Tuesday, November 24, 2009

Expectation is a Vascular Condition: Thoughts on Media Coverage of "Liberation Procedures" for Multiple Sclerosis

Disclaimer to all readers: I am not expert in multiple sclerosis. I am not intimately familiar with recent research findings on a novel surgical treatment ("liberation procedure") for multiple sclerosis that have received wide coverage in the Canadian media.

Now here are my "claimers:" recent media accounts of this novel approach border on the irresponsible, and point to serious problems with the way many media outlets cover translational clinical research. My second "claimer" is that such media coverage has important consequences for patients and the research community.

Finally, a point of clarification: my comments below concern the quality and consequences of media coverage, not the merits of the medical procedure discussed.

Here is the background: on November 20, the Globe and Mail ran a feature by veteran reporters André Picard and Avis Favaro titled "Researcher's labor of love leads to MS breakthrough." The story described a novel theory of an Italian researcher, Paolo Zamboni, that MS "is not, as widely believed, an autoimmune condition, but a vascular disease. More radically still, [an] experimental surgery offers hope that MS... can be cured and even largely prevented." Said Dr. Zamboni, "I am confident that this could be a revolution for the research and diagnosis of multiple sclerosis." The news story then describes an Italian study that performed the surgical procedure in 65 patients; the patients saw their disease virtually eradicated.

Like practically every other news article of this species, the reporters do two things. First, they truck out a few patients to proclaim the miracle cure (said one: "I don't remember what it's like to have MS"). Second, to establish credibility, the reporters throw in the perfunctory killjoy comments of a few scientists: "skeptics warn the evidence is too scant and speculative."

As observed on the excellent NPR program On the Media, media coverage of medical research and breakthroughs "overflow with optimism and excitement, offering hope for millions." According to long-time media analyst Gary Schwitzer, "What they don't overflow with is accuracy, context and journalistic responsibility." (Schwitzer, by the way, runs an excellent blog on health news coverage).

Here are some concerns I had about the Globe and Mail story:

• the story reports on clinical research findings. The story did not say, however, that the results have not been published and subjected to peer review.

• the story did not say whether the studies were well-designed: was there a control or placebo arm, for example? the story did not mention that placebo responses can be especially high in the setting of surgical interventions. Nor did it mention that placebo responses are often high in the context of remitting diseases like MS.

• the story wrapped logical fallacies within emotive proclamations. For example, what, precisely, could it possibly mean to say "I am confident this could be a revolution..."?

• the story was not linked in any way to any particular event. Usually reports like this follow from major scientific publications, or presentations at medical conferences. This story, however, is "free floating"- which makes it much more difficult to contextualize (why is it being reported now? how well have the findings been vetted? how did the researchers capture the attention of journalists?).

• the story contains statements that are deeply suspicious. One example is that Zamboni claims MS is not an autoimmune condition. Here is the very first line in the abstract of Professor Zamboni's most recent publication: "Multiple sclerosis is primarily an autoimmune disorder of unknown origin."

• the story did not address the correlation and causation problem. The story (and Zamboni) claim that vascular malformations cause MS symptoms, because the researcher discovered that many MS patients have "malformed or blocked" veins draining the brain. But an alternative explanation would be that malformations or blockages are themselves caused by MS- that they are symptomatic rather than causal. Any news coverage of correlation should always address the issue of cause.

And the consequences? Do a google search yourself on the procedure (CCVSI) to find out how much chatter there is among expectant patients, who (judging from discussions) are wondering whether they can travel to Italy to receive the "treatment." And today, the Globe and Mail reports that the MS Society of Canada- portrayed as sourpuss nabobs of negativism in the previous article- will now fund CCVSI "with significant research dollars" in response to "the overwhelming public response to the media stories."

