Below, Susan Dentzer talks with her about suggestions that researchers at the University of Pennsylvania may have violated protocols for their gene therapy trial and the FDA's role.
Q. Let's talk about a little bit more specifically about the University of Pennsylvania case, the hospital university has now said in effect they do believe that the young man in question died of the gene therapy. Does this make things any different from the standpoint of the FDA? Is this going to cause anything to happen differently from here on out?
A. In many experimental medicines, there are deaths, and there are deaths related to products at time. It is our job then to determine what are the circumstances surrounding those deaths, the relatedness to the therapy itself, and how can that be prevented from happening again. And right now we are doing an extensive investigation of the whole conditions and situations surrounding the University of Pennsylvania case, and preliminary evidence suggests that there were protocol deviations with respect to patient inclusion as well as stopping rules, and we are right now doing a thorough investigation of what's going on.
Q. So the investigation suggests protocol deviations. What were those?
A. As I said, the protocol deviations, at least two of them relate to entering a patient that did not have the entry criteria designated in the clinical research plan, and secondly, not stopping the treatment of patients based on the stopping rules that were agreed to in the original protocol.
Q. Does it appear that those played a role in the death of Jesse, or did these involve other patients?
A. This would be particular at this point in time to this young man, but we are currently doing an extensive investigation to see how this looks with respect to the protocols underway.
Q. So let's just go back over this a little bit more.
So it appears that Jesse should not have been in this trial, or should not have had the particular dosage level of the adno-virus used on him. What is the fact as it appears to the FDA?
A. As it appears right now from a more preliminary investigation is he should have not been eligible to enter that particular clinical plan.
Q. and the reason being?
A. He had certain chemistry tests which did not meet the criteria of the trial.
Q. And those chemistry tests revealed -
A. They revealed - in order to participate in the trial. There are certain aspects which are called patient inclusion criteria, and then there's certain parameters called patient exclusion criteria. And if you don't meet the inclusion criteria, or if you have a finding that would put you out of the realm of being included in the trial, then that patient should not be in the trial.
Q. Just to flush this out, did he have blood tests that showed something that would have excluded him?
Q. What was it specifically?
A. Ammonia levels in his blood.
Q. Which would have suggested that his liver was not functioning adequately?
A. At this point that would be one interpretation.
Q. That possibly his liver was not functioning adequately to make it appropriate for him to receive this therapy.
A. Enter the trial.
Q. Is there an indication that the investigators were aware of this?
A. At this point in time I would probably not comment until the investigation is complete.
Q. so at least one set of evidence seemed to suggest that this young man should not have been in the trial in the first place. That's the protocol deviations you were talking about.
Q. And the secondary you said that appears to be the case.
A. By the stopping rules.
Q. and in fact -
A. The stopping rules relate to when a particular level of toxicity is observed in patients, that the investigators are to stop the trial, call the FDA, discuss those particular circumstances with the FDA, and either not enter any other patients, or have a very good explanation of why they believe they are okay to enter additional patients. And there are some conditions surrounding this which it appears from our preliminary evaluation that the agreed upon protocol stopping rules were not followed by the investigators.
Q. And this is because some particular level of toxicity was observed in Jesse himself?
A. Well, in other patients.
Q. In other patients. Not necessarily Jesse.
A. that's correct.
Q. What was observed?
A. I think until the study is thoroughly investigated, I would like to defer any comments at this point, and we will - once everything is fully investigated, make that available.
Q. but the evidence appears to suggest that as far as other patients were concerned in the same trial, and my understanding if I'm not mistaken, the number was about 18, that there were other patients who had levels of toxicity such that the investigators should stop the trial altogether, or pull those patients out of the trial.
A. Well, at a point where the original stopping rules were, they should have stopped the trial. They should have either contacted the FDA and explained why they thought they should have continued, or they should just not have entered any additional patients.
Q. So one or the other should have taken place.
Q. And that was before Jesse?
Q. Given that that's the case, what do you all believe happened here? What is your impression of why the stopping rules were potentially violated, why the toxicity levels were not given adequate attention, etc.
A. Right now, until a complete investigation is done, I think it's premature to comment on that.
Q. Does this appear to be a unique situation? Does this appear to have been the case with this one particular trial, but not necessarily the case with other trials, or do you have reason now to be concerned that other trials could be similarly affected?
A. I believe right now, based on what we observed, this is something unique to this particular case, and we will take extra caution to make sure that we're looking carefully at all the protocols and the execution of those protocols.
Q. Let's talk a bit about the area you mentioned, adverse effects. What is supposed to happen when an adverse effect occurs in a trial?
A. When an adverse effect occurs in a trial, if it is serious and unexpected, they are to report it to the FDA within 15 days. If the adverse event is fatal or life threatening, they are to report it as soon as possible, but no later than seven days.
Q. So if in fact a patient is injured, or a discernible injury or death has occurred, basically they should get on the phone with the FDA.
A. That's correct, absolutely. Absolutely.
Q. Within seven days. And what is the other area which could happen that could give them up to 15 days.
A. Serious events or things where it might be the patient is required to go into the hospital and have medical care, or they have some reaction, or some new additional information is obtained with regard to the laboratory testing on a patient that causes a concern about their ability to tolerate the therapy.