Icarus, again: Adversity in another Gene Transfer Trial

Two weeks ago brought good news and bad news for gene transfer. First the good news. New England Journal of Medicine beatified a new gene transfer strategy for Wiskott-Aldrich Syndrome (WAS). WAS is a primary immunodeficiency that primarily affects boys. It is thus in the same family of disorders that have been, in varying degrees, successfully addressed using retroviral gene transfer. Like other immunodeficiencies, this represents relatively low hanging fruit for an approach like gene transfer, because scientists can access and target stem cells, and because corrected cells should be at a selective advantage for survival compared with uncorrected cells.

The NEJM article reported clinical, functional, and molecular outcomes for two boys in a trial based in Germany. Briefly the two boys were given a type of chemotherapy (in order to make space for genetically corrected cells), and then transplanted with “corrected” blood stem cells. The corrected blood stem cells contained a viral vector similar to those used in previous gene transfer trials of primary immune deficiency. The team saw: 1) stable levels of genetically corrected stem cells that expressed the WAS protein (indicating the genetically modified cells “took,” and produced WAS; 2) recovery of the function of a variety of immune cells; 3) reduction of disease symptoms, including improvement of eczema, and reduced severity of infections.

The article exhaustively ruled out events that have occurred in other, similar gene transfer trials in which children developed leukemias from the vector. Now the bad news. The same day NEJM published the results, American Society of Gene and Cell Therapy (the largest professional society devoted to gene transfer) released a statement saying that the German team just announced “a serious adverse event in a gene therapy trial for Wiskott-Aldrich syndrome (WAS)”- one of the ten children in the German trial developed a leukemia.

And so continues the saga of gene transfer: three steps forward, one back. (photo credit: vk-red 2009)

Are Trials Necessary?

Today's New York Times ran a heartbreaking story by Amy Harmon about two cousins who developed melanoma. One was entered into a cancer clinical trial and received the investigational drug PLX4032. The other was ineligible for the trial, and therefore unable to access the experimental drug. Guess which cousin died?

The article is one in a series of Harmon articles that seems to raise questions about whether rules governing drug testing and research are depriving desperately ill patients timely access to curative therapy. In this article, the narrative takes aim at two practices: 1- the practice of including control groups within trials, and randomly determining that some patients will receive standard care that is widely regarded as inadequate; 2- excluding patient access to drugs that have not yet demonstrated unequivocal therapeutic advantage.

As with many of my blog entries, I preface this one by saying that I am not a cancer doc, and therefore not in a position to evaluate whether PLX4032 is the wonder drug this story makes it out to be. I also preface my comment on this article by acknowledging the incredible pain and anxiety that patients suffer when denied access to a trial, or when denied access to a preferred drug within a trial. These disclaimers aside, I found the tenor of this article very problematic.

First, the reason investigators randomly determine treatment choice in trials is because, at the outside of a well designed trial, there is genuine uncertainty about whether the new drug is better, the same, or worse than the (inadequate) standard treatment. Many doctors participate in trials because they fervently believe the new regimen is better than the standard one. But the evidence shows, again and again, that on average, new drugs outperform old ones in a small portion of instances (maybe around 15-20%). It is just as likely that new drugs will underperform standard treatments- making patients sicker perhaps, or failing to deliver as much punch. So one concern about the article is the premise that doctor's personal beliefs about which cancer drug will perform better in a randomized controlled trial carries some moral weight. The evidence shows doctors in the aggregate haven't a clue- which is why functional healthcare systems run trials.

A second troubling premise here is that there is no harm to allowing public consumption of drugs that are not yet validated in rigorous clinical trials. CEOs of many pharmaceutical companies perhaps may share this view. But the historical record shows otherwise: in fact, many patients are severely harmed when drugs are introduced into clinical use before they have been established as safe and effective. Perhaps a few readers out there may be familiar with thalidomide? Or autologous bone marrow transplantation for breast cancer? Ever considered the price tag on these new cancer drugs, and do you want your government or insurance company purchasing a potentially useless drug?

