I have a couple of thoughts to add here...first, I don’t know what role the FDA plays in the use of sham surgery in these trials (require? suggest?) but I think it's important to tease some of these basic issues apart regardless--some issues are about sham surgery as a tool for determining efficacy and some issues are around the ethics of sham surgery.

Starting with the value as a tool for interpretation....In phase I trials, where the goal is simply (and importantly) to ascertain human safety of a treatment you would not see a placebo group and therefore sham surgery is irrelevant. In the Ceregene phase I for instance, there was no placebo group.

In phase II trials, where the goal is continued safety monitoring as well as hints of efficacy, you might expect to see the double blind, placebo controlled trial design. Given the strong positive responses we often see for many phase I trials in PD there is great weight given to structuring trials in ways where one can observe true treatment effect. So the important question is how do you accomplish the “blind” in a delivery strategy such as gene therapy. Although there is probably no perfect way to completely guarantee a blind to the study, most stakeholders (sponsor, trial sites, IRB’s and patients through informed consent) settle on the sham surgery as the best way to test this type of treatment. Also, the trial sponsor itself (typically a company) needs to get the most informative read-out possible as it contemplates taking the treatment to the next experimental phase. If there wasn’t a sham option at phase II and potentially robust placebo responses persisted, the company might naturally (and ill-advisedly) continue on to phase III… At phase III, more patients are exposed to the treatment (again, in this case, a high-risk surgery is involved) and the costs are significant as the study population is expanded.

Jean’s question seems to merge two questions…if the treated patients react so obviously different to the untreated participants then one would expect that the blind would be useless and we’d see no placebo effect. In the case of Ceregene, if in fact the treated and untreated had any different responses, it didn’t negate the placebo since a statistically significant improvement was measured in both groups...ie, no hat was tipped.

The ethics of sham surgery can be viewed many ways I’m sure and is likely (as almost anything in the ethics field) a matter of personal interpretation. For instance, where a high-risk surgery is undertaken, neurologists commonly state that they won't consider prescribing such a treatment without evidence from a controlled clinical trial that it is efficacious (which includes beating placebo). In their mind it is unethical to subject a large patient population to such a risky procedure without evidence that it works and the benefits of treatment outweigh the risks and are measurably better the existing, alternative treatment options. I guess in a sense, they weigh the consideration of a few who, with informed consent participate in these trials (and are possibly subjected to sham surgery) versus the consideration of later inappropriately making the treatment available to much larger numbers.

Not sure I’m clarifying much but trying to bring additional perspectives to the discussion.

Debi Brooks