Inflation, Health Care Reform, and Translational Research

"It's Health Care Costs, Stupid."  So says Ezekiel Emanuel, paraphasing James Carville, in a Feb 29, 2008 commentary in JAMA.  Emanuel argues that expanding health care coverage to the uninsured will be impossible and unsustainable unless the health care system gets a handle on cost inflation.

What does this have to do with translational research?  A lot.  Most economists agree that new technologies are one of the largest drivers of health care cost inflation. Though unmentioned in Emanuel's piece, any attempt to rein in cost inflation will need to address incentive structures in biomedical innovation. This would have major implications for translational research (for example, cost controls would adversely affect the ability of biotechnology firms to raise capital).  (photocredit: Sister72, 2006)

Masks and Random Thoughts on Preclinical Research Validity

Epidemiologists and biostatisticians have evolved numerous ways of reducing bias in clinical trials. Randomization of patients, and masking them to their treatment allocation are two. Another is masking clinicians who assess their outcomes.

Why are these simple measures so rarely used in preclinical animal studies? And do animal studies show exaggerated effects as a consequence of poor methodology?

The March 2008 issue of Stroke reports a "meta-meta-analysis" of 13 studies comprising over fifteen thousand animals. Perhaps surprisingly, the study did not show a relationship between the use of randomization or masked outcome assessment and the size of treatment effect. It did, however, show a positive relationship between size of treatment effect and failure to mask investigators during treatment allocation.

This is probably the largest analysis of its kind. It isn't perfect: publication bias is very likely to skew the analysis. For example, size of treatment effect is likely to strongly influence whether a study gets published. If so, effects of methodological bias could be obscured; preclinical researchers might simply be stuffing their methodologically rigorous studies in their filing cabinets because no effect was observed.

The conclusion I draw? Preclinical researchers should randomize and mask anyway.  There is some evidence it matters. Moreover, the logical rationale is overwhelming, and the inconvenience for investigators seems more than manageable. (photocredit: Chiara Marra 2007)

siRNA: Caveat Emptor for Preclinical Studies?

Small interfering RNA molecules (siRNA) are generating a lot of excitement in biomedical research for their ability to "knock down" specific genes– say, those of an invading virus or a tumor cell.

But because viruses tend to produce small pieces of RNA, the body often "interprets" siRNA as a viral infection and launches an immune response.  In the Februrary 2008 issue of Human Gene Therapy, Adam Judge and Ian Maclachlan of Protiva Biotherapeutics describe some of the consequences of this.  A major one is that studies testing siRNA in animals or humans might be prone to false positives, especially for medical conditions where the immune system is implicated in disease control.  The problem is (according to these authors, at least), there seems to be little consensus about how to design experimental controls to sift true from spurious claims of specific efficacy.  Yet another complication in the interpretation of preclinical studies, as well as the decision to initiate human testing.

Still Life with Duchenne Muscular Dystrophy

In the February 20th edition of the New York Times, Reed Abelson reports a "New Tack on a Muscle Disease."  The "new tack" is, in fact, a scaling back of ambition in muscular dystrophy (MD) research.  Since identification of various genetic mutations that cause muscular dystrophies, gene transfer has been a logical goal.  But because the gene is so large, and delivery to all of a patient's muscles so difficult to achieve, gene transfer against MD has presented a formidable challenge to researchers.

What is so striking about Abelson's article, in my view, is his suggestion that the ambition of a one-off cure has clouded recognition of interventions that extend life and improve its quality for MD patients.  Abelson writes "the lack of interest in the mundane has... slowed progress in knowing what available therapies are the most useful."

One researcher stated "for too long, I was stuck on [Duchenne] as the home run or nothing."  Though speculative, "home run" research deserves sanctuary in biomedical research, I regard a critical role for disease advocates, caregivers, and bioethicists to advocate on behalf of the quotidian needs of present day patients (and, I should add, gene transfer will likely play an important role in serving these quotidian needs). (photo credit: Evamol, "Still Life," 2007) 

Can You Keep A Secret?

People often enter drug studies in order to access a promising new drug.  But clinical trials take place over a set time period.  So is it ethical to withhold from prospective trial subjects preliminary data on safety or efficacy that have been gathered from initial volunteers?  In the Feb 1, 2008 issue of Journal of Clinical Oncology, Robert Wells argues it isn't.  Biostatistician Steven Piantadosi, in a rebuttal, argues that it is.

Wells argues (I paraphrase) that anything short of total transparency frustrates patient autonomy and breaches scientific and clinical duties.  Piantadosi offers two counter-arguments:  first, there are no obligations to disclose uninterpretable data, and second, in research, clinical obligations for full disclosure do not "supercede" societal interests in safeguarding the integrity of data.

The debate revolves around the tension between clinical research (which is primarily aimed at serving society) and clinical care (aimed at serving individual patients).  Though I agree that the withholding of preliminary data should make us uncomfortable, total transparency in clinical research would necessitate abandoning well established practices– like blinding and placebo use– that maximize the reliability of knowledge gleaned from clinical trials.  The key to navigating the ethical tension lies in making sure volunteers recognize that trials are aimed primarily at serving society.  (photo credit: Kah Zanon, 2007)

Vector Calculus is Out: Nature Reviews—Genetics Article

As per usual when an article has moved into the post-galley stage, on Monday I woke to a string of friendly reprint requests mainly from Eastern European researches lacking good library facilities.  I guess that means my review on the ethics of gene transfer has been published in Nature Reviews—Genetics.  In it (the editors rejected my preferred title, "Vector Calculus"), I argue that despite numerous advances, researchers and policy makers continue to confront unresolved ethical and policy issues around gene transfer— among them a series of questions about research ethics, licensure of novel interventions, enhancement of human traits, and genetic modification of tissues that will be passed to progeny.  I hope the review does justice to the complexity of the field, as well as the ethical issues associated with it. (photo credit: Nature Publishing Co.)