Still, article zeros in on an ethical tension that is very difficult to eradicate from clinical research. Patients want- and are entitled- to be treated as individuals. Physicians also prefer to treat patients as individuals. Clinical trials, however require that patients be treated as tokens of larger populations- that they be treated, in a sense, as "stand ins" for future patients. Randomization has not been shown to deprive patients of access to life preserving drugs. However, it does rob patients of fulfilling their desire to be treated as individuals and to exercise personal choice. And this is one of the reasons why the field of research ethics is endlessly fascinating, important, and nettlesome. (photo credit: travelingMango 2008).

Embryonic Stem Cell Trials Start Development

So, FDA has lifted a hold on the first ever clinical trial testing cells derived from human embyonic stem cells. The study- based in California and sponsored by the biotechnology company Geron (view press release here)- will administer cells derived from human embryos ("neural support cells") to ten patients with recent spinal cord injury with the primary aim of demonstrating safety. The same study had been initiated last year- but halted after safety concerns arose in rodent tests. According to news reports, Geron was able to deliver a clean package of studies to FDA. And so- roughly 20 years since the first ever gene transfer study, we now have the first ever human trial of embryo stem cell derived tissue.

Circumstances surrounding this study show all the signs of repeating phenomena surrounding other, highly publicized first in human trials. My book picks up on these signs as harbingers of challenge. Take, for example, the way the initiation of the study itself is seen as a milestone- as a visible sign of medical progress. This presents a regulatory decision as a stand in for study results; it confuses desire with results. And so, I worry when people like Alan Trounson, president of California Institute of Regenerative Medicine, say things like "I think it's a very important milestone for the whole industry... It's very important that they get on and treat the patients...." I also worry when I hear that share prices in Geron rose by 17% on news of the decision- as if permission to study a product is evidence of the product's promise.

The New York Times article reports that Advanced Cell Technology is seeking permission to test another embryonic stem cell derived tissue in human beings- this time for an eye condition. Approval of Geron's trial will surely blaze a path for the latter- though the ethical justification for proceeding in such research may prove more difficult than for spinal cord injury

(photo credit: Brennan G. Wills, 2010)

Information: Stem Cell Tourism Redux (part 1)

The current issue of Kennedy Institute of Ethics Journal contains the first installment in a two part series on the ethics of stem cell tourism, by long time stem cell watcher Cynthia Cohen and Peter Cohen. The Cohens pull together a large body of news reports and internet posts on Russian and Indian private clinics offering stem cell interventions to foreign patients (who travel to these clinics because they cannot receive the nonvalidated interventions in their native countries).

They provide a very critical view of these clinics and the practice of offering nonvalidated stem cell interventions to large numbers of patients outside of clinical trials- a view that readers of this blog will recognize as one that I share: "those who travel to other countries for stem cell treatments enter into a sort of medical Russian roulette." I would add: they pay large sums to shady characters for the privilege.

The back end of the article takes issue with commentators who have offered a quasi-defense of stem cell tourism, viewing stem cell development as analogous to surgical innovation. These commentators have thus defended the idea of offering stem cells outside the trial context. According to the Cohens, these commentators "do not explain in what respects these interventions resemble surgical procedures and do not furnish reasons why clinical trials are not possible for them."

There is an intriguing theme in this article that ties in with my recent Science article. Namely, the Cohens are careful to point out that there are many legitimate stem cell scientists in Russia and India that have called on their governments to regulate stem cell clinics because their activities harm the reputation of unaffiliated stem cell researchers in the same country. More on how stem cell scientists have attempted to draw boundaries between their own work and that of these clinics in my next post... (photo credit: Alex McGibbon, (courtesy Banksy), 2006)

ASGCT, cont': Results on Fetal Tissue for Battens Presented

Robert Steiner, co-principal investigator in a fetal cell transplantation study involving the rare, fatal hereditary disease Neuronal Ceroid Lipofuscinosis (also known as Batten disease), presented results of a now completed phase 1 study. According to Steiner, the study involved the highest ever dose of stem cells delivered to the human brain. The trial involved six children with infantile and late-infantile forms of the disease.

Elsewhere, this safety study has been reported as "positive"- in the sense that there were no unexpected, stem cell related complications. Which is not to say the protocol was a picnic: the study involved (if I understood the presentation correctly) 14 trajectories to the brain, and an extended regime of immunosuppression that caused 23 adverse events. Steiner reported that none of the patients showed a clinical response- which is what one would expect in patients with such advanced forms of disease (hopefully, the research team conveyed the unexpectedness of clinical benefits to parents when they obtained informed consent).