Surely, more research, more trials, more basic science is needed. If indeed this approach is a promising as reported, it should be subject to rigorous clinical testing. But can anyone seriously argue that media coverage of this low quality should set the research agenda and decide how scarce research resources are allocated? (photo credit: xbloodsin, sepulcrum, 2008)

Thursday, November 12, 2009

More on Lenti's, Gene Transfer and Adrenoleukodystrophy

(...continued from the previous post). There are several features that make the recent Adrenoleukodystrophy (ALD) gene transfer study noteworthy.

1- A New Viral Vector Debuts: this is the first successful application of HIV-derived viruses in gene transfer (lentiviruses). These vectors have various advantages over retroviruses used in other protocols. One is that, in theory, at least, they are supposed to be safer. Previous trials of the same team (different disease) involving retroviruses triggered leukemia-like disorders in several volunteers. In this study, the authors do not detect any evidence that cells are poised to cause a malignancy. However, in a post this summer, I noted that another trial involving thalessemia and lentiviruses did, indeed, detect clonal enrichment. And the ALD study enrolled only two patients- if there were going to be safety problems detected, they'd need to be massive to be detected in so small a sample of patients. Thus, despite the encouraging findings in the ALD study, the safety of lentiviral gene transfer remains to be firmly established.

2- Prior Animal and Clinical Experience are Successfully Integrated: here is one instance where favorable clinical outcomes were achieved on the basis of limited preclinical evidence. Specifically, the authors previously tested their approach in mice, but because rodents do not develop the same pathology as human beings, they were uncertain whether the gene correction would be sufficient to correct the disorder in human patients. These animal studies were bootstrapped with extensive experience with bone marrow transplantation in children with ALD. Rarely is this transition from rodents into clinical applications so successful. All the more surprising- this is occurring within the realm of central nervous system disorders, which have a particularly high rate of failed drug development.

3- Patients in the Service of Science: This study will no doubt be perceived as a story of "science in the service of patients:" a team of clinicians applying cutting edge discoveries to do the best they can for their patients. But it is as much- perhaps more- a story of patients in the service of science. The study is notable for how well it used the occasion of ALD to make more fundamental discoveries. For example, in a "Perspective" piece that accompanies the published trial, Luigi Naldini describes this as what "may be a first glimpse of live [generation of new blood and immune cells at the level of DNA]." Naldini also notes how the study developed and applied new techniques for ruling out clonal dominance that "will likely become a gold standard." Also intriguing is the hint that this approach may be applicable for other disorders involving the central nervous system, and the finding that only a small amount of gene correction is needed to arrest the pathology. (photo credit: photobunny 2007)

Gene Transfer and Adrenoleukodystrophy: There Will Always Be Paris

Last week's Science magazine reported what seems likely to count as one of gene transfer's greatest clinical successes to date: stabilization of adrenoleukodystrophy in two boys receiving genetically modified blood stem cells. Preliminary results of this study had been presented at this summer's American Society of Gene and Cell Therapy meeting.

Adrenoleukodystrophy (ALD) is a rare hereditary brain disorder in which a deficiency in a gene, ABCD1, causes degeneration of tissues (myelin) that insulate cells in the central nervous system. The disease is familiar to many because of its most famous patient, Lorenzo Odone, whose story was featured in the movie Lorenzo's Oil. Untreated, ALD is invariably fatal.

Because myelin cells originate from blood stem cells, researchers had previously used bone marrow transplantation to successfully halt progression of demyelination in ALD patients. However, bone marrow transplantation has two severe limitations: many patients lack matched bone marrow donors; second, even when a matched donor is available, the procedure is burdensome and risky.

In this most recent study, researchers at Hôpital Necker in Paris transplanted genetically modified bone marrow cells into two Spanish boys who lacked matched bone marrow donors. The boys were also given myeloablative conditioning- a type of chemotherapy that increases the likelihood that genetically modified cells will repopulate the bone marrow. The Science report showed:

1- genetically modified cells did, indeed, survive and were maintained at stable levels for two years.
2- the modified cells expressed the therapeutic gene, ABCD1, again for two years.
3- brain demyelination was halted after 14 months- the timing is similar to what would occur for patients receiving bone marrow transplantation.
4- the two boys did not appear to decline on various measures of neurological or verbal tests, as would almost certainly have occurred with the natural course of ALD.
5- the authors did not detect "clonal dominance" in their modified cells– that is, evidence that genetically modified cells were poised to cause a malignancy.

