Teaching Kills Blogging: Somewhat Recent Developments...

Dear Faithful Readers: Teaching has cut my blogging to a trickle, though the teaching has now begun to taper off. My silence is not for want of major developments in the last two months. Among a few highlights:

• Obama picks members for his Bioethics advisory panel: White house recently announced membership of its "Presidential Commission for the Study of Bioethical Issues." The group is smaller than past Presidential panels. Its membership is lean on working bioethicists (3 or 4 who clearly fit the classic definition-- all others scientists, clinicians, federal employees, university administrators, or a disease advocate).

• Health care reform (+ Translational Research) passes in the U.S.: Among the intriguing elements here is the relationship between reform and biomedical research. When Clinton proposed healthcare reform in the 1990s, there was much consternation in the research community that this would spell a retreat from investment in basic research. Indeed, failure to enact reform propelled a massive expansion of the NIH budget through the 1990s. This time around, healthcare reform has specifically integrated basic research. The law includes language creating a "Cures Acceleration Network" that would fund up to $15M/year in translational research (though the budget will depend on direct appropriation from Congress, and there is no certainty that it will be funded).

• Gene Patents Voided: Following an ACLU challenge, a U.S. District Court Judge threw out Myriad Genetics' patent on BRCA1 and BRCA2 (genes associated with hereditary breast cancer; the company markets a $3K per pop test for mutations in the genes) by ruling that the genes are "products of nature." Products of nature are not patentable, though products purified from nature (e.g. enzymes, wood chemicals, etc.) are. The logic behind the decisions is that genes are better thought of as information rather than as chemicals, and that information extracted from the natural entities does not have distinct properties in the way that chemicals do. If ever there were a demonstration of the power of metaphors; suffice it to say, biotechnology companies will appeal. (photo credit: aurelian s 2008)

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)

Mice- Three Different Ones: Towards More Robust Preclinical Experiments

One of the most exciting and intellectually compelling talks thus far at the American Society of Gene Therapy meeting was Pedro Lowenstein's.  A preclinical researcher who works on gene transfer approaches to brain malignancies (among other things), Lowenstein asked the question: why do so many gene transfer interventions that look promising in the laboratory fail during clinical testing? His answer: preclinical studies lack "robustness."

In short,  first-in-human trials are typically launched on the basis of a pivotal laboratory study showing statistically significant differences between treatment and control arms. In addition to decrying the "p-value" fetish- in which researchers, journal editors, and granting agencies view "statistical significance" as having magical qualities- Lowenstein also urged preclinical researchers to test the "nuances" and "robustness" of their systems before moving into human studies.

He provided numerous provocative examples where a single preclinical study showed very impressive, "significant" effects on treating cancer in mice. When the identical intervention was tried with seemingly small variations (e.g. different mouse strains used, different gene promotors tried, etc.), the "significant effects" vanished.  In short, Lowenstein's answer to the question of why so many human trials fail to recapitulate major effects seen in laboratory studies is: we aren't designing and reviewing preclinical studies properly. Anyone (is there one?) who has followed this blog knows: I completely agree. This is an ethical issue in scientific clothing. (photo credit: Rick Eh, 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)

Stems and Blossoms (part 2): Really Informed Consent

There is a strain within the clinical and bioethics community that takes a minimal view of informed consent: investigators are supposed to provide requisite information to volunteers; if research subjects fail to comprehend this information, pity for them. This view brings to mind a memorable exchange between Inspector Clouseau and a hotel clerk (Clouseau: "does your dog bite?" Clerk: "No."  Clouseau then extends a hand; the dog lunges at him.  "I thought you said your dog doesn't bite." Clerk: "Zat is not my dog.")

The ISSCR guidelines take a bold stand on informed consent. "Investigators involved in clinical research must carefully assess whether participants understand the essential aspects of the study."  The guidelines go on to state "ideally, the subject's comprehension of information should be assessed through a written test or an oral quiz during the time of obtaining consent." Once again, ISSCR shows vision here in going well beyond the legalistic conception of informed consent described above.

The ISSCR guidelines also urge researchers to:

• explain possible irreversibility of some toxicities

• describe the sources of stem cells

• inform patients that researchers "do not know whether they will work as hoped"

These laudable recommendations aside, I might have hoped for more guarded language about the therapeutic value of early phase studies. For one, the guidelines use mostly "therapeutic" language, for example, using the aspirational term "cell therapy" instead of the neutral term "cell transfer." Second, the third item above logically means that the probability of benefit is less than 100%; experience tells us, however, that when interventions are highly novel, major therapeutic benefits for early phase trials are very improbable. (photo credit: Helen K, Stems, 2008)

Stems and Blossoms (part 1): Justice

Shortly before I left for holiday, the International Society for Stem Cell Research (ISSCR) issued a policy paper, "Guidelines for the Clinical Translation of Stem Cells," outlining ethical and scientific considerations for researchers designing translational trials involving stem cells (whether stem cell derived, adult, or embryonic).

In my opinion, the document wins the award for most forward thinking and comprehensive statement on the ethics of a translational enterprise. It shows that the stem cell research leadership has closely studied mistakes made by translational researchers in other highly innovative fields.  But the guidelines do more than look backwards; they proactively contemplate fairness and justice considerations as well.  Here are a few justice-related excerpts:

On responsiveness: "The ISSCR strongly discourages conduct of trials in a foreign country solely to benefit patients in the home country of the sponsoring agency. The test therapy, if approved, should realistically be expected to become available to the population participating in the clinical trial through existing health systems or those developed on a permanent basis in connection with the trial."

