Wednesday, October 28, 2009

Remembrance of Things Past: Fetal Tissue Transplantation and Parkinson's Disease

In a recent article in Science magazine, Constance Holden reports that European researchers are contemplating a revival of fetal tissue transplantation for the treatment of Parkinson’s disease. As the article recounts, fetal transplants were subjected to sham controlled studies in the late 1990s; none performed better than sham, and several caused disabling dyskinesias. So should fetal tissue transplantation be revived, and if so, how?

The challenges seem all the more formidable today. We now understand that Parkinson’s disease is not restricted to the dopaminergic neurons in the basal ganglia, but instead involves diffuse pathology. And yet, studies will not involve implantation of tissues throughout the brain. As Holden’s article points out, previous fetal transplant studies revealed that brain pathology spreads to implanted tissues, suggesting that permanent responses may be difficult to achieve.

The ethical issues seem just as daunting. Deep brain stimulation has greatly improved the management of Parkinson’s for patients who are no longer responding to dopamine replacement. And yet, those pursuing fetal tissue transplantation will likely advocate pursuing trials in younger patients with less advanced disease. As pointed out by a European team of researchers, "A significant effort of bioethical research and conceptual clarification is required in anticipation of the first protocols involving human subjects." And in a recently published article in Movement Disorders, several coauthors and I outline various ethical challenges presented by such studies. These include a high degree of uncertainty about the safety of interventions, and a baseline risk associated with delivery that approaches levels of risk encountered in phase 1 cancer trials (for studies that involve eight inoculations to the brain, risk of intracerebral brain hemorrhage leading to permanent neurological deficits is on the order of 2%).

Advocates of the new wave of studies insist we know much more about the properties of fetal tissues than we did in the 1990s; they further note that such studies will provide a basis for later studies involving induced pluripotent stem cells and other tissues. Perhaps, but given the remaining uncertainties and promise of DBS, it’s hard to imagine how fetal graft experiments could credibly establish a claim of clinical equipoise with deep brain stimulation. For these reasons, a more prudent ethical course—if fetal transplant studies for Parkinson's are to be done at all—would be to pursue safety and feasibility studies in patients who are no longer responsive to standard care. Only once parameters are optimized and mechanisms well understood should clinicians consider studies in patients who are earlier in the disease process. (photo credit: Ethan Hein 2008)

Monday, October 26, 2009

Disclosure in Phase 1 Cancer Trials

Followers of this blog may recall my continuing concern with the way informed consent is obtained in phase 1 trials involving patient-volunteers (typically, these patients have exhausted standard care options and enter phase 1 trials as a final shot at managing their disease). Language used by investigators in these studies is often suggestive of therapeutic benefit, even though meta-analyses of phase 1 studies show that chances of major clinical benefit in phase 1 studies are exceedingly low. In previous posts, I described my own experience with an ethics review committee that actually defended giving patients vague and almost meaningless information about the therapeutic benefits of phase 1 trial participation. Meantime, evidence from surveys indicate that phase 1 cancer patient-volunteers tend to overestimate the probability of therapeutic benefit.

In the July-August 2009 edition of the ethics journal IRB, Shlomo Koyfman and co-authors at NIH offer up a "Consent Form Template for Phase I Oncology Trials." Their recommendations are comprehensive and excellent. Among the items they recommend are:

• use of more therapeutically neutral language, like "research agent" instead of "therapy"

• disclosure of dose escalation design; in particular, the authors recommend that patients be informed about risks and benefits relative to the cohort they are entering.

• a statement (where appropriate) that patient-volunteers will not have the option of adjusting their dose assignment in the study

• a statement that "the chances that this agent will... allow you to live longer [is] very low."

One can quibble with various particulars (I think, for example, discussion of subtherapeutic dosing should be more explicit). But on the whole, these recommendations provide an excellent standard– along with NIH Guidance on Informed Consent for Gene Transfer Research– against which typical phase 1 cancer study consent forms should be measured. (photo credit: banlon1964)