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)

Sell Therapy, European Style

Two side-by-side news reports in the August 21 issue of Nature spell more trouble for cell therapy in Europe. The first story follows on previous reports about Austrian urologist Hannes Strasser (see postings on Jul 23 and May 27, 2008). According to an Austrian government report, Strasser "failed to get appropriate approval for the trial from authorities... failed to adequately inform patients... [and used] poor study design." Strasser's university has banned him from seeing patients. Somewhat cryptically, the article mentions that "several of the hundreds of patients who have undergone the procedure by Strasser's team... claim that they have had serious side effects."  Are these attributable to the intervention?  We shall see.

About 600 kilometers to the Southeast, a Bulgarian deputy minister resigned after the European Union shut down a Sophia-based clinic that provides non-validated bone marrow therapy treatments for victims of spinal-cord trauma, stroke, and neurodegenerative diseases.  The minister reportedly has family members who "own two private companies" that perform the procedures. (photocredit: Eesti, Central Hali Market in Sophia, 2005)

Seeding Trials: Misled in Translation?

Translational research- defined as research aimed at bringing discoveries in the basic sciences into clinical practice, is often divided into two types: T1 and T2. This blog is almost entirely focused on the former, which involves testing laboratory discoveries in human beings. 

Often lost in the glitter of T1, however, is the nettlesome challenge of taking clinical findings and translating them into community practice. Such T2 research in many cases involves 'phase 4' studies: trials that test a drug that has already been licensed by regulatory authorities.

A few years ago, I organized a research ethics symposium at McGill on phase 1 and phase 4 studies, titled "Dirty Business?" because such studies are often perceived as the most ethically suspect (the former because of their risk-benefit balance, the latter because they are often drug promotion masquerading as science).

The current issue of Annals of Internal Medicine features an article "The ADVANTAGE Seeding Trial: A Review of Internal Documents" (August 19, 2008) where Kevin P. Hill and co-authors show that Merck ran and published the ADVANTAGE study primarily to promote Vioxx sales(gasp!)  rather than to answer a question about the drug's performance.

In an editorial accompanying the article, editors Drummond Rennie and Harold Sox condemn such "seeding trials" and offer a series of recommendations for ending this abuse of study volunteers and health care professionals. Specifically, they urge physicians and IRBs to "ask... about the study hypothesis and whether it addresses a settled question... they should look for clues [that it does]: such as a sttudy with an open label design, no control group, a very large projected enrollment relative to the importance of the question, a short-term study of a chronic disease, a study of an already approved drug...."

Rennie and Sox couch the ethical problem with seeding trials as one of risk– "few physicians would knowingly enroll their patients in a study that placed them at risk in order to provide a company with a marketing advantage." But in my opinion, IRBs are reasonably good at sniffing out risk and harm.  Where they underperform is in assessing value. In my experience, IRBs seem to take the attitude "if nobody is going to get hurt, what the heck?" Phase 4 studies are generally harmless– probably more so than typical medical practice. What is troubling about them is that they are often valueless and– in the case of seeding studies– deceptive as well. And current review procedures at IRBs, focused as they are on risks rather than ends, are ill equipped (and frankly unmotivated) to staunch such unethical conduct. (photo credit: nutmeg66 2007)

Fazing Phase 0?

Phase 0 studies are a new class of drug trials that involve delivering tiny doses of a new drug to human volunteers to study how the drug is distributed and metabolized in the human body.  Both FDA and its European counterpart, EMEA, have recently issued statements encouraging drug companies to consider 'phase 0' studies before going on to phase 1 trials.

I have written elsewhere (Journal of Law, Medicine, and Ethics, 2007) on the ethics of phase 0 studies, and a recent cluster of new articles on their ethics was published in the journal Clinical Cancer Research.  In general, I have tended to support such studies as a way of reducing risk and uncertainty in phase 1 studies.

But the August issue of Nature Medicine contains a small news report describing ongoing controversies about whether such studies accurately predict drug behavior at higher doses.  One company that is marketing itself as a supplier of equipment for phase 0 studies claims such studies are highly predictive, but according to the report, chemists and others question their validity, and fault the company for not releasing "specific criteria" they use to support their claim that phase 0 studies are predictive.

The upshot seems to be: 1- buyer beware on phase 0 studies, and 2- companies that pursue phase 0 studies should publish results (few probably do-- they contain sensitive proprietary information) so that policy makers and others can evaluate their value. (photo credit: e-chan photo of Kusama Yayoi artwork, 2008)

You are being (ethically) watched!

In the current issue of Bulletin of the World Health Organization, authors Margaret Carrel and Stuart Rennie describe ethical challenges presented by demographic and health surveillance activities performed in low-income countries ("Demographic and Health Surveillance: Longitudinal Ethical Considerations").  What's the link to translational research and gene transfer?

A number of issues identified in this article represent continuing challenges for fields like gene transfer, and this article offers analysis on these from an entirely different angle and context.

The most prominent example is the problem of distinguishing between research and care. Health surveillance activities inevitably identify health problems that demand intervention. But because surveillance sites are designed to provide information that will predict trends in similar, unmonitored sites, intervening risks diminishing the reliability of information about disease patterns. Some readers of this blog might be aware that I have argued that clear demarcations between research and care are impossible, and ethicists should abandon the project of trying to devise a dichotomous distinction (Hastings Center Report 2007). Health surveillance provides yet another example.

A second parallel is the issue of consent. The authors of this article ask whether new members of a household–children, for example–must provide consent for surveillance activities that their parents agreed to before they were born. This is analogous to issues encountered around germ cell interventions (intentional or otherwise) in gene transfer. Same is true for infertility treatment research.

Finally, a recent entry in this blog describes a paper Alex John London and I published on gene transfer trials in low and middle-income countries. The kinds of surveillance activities described in this article provide the types of information that research sponsors will need to make the case that an intervention they intend to test will be "responsive" to local health needs. Getting the ethics right for this "leg work" will be necessary for getting the ethics right for translational trials. (photo credit: Christian et Cie, 2008).