The Octopus of Reference Standards

When gene transfer researchers perform an experiment, how do they measure the dose of their vectors?  For that matter, when investigators perform a study using any novel biologic, how have they characterized their agents?

Few would think the questions are ethically significant. But consider the fact that research teams often use different techniques to determine vector dosage, and as a consequence, results from different human and animal studies cannot be compared with each other.

In the July issue of Molecular Therapy, Richard Snyder and Philippe Moullier outline international efforts to estabish reference standards for AAV vectors (a class of viral vectors widely used in gene transfer studies). After about six years (and nearly twice that of trials using human beings), reference standards for two serotypes (AAV2 and AAV8) will soon be available. The authors describe a number of logistic and funding problems for establishing reference standards. Not mentioned are the numerous sociological challenges with herding feline-like researchers.

In my book, I argue that standards represent a critical vehicle for risk management in novel research arenas: small-scale human safety studies have limited value unless results can be linked up with other human studies to identify trends. Standard setting, and the octopus–like extension of standards into all preclinical and clinical studies–thus have important ethical implications. IRBs reviewing early phase novel agent protocols should be on the alert where study agents are not characterized using reference standards (photo credit: Roadsidepictures, 2007)

NOTES from the Underground

Surgical innovation has always been a problem for medical ethics.  Surgeries are unregulated, and partly as a result, few are introduced to clinical practice having been validated in randomized controlled trials. Moreover, attempts at novel surgeries typically fly beneath the radar of ethical review, because they are viewed as innovative clinical practice rather than research. There are some good–and not so good– reasons for such "surgical exceptionalism."

On Sunday, the Washington Post ran a story ("Scarless Surgery Uses Body's Own Openings," Rob Stein, Sept 21) on a new type of surgery, Natural Orifice Transluminal Endoscopy (NOTES), which avoids skin incisions by accessing organs through the mouth, anus, or vagina. Various teams are testing and/or using NOTES to remove gall bladder stones, to perform appendectomies and cholecystectomies, and to collect tumor tissue for cancer staging.

NOTES has the potential to reduce pain and scarring, and to hasten recovery. But the technique still requires validation in animal models. One major concern is infection: NOTES requires incisions through flora-rich environments like the rectum, stomach, or vagina.

Several U.S. and European medical societies have established initiatives aimed at guiding development of this technique. One example is NOSCAR (www.noscar.org), which maintains an outcome registry and identifies unmet research needs. The group also urges surgeons to seek independent ethics review before attempting NOTES in humans.

However, many first tries at NOTES have been performed outside traditional centers of medical innovation. For instance, the first team to perform a NOTES appendectomy is based in Hyderabad, India; several surgical teams in Brazil are also publishing a disproportionately large volume of human case reports (the prominence of Latin America and Asia is briefly NOTEd in the Washington Post story). One searches far and wide for any commentary on this phenomenon. Why are Brazil and India at the vanguard of surgical innovation? Is this simply one manifestation of the knowledge economy moving overseas? Or does it have something to do with laxer regulations and safety standards? Are there characteristics of NOTES that make it particularly attractive for surgeons working in resource-limited circumstances? (photo credit: photosan0, Pink Floyd album, 2006)

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).

In the Dark?

Most cancer patients who enter phase 1 clinical trials are motivated by the prospect of controlling their cancer. Increasingly, however, such studies, in the words of one ethicist, "take without giving in return" by involving biopsy procedures in which tissue is collected before and during the study in order to gauge whether a new drug is having intended biological effects. Such procedures are potentially burdensome, and offer no direct benefits for patients.

So is it ethical for clinical investigators to "stick it to" their research subjects? Depends in part on the level of risk. In the August 20, 2008 issue of Journal of Clinical Oncology, Aaron P. Brown and coworkers at NIH performed a literature review examining the complication rate for research biopsies in the context of studies involving radiotherapy ("Performing Nondiagnostic Research Biopsies in Irradiated Tissue: A Review of Scientific, Clinical, and Ethical Considerations"). One might expect to find higher than usual complication rates in this context, because irradiation can interfere with wound healing.

Here is what they found. Of 29 eligible studies, only 3 (!!) actively evaluated adverse events related to biopsy (another 16 reported adverse events– but not specifically related to biopsy) These 3 studies reported a total of 17 adverse events.

Here is what the authors concluded: "Limited data suggest that biopsies can be performed in irradiated tissues without clinically significant excess risk."

The authors sagely argue that "all clinical trials that perform biopsies in combination with other therapies should actively study and report complications." But with their specific study question- the complication rate of tissue biopsies- so underexposed, the their conclusions are dodgy. (photo credit: Moominsean 2006)

A Thick Frosting of Science...

On September 2, the Washington Post ran a story ("Injections of Hope: Doctors Promote Offshore Stem Cell Shots, but Some Patients Cry Foul") on an emerging global economy of stem cell medical tourism. It described how patients with conditions ranging from ALS to spinal cord injury travel to offshore clinics to receive unvalidated cell "therapies"–embryonic or otherwise– for $15-50K; less if they bring in new customers.

The article portrays many of the doctors performing these procedures as well outside the mainstream. Many are. But a closer inspection shows many of the scientists and physicians associated with these outfits are having their cake of staying in the mainstream of scientific practice, while getting to eat the fees provided by desperately ill patients.

One example I encountered in my research is Thailand based Vescell, which claims to provide "a revolutionary new treatment for heart disease that actually rebuilds heart tissue using the patient's own stem cells." Their web site is a rich trove of moving patient testimonials. These treatments are not approved in the U.S. or Europe, and using them would be considered a flagrant breach of medical ethics outside of clinical trials. Who is on the scientific advisory board of this company? Nobel Laureat Aaron Ciechenover, and University of Toronto-based Ren-Ke Li. Who holds the patent on Vescell's procedures? The Toronto-headquartered biotechnology company, Theravitae. Surely, policy-makers and fellow researchers can do much more to police these medical confectioners. (photocredit: mityrina 2007)