  Patient advocates view it as a lifeline, and over the years, drug regulators like FDA and EMEA have eased restrictions on patient access to untested agents.  In late 2006, for example, the FDA proposed new rules that would make it easier to provide untested agents to groups of patients (rather than individuals); the rules would allow companies to recover manufacturing costs from patients seeking access. A related set of proposed new rules would allow companies to charge patients for entering early phase clinical trials. 

Compassionate Use raises troubling questions for ethics and policy. With respect to the former, is it really an act of compassion to offer terminal patients a completely untested composition of matter? If the answer is "yes," well, that makes any future clinical trial that will randomize some patients to standard of care (which, for terminal patients, is nothing) diabolical. That leads me to the policy concerns: if you can get access to a drug outside a study, why enter the trial at all? Compassionate use potentially complicates the collection of rigorous data about the safety and efficacy of new interventions, and thus has public health implications. As for the idea of actually charging patients for access– whether on or off a trial: that's plain wrong.

According to the American Cancer Society, no records are available on the number of agents provided through compassionate use, the volume of patients who receive drugs through compassionate use, or their outcomes. Regardless of where one stands, the practice would seem a policy black box.  (photo credit: fgm878, 2007).

In Brugge: The Cure

One of the most striking themes at the European Society of Gene and Cell Therapy was the extent to which continental European researchers conceptualize first-in-human gene transfer experiments as therapeutic interventions rather than research protocols.

Perhaps the most extreme and explicit expression of this was view was presented by Bonn internest Thomas Heinemann (he also studied philosophy and serves on several ethics committees in Germany). Heinemann advanced the notion of the "controlled individual therapeutic attempt," for which the primary objective is therapeutic gain; the scientific dimensions of such studies (e.g. collecting safety data) are necessarily secondary. As he put it, research is only justified "ex post facto."

I found this argument intriguing for several reasons. First, Heinemann justified this claim largely on grounds of autonomy and instrumentalization of desperately ill patients. In contrast, North American bioethicists typically use autonomy and instrumentalization to argue the opposite: that research is primarily intended to serve the ends of others, hence the paramount importance of obtaining consent from volunteers and their guardians, hence the need to be extremely cautious going into a desperately ill population, where autonomy might be compromised.

Second, I was impressed by the speaker's conviction that first-in-human trials have therapeutic warrant. After almost twenty years of painstaking and at times discouraging research, we seem to have learned two things:  first, that first-in-human trials rarely go as expected, and second, that such studies often yield important insights about new interventions. I might have expected a more cautious and seasoned view about the therapeutic merits of first-in-human attempts: does it really enhance the autonomy of volunteers to offer so little by means of therapy, but to foreseeably get so much in terms of social good? (photo credit: virtualais //www.77click.it, Brugge, 2008)

Just the FACS: Reprise on Insertional Mutagenesis

I've just returned from the annual European Society of Gene and Cell Therapy meeting in Belgium.  Lots of great material for upcoming posts. For now, I want to follow on the last posting on the leukemias in the X-SCID study.  A warning: those lacking a stomach for science geek-talk might want to skip this posting.

In the previous posting, I stated that a recent paper provided evidence that retroviral integration in the genome ("insertional mutagensis") had triggered leukemias in the X-SCID study rather than over-expression of the corrective gene ("transgene"), the gamma c-chain (hereafter, "gc").  This was on the basis of data in the graphic above, which used cell sorting to show that levels of gc on the surface of T-cells was within a normal range.  In Belgium, Adrian Thrasher presented similar data for the fifth leukemia.

When I first encountered this figure, it bothered me: why did the authors measure gc expression by cell surface markers (a technique called "FACS") rather than Western or Northern blotting, or quantitative PCR, or something along these lines?  It seemed a very indirect way of seeing whether gc expression levels are in fact normal. Here are two possibilities that this figure fails to rule out:  1- gc is expressed at very high levels, but not packaged and presented on the surface of T-cells, perhaps because of insufficiency of other receptor components; 2- some gc transgene is aberrantly spliced, such that surface levels are normal, but intracellular concentrations of the alternate splicing product are abnormal.

A few years back, one team of researchers presented data indicating that gc transgene overexpression contributes to T-cell transformation. Another team claimed it was unable to reproduce this. The jury seems to still be out on whether the gc product contributed to the X-SCID leukemias, and I'm not yet convinced that the latest round of data fully exonerates the gc chain. (Graphic: figure from Salima Hacein-Bey-Abina et al, J Clinical Investigation 2008; 108: 3132-42).

Burst Bubbles

Among the greatest traumas for gene transfer was the development of leukemias in several children participating in trials using retroviral vectors against X-linked Severe Combined Immune Deficiency (X-SCID-- also known as "bubble boy syndrome").  About 20 or so children have had their immune systems fully restored by this gene transfer strategy.  Tragically, however, five children in two X-SCID studies (one in Paris, the other, London) developed T-cell leukemias that were causally linked to the gene transfer approach.

In the September 2008 issue of Journal of Clinical Investigation, Salima Hacein-Bey Abina and 28 other authors characterize the molecular nature of four of the adverse events, and report the outcome.  Before this article, it was known that one of the children died. This article now reports that the other three children have "sustained remission" after chemotherapy. 

The authors report that the vector inserted itself at the same genetic locus (LMO2) in 3 of the 4 cases.  In one case, vector inserted at a different genetic locus (CCND2); in another, vector inserted itself at LMO2 as well as a second locus, BMI1.  This suggests that LMO2 disruption is not the only path to causing cancer for this vector.  One other finding stood out.  Since the first leukemia was detected, many have speculated that the cancer was partly caused by the gene (rather than just the vector). However, the authors present evidence that the gene was expressed at normal levels in the children who developed leukemia. This lends support to the theory that the leukemias were not caused by the gene, but rather by some combination of the vector, the cell types used, and perhaps some characteristic of the underlying disease. (photo credit: concretecandy, boy in the bubbles, 2006)

Keeping Alive with Hope

Hope has been a consistent theme in Barack Obama's campaign, which thankfully came to a glorious end (many of us can now "hope" to actually get some work done after weeks of checking fivethirtyeight.com every ten minutes). His book was titled The Audacity of Hope. In the close of his victory speech, he stated "Let us keep that promise, that American promise, and in the words of scripture hold firmly, without wavering, to the hope that we confess." Newspaper headlines proclaim "Elections Unleash Flood of Hope Worldwide (NYTimes) and "Time to Hope Again" (Washington Post).

Hope is also a central theme in translational research, driving research advocates ("Hope for a Cure"), perseverance at the lab bench, and for better and for worse, the participation of gravely ill patients in trials that offer the slimmest prospect of serious medical benefit. Hope in many settings– particularly in the political– is an unalloyed good. 

But in the context of enrolling patients in early phase trials, hope becomes morally ambiguous.  Or at least, so Penn philosopher Adrienne M. Martin would seem to suggest in her critical analysis of hope ("Hope and Exploitation," Sept / Oct issue of Hastings Center Report).

Martin begins her essay with a set of consensus observations about hope: 1- it involves a desire for an outcome; 2- it involves imaginative engagement with a desired outcome– like praying or fantasy; 3- it often frames how people interpret and use information.  She then goes on to explore the various ways that hope can lead to exploitation in clinical research.

Much has been written about "hope" in bioethics, and much of it is drivel. I have a number of reservations about Martin's article. For my money, however, this is the most compelling analysis of the phenomenon that I know of. I highly recommend this article to anyone who takes seriously the moral dimensions of how translational research engages hope. (photo credit: San Diego Shooter, Tattered Hope, 2008)