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).