In an accompanying editorial, Luigi Naldini calls this study a "Comeback for Gene Therapy," describing it as a "long-sought rewarding achievement in the field of gene therapy." In my next post, I will discuss some implications, interpretations, and other interesting dimensions of this very encouraging study (photo credit: tgif28, chalk graffiti at Hopital Necker, 2009)

Wednesday, November 4, 2009

California Dreamin: CIRM Announces New Stem Cell Awards

California's Institute for Regenerative Medicine just announced a series of large funding awards to fund translational research initiatives involving (mostly) stem cells. The projects funded are telling with respect to what was funded, and what they will attempt to achieve.

First, notwithstanding a press release containing the words "bringing stem cell therapies to the clinic," several projects are really dressed up gene transfer studies. Thus, one team will use gene transfer in hematopoietic stem cells for sickle cell anemia; another two will use gene transfer to stem cells for treating brain malignancies; another RNAi for HIV. All this is only further evidence that the field of stem cells is devouring gene transfer. Other projects are aimed more at getting "stem cells out of the clinic" by using small molecules or monoclonal antibodies to destroy stem cells causing malignancies.

Second is the sweeping ambition. As it stands today, only one clinical trial involving embryonic stem cell-derived tissues has been initiated. The projects funded under these awards are "explicitly expected to result in a filing with the FDA to begin a clinical trial." Given that these projects are funded for four years, CIRM seems to be banking on the prospect of at least a few of these initiating phase 1 trials within five years. Four of these proposals involve goals of implanting embryo-derived tissues, and two of these involve non-lethal conditions–macular degeneration and type I diabetes (technically, other awarded projects involve nonlethal, though extremely morbid conditions). Another involves implantation of embryo-derived tissues for Amyotrophic Lateral Sclerosis. It will be interesting to see how many of these meet their translational objectives, and how investigators will navigate the ethical, regulatory, and social complexity of initiating clinical testing. (photo credit: Michael Ransburg, 2008)

Sunday, November 1, 2009

The Need for Speed: GAO Reports on Accelerated Approval

Several blog posts ago, I wrote about the policy of accelerated approval (briefly, a mechanism whereby new drugs can be approved for sale by the FDA before definitive evidence of efficacy and safety are available). In that post, I reported on a recent paper where the authors claimed that, all things considered, accelerated approval enabled patients to get quicker access to life saving drugs without major adverse impacts on patient safety.

Last week, the Government Accounting Office issued a report on the subject that took a less favorable view of the program. Rules require that companies receiving accelerated approval for new drugs complete post-marketing studies confirming their efficacy. The GAO investigated the frequency with which companies fail to submit post-marketing trial data. They found that over a third of FDA-required post-marketing studies aimed at confirming efficacy had not yet been completed. Many of these studies might be incomplete because accelerated approval was only recently granted, and it can take as long as five years to complete requested studies. Disturbingly, however, the report found that a quarter of these studies had been incomplete for over five years; other studies have been completed but not yet reviewed by the agency. The figures are worse for other types of post-marketing studies requested by the agency.

The "poster boy" drug singled out in the GAO report is the hypertension drug Proamatine, which earned Shire Pharmaceuticals $257M since it was approved under accelerated approval 13 years ago. Apparently, the drug has not been subject to adequate confirmatory testing in all this time, though FDA has issued warning letters to the company over its promotion practices.

The report saves its criticism for the FDA, which it says has not reviewed sponsors' submissions in a timely manner, does not adequately monitor progress of post-marketing studies, and has neither specified conditions under which it would exercise its authority to withdraw drugs from market, nor has it ever exercised its authority to do so. But isn't some criticism also warranted for companies exploiting FDA's deficiencies? (photo credit: lindsay kay photography 2009)