Probiotics take a knock in the gut?

Probiotic therapies involve the use of living microorganisms to treat or prevent disease.  A number of creative applications are being developed for treatment of colitis, prevention of dental caries, and control of infectious disease.  Some of these applications are likely to involve genetically modified strains of bacteria. Look for more of these in the next decade.

Yet as with gene transfer, active (that is, living) pharmaceuticals might pack surprises.  A news item from the Feb 1, 2008 issue of Science provides one possible example.  In a placebo-controlled trial testing a cocktail of different bacteria for the prevention of infection in patients with acute pancreatitis, death rates were significantly elevated in the probiotic group.  One explanation, of course, is that the results are a statistical fluke.  A less comforting possibility, however, is that the bacteria mixture prompted an unexpected immune reaction. Stay tuned as scientists and investigators scope out what happened.  (photo credit: Rowett Research Institute scanning electron microscope image of Lactobacillus bacteria)

In Utero: Gene Transfer Nirvana?

The February 2008 issue of Molecular Therapy has an editorial by Charles Coutelle defending in utero gene transfer (that is, the application of gene transfer to fetuses).  Coutelle makes several attractive arguments in its favor.  Among them: that many parents opt against abortion after receiving  a prenatal diagnosis, and that in utero gene transfer would provide these parents with a therapeutic option.

What troubles me about this position is this:  1- what makes in utero gene transfer attractive–favorable "vector-to-cell" ratio, and the "presence of expanding and developing stem cell populations," is precisely what makes this procedure risky as well; 2- how often do parents opt against pre-implantation diagnosis, but then go on to seek prenatal pregnancy screening?  Specifically, does the frequency of the latter justify the risks of the former?

Why the Title “Lost in Translation?”

The title of this blog derives from that of my book on the ethics of human gene transfer research, which is contracted with Cambridge University Press.

As the title suggests, the translation of gene transfer into clinical application has not gone as smoothly as predicted.  The word "lost" is not intended to suggest incompetence, or blanket moral culpability on the part of gene transfer researchers, nor to disparage the field in particular.  My thesis is that nearly all parties to gene transfer research– ethicists, patient advocates, members of the public, news organizations, policy-makers, and researchers– have in a sense been lost in appreciating the distinctive ethical, policy, social, and scientific challenges in making gene transfer a reality.

There's another way in which the title is intended.  Many of the ethical frameworks and principles for evaluating human experiments were derived with randomized controlled trials in mind.  These concepts often apply awkwardly to the setting of the highly technical first-in-human experiment. In a sense then, the research ethics has been lost in translating approaches from the controlled clinical trial to the exploratory, early phase human study.

The Scope of this Blog

Though my primary focus is on gene transfer, I will occasionally wander into other areas of translational pharmaceutical research, including cell transfer (also sometimes called "cell therapy"), monoclonal antibodies, small-molecule drugs that target novel biological mechanisms, or large-molecule drugs.

These types of translational clinical research raise a similar cluster of issues-- namely, high degrees of uncertainty, risk, scientific complexity, desperately ill volunteers, ambitious investigators, financial interests, and complicated intellectual property issues.

Why not call it Gene Therapy?

What I term "gene transfer" is often also called "gene therapy."  I prefer the former, which is based less on aspiration than fact.  That is, therapy implies validation for efficacy.  There are, at best, only two examples of gene transfer interventions where efficacy seems well established.  Use of the term "gene therapy" potentially misleads members of the public— and even experts not steeped in the gene transfer literature—into thinking that interventions are in advanced stages of development.

I realize "gene transfer" presents some grammatical problems (as in: "the patient received gene transfer for her disease" sounds awkward).  I'm afraid this is a compromise we'll have to live with.  In general, I tend to prefer using "gene transfer" as an adjective—say, the way people use "thrombolytic" to modify "drug."  I note that it is not uncommon within medicine for adjectival terms to graduate to noun status (e.g. anxiolytic).

What is Gene Transfer?

In this blog, I define gene transfer as the use of genetic materials or genetically modified organisms for therapeutic or research purposes.  This is a much broader definition than typical.  For instance, the American Society of Gene Therapy defines gene therapy as "...an approach to treating disease by either modifying the expressions of an individual's genes or correction of abnormal genes."  My definition would include gene-marking protocols (whereby a patient's cells are genetically modified not for therapeutic purposes, but instead so that researchers can track their growth or location in the body).  My definition also includes the administration of genetically modified organisms-- like genetically modified gut flora—for therapeutic purposes.  My definition also includes vaccines made by genetically modifying viruses; several of these are presently being tested against cancer and HIV.

Introduction to Lost in Translation

Within the past six months, a fifth patient developed a lympho-proliferative disorder in an X-SCID gene transfer trial.  The RAC has all but cleared AAV vector as a causal agent in the death of Jolee Mohr in a rheumatoid arthritis study.  A Merck HIV-vaccine trial involving adenoviral vectors was terminated after a data safety monitoring board found that volunteers receiving placebo had lower rates of sero-conversion.

I created this blog to establish a forum to report and comment on developments in gene transfer—and other areas of translational clinical research— that raise interesting or important ethical questions.  The first several posts will contain some introductory material that provides definitions and describes the scope of this blog.