Steiner also reported that, when one of the patients died due to natural course of illness, the family permitted the team to perform an autopsy. The autopsy ruled out the cell transplantation as a cause of mortality, and established that the tissues engrafted successfully. In the words of a press release, "By permitting the autopsy, the family allowed the researchers to learn very important details that will potentially benefit future patients."

Did the research team use the autopsy to determine whether the transplanted cells were expressing the therapeutic gene? If so, was the gene product taken up by surrounding tissues? Answering these questions would be key to maximizing the scientific value of the study, and thus redeeming the risks of surgery, immunosuppression, stem cell transplantation, and the many follow-up visits required of patients participating in the study. But from what I heard, the brain is in the hands of the company, and it is unclear whether they have performed these studies (and if so, whether the results will be reported). Let's hope the family's permission for autopsy allows the researchers to learn still more. (photo credit: dopamineharper 2009)

ASGCT, continued: Eyes on Stage

Predictably, the big presidential symposium at ASGCT reserved a slot for Jean Bennett, who led one of the three teams that have tested a gene transfer strategy for a rare genetic form of blindness, Leber's Congenital Amaurosis (LCA). Unpredictably, however, Bennett trotted out one of her "treated" patients, Cory Haas, along with his two parents, who sat up on the podium as Bennett went through her 45 minute presentation, which was titled "An Aye for Gene Therapy."

First, let me say that Bennett's results- as well as those of the other teams- continue to be very encouraging. In adults whose retinal tissues have degenerated, the approach has not restored vision, but it has also not raised any major safety concerns (apart from a surgical complication in one patient). In younger patients, the approach has shown safety with restoration of vision, and Bennett this time presented various functional data, along with neuroimaging data consistent with restoration of vision. And nothing that follows detracts from all the credit she and her team deserve for their smarts, scientific rigor, perseverance, and clinical accomplishments. Second, the family has agreed to go public, and this was not their first time on display. No doubt, they feel that putting themselves on display like his helps bring visibility to this important research. As well, they have their own battles to fight: only one eye has been corrected, and perhaps they feel that going public like this may help nudge regulatory authorities to clear the investigators to apply gene transfer to the second eye.

Nevertheless, I found Bennett's exhibition of her subject, and his parents, a case of poor judgment. And judging from one or two conversations with others in attendance, I was not alone. In my book, I warn against the perils of putting patients on display. It performs a rhetorical function that tends to neutralize critical thinking and indulge sentimentality. I found it particularly problematic that this would occur at a major scientific address: if there were skeptical questions to be asked (as there typically are at scientific meetings), who would dare ask them in front of a child and his parents? At any rate, Bennett used a short question and answer period following her talk by asking Corey and his parents a series of Diane Sawyer-like questions: "are you glad you joined the study?" "what was the most difficult part?" "do you have any questions?" She then elicited a round of applause "for the patients" from the >500 assembled attendees. Was the Q and A scripted? Was this a kind of victory lap for Bennett? Who knows.

Spectacular research, to be sure. But it makes for spectacle science as well. (photo credit: strangejourney 2009)

ASGCT in Washington DC

Another year, another annual meeting of the American Society of Gene Therapy- now rechristened American Society of Gene AND CELL Therapy. The meeting ends today, and I am way behind in posts. There have been, to my knowledge, no startling new revelations about high impact trials or disastrous adverse events. The studies of Leber's Congenital Amaurosis- a rare genetic disorder causing blindness- continue to dazzle, with several groups presenting results showing consistent safety and functional recovery- especially in younger patients. The ADA-SCID data continue to show very encouraging results without any indication of the safety problems encountered using similar vectors. Same goes for the adrenoleukodystrophy study- now three children have received a lentivirus-based cell intervention. Again- no evidence that delivered cells are expanding in a way that would raise concerns about a malignancy, and the disease course for children appears to be significantly improved. Off, now, to catch a session on a new product for another genetic disease- LPL deficiency- which (by the title of the session) has been submitted for regulatory licensure. To be continued, with some ethical commentary... (photo credit: afagan 2007)