Bladder Trouble at the Frontier

In the May 1, 2008 issue of Nature, Alison Abbott reports on fraud allegations against Austrian researcher Hannes Strasser for performing an adult stem cell trial for urinary incontinence without having his protocol reviewed by an ethics committee.

According to the story, the volunteers paid approximately $17K U.S. to enter the study. They also were not told the procedure was investigational. The researchers might also have lied to their ethics committee, as well as Lancet (where they published the results). There also appear to be questions about whether the promising results obtained by Strasser are reproducible.

Of course, the allegations have yet to be proven. But the story will sound familiar to anyone that has followed the history of gene transfer- and indeed any cutting edge research area. The allegations highlight a key point I make in my book: part of what makes risk assessment at the medical frontier difficult has to do with the mercurial individuals and institutions– and the unstable relationships among various interested parties– that surround high-risk, high-payoff research. These "social" components of risk need to be par of the equation when policy makers, ethicists, and others evaluate the ethics of a study. (photocredit: DisneyKrazie 2007)

Goodbye, Helsinki

According to recent news reports, the U.S. FDA recently decided to abandon its endorsement of the Declaration of Helsinki when sponsors submit clinical trial data obtained overseas.

The Declaration of Helsinki (DoH)- which was first adopted in 1964- is the World Medical Association's statement on ethical requirements for human experimentation.  According to an editorial in Nature (22 May 2008), 85 countries have endorsed the DoH.

The FDA had long ago began distancing itself from the DoH when it refused to endorse revisions to the statement that followed controversies over the use of placebos in HIV mother-to-child transmission studies.  But the FDA has now opted to slam shut a door it had, for years, left ajar.

Helsinki is an imperfect document.  Certain paragraphs– particularly those involving international research– have continued to provoke heated debate.  But it is arguably the most influential, multilateral statement on ethical human experimentation, and it speaks clearly to considerations of justice when high income countries pursue trials in resource-poor settings.

Shame on FDA, and the U.S. government, for favoring parochial interests over international policy and, indeed, human rights. (photo credit: sobergeorge 2007)

Kid Time for LCA gene transfer?

(...continued from previous posts).  The promising results, and the surge of expectation they generated, will be used by the investigators and many advocates for the blind to defend pursuing the remainder of the study in children.  After all, children stand a better chance of benefiting, because their retinas have not yet degenerated.

Traditionally, bioethicists have frowned on pursuing studies in children that could otherwise be done in adults, because children are unable to provide valid consent.  Given that the primary objective of the study is safety, and that a sample size of 3 (or, combining the two studies, 6) and a follow-up of less than a year is minimally meaningful in terms of projecting safety, many bioethicists would question the prudence of continuing the study in pediatric populations.

The third volunteer in the Moorfield study was not an adult.  A report in Science magazine (2 May 2008) indicates that the Philadelphia team will test the agent next in an eight-year-old.

(photo credit: kiddocone 1998) 

Imprinting Expectation

(...continued from previous post)  Whatever the ambiguity and severe limitations in terms of sample size and interpretability, the NEJM studies have unleashed a torrent of expectation. Accoding to the U.K. Guardian, "an 18-year-old man... has amazed doctors by navigating a maze..." and the technique "represented a 'huge advance.'"

The Washington Post's Rick Weiss was harshly critical of Targeted Genetics when a volunteer died in a study involving AAV vectors and arthritis. Those who view Weiss as sour on gene transfer should consider his enthusiastic coverage of the LCA results.  The lede states unequivocally that three volunteers "regained modest amounts of vision," and describes the results as "something short of miraculous."

In Canada, the Globe and Mail's Hayley Mick reports on a Canadian undergoing a similar procedure in Florida (their results are unpublished). "Within weeks, the patients who took part [in the Penn and U.K.] trials reported varying degrees of vision improvement."

Per usual, all three present a human drama narrative– which is certain to amplify expectations further– naming (and in some cases, photographing) two volunteers: Dale Turner and Steven Howarth. (to be continued... photo credit: GiantsFanatic 2007)

Seeing Light?

...continued from previous post:  So did the researchers make the blind see?  Any suggestion that vision has been restored is premature. The authors of both reports acknowledge that measures of vision are subjective and visual improvements might reflect a placebo effect. What can be said– at least of the U.S. study– is that the pupil reflex is behaving as if the eye (and brain) are responding to visual stimuli better than before the experiment.

Many will view these two studies as confirmation of the promise of gene transfer– as evidence that gene transfer, in the words of one leader in the field, "has turned a corner." Though I understand the sentiment and view these results as encouraging, I also worry about the way these modest findings are being amplified into a signal event. (to be continued... photo credit: daniel y go, 2008)

Safety First: Two Gene Transfer Studies Against Blindness

...continued from previous post:  The preclinical studies supporting these human trials are about as good as it ever gets in translational research: numerous large animals (dogs) were treated effectively, and their vision in treated eyes seems to have been restored out to as much as eight years.

The NEJM papers report delivering nearly identical vectors to one eye of volunteers with Leber's Congenital Amaurosis type 2 (LCA2). The U.K. group did not observe any clinically "significant improvement in visual acuity," though one of the three volunteers showed some improved retinal function. The U.S. group (based at the University of Pennsylvania) shows significant improvement using an ostensibly objective measure– the pupillary light reflex. The authors also claim all three volunteers had improved visual acuity.

Importantly, neither group reported any adverse events attributable to the gene transfer product.  No immune response to the transgene was detected in sera.  Immune response to vector was detected in only one instance– and only transiently. Importantly, no vector was detected outside the eye. Thus, the vector does not appear to present any really big, extremely common, and almost immediate safety concerns.  All good. (to be continued... photo credit: lu lacerda 2007)