On reasonable availability: "As far as possible, groups or individuals who participate in clinical stem cell research should be in a position to benefit from the results of this research."

On diversity: "Stem cell collections with genetically diverse sources of cell lines should be established"

On access and licensing: "Commercial companies, subject to their financial capability, should offer affordable therapeutic interventions to persons living in resource-poor countries who would otherwise be wholly excluded from benefiting from that stem cell-based therapy. Academic and other institutions that are licensing stem cell therapeutics and diagnostic inventions should incorporate this requirement in their intellectual property license"

On review: "Regulatory and oversight agencies (local, national, and international) must explicitly include the consideration of social justice principles into their evaluations."

On trial participation: "... the sponsor and principal investigator have an ethical responsibility to make good faith, reasonable efforts whenever possible to secure sufficient funding so that no person who meets eligibility criteria is prevented from being considered for enrollment because of his or her inability to cover the costs of the experimental treatment."

In upcoming posts, I will comment on other aspects of the ISSCR guidelines. (photo credit: Helen K, Stems, 2008)

From Bench to Ringside: The Presidential Debate

Last night, Obama and McCain confronted each other in the final Presidential debate. A flagging economy and two wars have left little room in the two campaigns for discussion of science, policy, and human research. Yet last night's debate touched on two themes: embryonic stem cell (hES) research, and biomedical research funding.

Obama accused McCain of opposing embryonic stem cell research. From what I can tell, McCain actually supported the use of embryonic tissue for research and opposed Bush's ban and vetoes. But the logic of McCain's attacks on Obama, of late, are that personal associations tell us something about who a person is and where they stand. And McCain pals around with embryo research opponents like his running mate.

Contrast the two candidates' statements on hES research from Sciencedebate 2008– a group that invited McCain and Obama to declare positions on various science policy issues. McCain stated "While I support federal funding for embryonic stem cell research, I believe clear lines should be drawn...."  The remainder of his response qualifies his support.  On his own website, McCain stops short of declaring support–or opposition– for hES research, and talks more about what he would oppose than what he would support.  Obama's support is more full-throated at Sciencedebate 2008: "As president, I will lift the current administration's ban on federal funding of research on embryonic stem cell lines... embryonic stem cells remain the 'gold standard,' and studies of all types of stem cells should continue in parallel for the foreseeable future."

Elsewhere at Sciencedebate 2008, Obama's campaign singled out gene transfer in a statement on genetics: "As a result [of safety issues involving 'gene therapy'], the NIH established the Recombinant DNA Advisory Committee.... Until we are equipped to ascertain the safety of such methods, I will continue to support the activities and recommendations of the Recombinant DNA Advisory Committee." [Note: Harold Varmus chairs a science advisory committee for the Obama campaign. Varmus reorganized RAC when he was the director of the NIH under the Clinton administration]

What about research-- specifically translational research?  Just as they do for Joe the plumber, both candidates support NIH research. According to a report in Science ("Scientists Strive for a Seat at the Table of Each Campaign," Jeffrey Mervis, 26 Sept), Obama pledged to double the NIH budget in five years. Elsewhere, his campaign said 10 years. Maybe the latter figure is inflation adjusted? Obama's statement on Science and Innovation singles out "rapid translation of medical research."

I am not aware of any clear statements on translational research from McCain, though he favors greater funding for NIH, and based on his debate and website, he seems to have a soft spot for autism research. As on other issues, McCain is less willing to commit to a timetable on NIH budget doubling. (photo credit: Thomas Hawk, Wordle of McCain and Obama convention speeches, 2008)

The Long and Winding Road(map)

The research team led by John Ioannidis has, for my (evaporating) money, done some of the most interesting work looking at the "epidemiology" of translational research: how often are high profile genetic linkage studies refuted? (answer: usually); to what degree are translational studies biased? (answer: a lot); how often are major scientific findings translated into clinical applications? (answer: rarely).

Now, Ioannidis's teamm (led by Despina Contopoulos-Ioannidis) at University of Ioannina in Ioannina, Greece, has a new report in Science (September 5) looking at "The Life Cycle of Translational Research for Medical Interventions." Here is what they did.

First, they created a pool of important medical interventions, defining "importance" on the basis of 1000 or more citations in the scientific literature for any study that claims an intervention was effective between 1990 and 2004. From this, they identified 32 "important" interventions. Next, they looked at the lag in time between publication of the "1000 cited article" and various milestones in development: the first article suggesting the intervention was effective; the first article about human use; the first article describing the compound's isolation.

They found that the median lag between initial discovery of an intervention and publication of a highly cited article claiming efficacy was 24 years. They also found a much longer lag for interventions that, though claimed effective, were subsequently shown to be ineffective in other studies (e.g. Vitamin E for the prevention of heart disease).

The article is dense, as is probably my description of it. I worry that, by depending on a "1000 citation count," lots of important translational discoveries are excluded, making this study biased towards applications used against high profile or highly prevalent diseases.  In other words, their search strategy is likely to emphasize the high profile of specific diseases rather than the high profile of specific interventions. So, for example, many of the most important "successes" in translational research are excluded from their list.  Bone marrow transplantation didn't make the cut. Nor did any important monoclonal antibodies used in cancer.  Nor did recombinant protein products. Nor did any gene tests.

The authors conclude by saying that 1- don't expect major new medical uses from drugs that have been sitting around for a long time; 2- translation tends to be faster when research involves multidisciplinary collaboration involving basic and clinical researchers. I expect we'll see more elaboration from this team on the latter point in the years to come (photo credit: romeo66, 2008).