On gene therapy and informed consent
By Alan Milstein
January’s issue of Human Gene Therapy offers some intriguing commentary on the issue of informed consent in gene transfer trials. I became aware of the articles when a writer for TheScientist Blog called for my reaction to the Editorial by James Wilson, because I had represented the Gelsinger family after the death of their son in the experiment sponsored by Dr. Wilson and because I currently represent the family of Jolie Mohr, whose recent death renewed the debate over the informed consent process in this field of research.
My initial reaction reported by the caller reflects my surprise that Dr. Wilson would thrust himself into the debate when the informed consent process he used during his trial was so deficient.
In the Editorial, Wilson writes:‘I encourage the professional gene therapy societies and various related foundations to work together in the new year to undertake a critical review of the conduct of our clinical trials... it behooves us to get ahead of this issue and put in place more effective ways to assure that research subjects who courageously give of themselves can do so with a full and unbiased understanding of the risks and benefits of their participation.”
The Issue includes commentaries by Art Caplan and Jeffrey Kahn who both question whether subjects in such trials are ever able to understand the mechanism of gene transfer and the risks associated with this nascent technology. Both call for subject advocates to be included in the process so that the human subject has a representative who can understand the risks and benefits of participation and offer advice on whether participation is in his or her best interest. Kahn questions whether the name of the field itself, splattered through the pages of the informed consent documents, misrepresents gene transfer as a proven therapy when, of course, it is not. Caplan laments: “very little has changed in the past decade in the way informed consent is obtained from perspective subjects.”
Wilson makes no mention of the specific problems in the informed consent process in the Gelsinger experiment but some of the commentators imply they were primarily the inability of an 18 year old subject and his father to understand such complex research. While that certainly was the case, it ignores the failure of Wilson and his team to include in the document the monkey deaths that had occurred in the pre-clinical research, the prior adverse events involving other human subjects in the earlier cohorts, and the extent of the financial stake both Wilson and the University of Pennsylvania had in a successful outcome. These are issues the family could understand without a subject advocate.
What is most troubling is that Wilson has not written an explanation of what really went wrong in the Gelsinger research and what lessons should be learned. Such an article was supposed to be an express condition of the settlement of the claims brought by the government against Wilson and the University of Pennsylvania. At least this was the promise made by the United States Attorney to me and Mr. Gelsinger, a promise as yet still unfulfilled.
Alan C. Milstein is a nationally recognized litigator in the areas of insurance law, products liability, bioethics and clinical trials litigation.
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" it ignores the failure of Wilson and his team to include in the document the monkey deaths that had occurred in the pre-clinical research, the prior adverse events involving other human subjects in the earlier cohorts"
Hi Alan,
As a litigator you're responsible for redress after the problem occurs but this is an awareness issue before the fact also - if a young person and their parent can't understand what's involved, more explanation won't help. At some point it becomes so simplified as to be meaningless.
If anyone kept presenting more negatives in a "are you really, really sure you still want to do this?" tone, no medicine would ever get done?
So what is the solution? How much constitutes informed consent?
- by Hank on Jan 29, 2008 at 11:42 AM | link
That is why subject advocates are necessary in gene therapy trials. But researchers also have to understand that if you can't get informed consent by being honest with the potential subjects, then you can't do the research. If you or I would not volunteer or would not volunteer our family members, then the poor or uneducated should not be the default position. If this stops or slows progress, that is the price for conducting ethical research.
- by Alan Milstein on Jan 29, 2008 at 7:04 PM | link
Some people wouldn't make the same decision you would make, though, even if they had the same understanding you do. Remember the case of Abraham Cherrix, who opted out of his chemo for Hodgkin's disease. The fact that he made a decision different than the one (some of) his doctors would have made for him didn't mean he didn't have valid reasons or know what he was doing.
People who have worked in a technical field for a long time tend to speak in jargon. I know I do. It expresses what we want to express, and our usual audiences understand us, so we don't necessarily realize when we do it. And lawyers tend to write legalese, and are used to it, so it's hard for them to drop out of that. We had some new regulations at work that we had to comply with. The corporate lawyer boiled them down for us in a one-page summary that read like pea soup. I found a Q&A on EPA's website that was clear and complete and explained exactly what we needed to do.
I think it's an extra skill besides knowing your stuff, to be able to explain it to someone not of your group. Not everyone can do it, no matter how smart or compassionate. Unfortunately, because the consent documents are legal documents, they are going to be written by and for lawyers. There has to be a way to break down the information so that a non-lawyer, non-doctor can get at what he needs to know, without simplifying to the point of meaninglessness. Actually, a Q&A really isn't a bad idea. The doctor or the patient advocate can come up with questions that the patient ought to be asking (like what happened to the animals in the animal trials) and then answer them. The list of questions should evolve over time to include questions patients ask that no one had thought of. The exercise of putting one together encourages the writer to look it the document from the patient's point of view rather than that of a future lawyer in a hypothetical lawsuit. (It occurs to me that you may already be doing this.)
- by Laura(southernxyl) on Jan 30, 2008 at 7:46 AM | link
I think the average 6-year old child can understand this technique is it is described in 'normal' language with a question and answer period. At the macro level it isn't that complicated, biology not n-dimensional physics.
- by emily on Jan 30, 2008 at 10:55 AM | link
To clear the air about what really happened, let me take you back nearly 9 years to the meeting we had with the principal investigator 3 months before Jesse's actual participation in the "gene theray" clinical trial. Understanding the information regarding the gene therapy that Jesse was to receive wasn't all that difficult for me, since I had extensive experience in science. The risks were fairly well spelled out. There was the possibility that he would have an immune response, that his liver could be seriously damaged, that a liver biopsy to be done a week after the vector infusion had the risk of serious side effects. When I questioned this investigator as to whether they had seen any ill effects, he stated that they had only had to deal with flu like symptoms. In further conversation, he remarked that the liver was a remarkable organ, the only organ in the body capable of regenerating itself. The risks were downplayed. There was no mention by the investigator or the consent form of any animals having died in the research.
A month later, a call from the expert on Jesse's disorder, another of the principal investigators, led us to believe that the most recent patient had benefited from the vector infusion. He stated that she showed a 50% improvement in her ability to excrete ammonia following the gene therapy. When I said, "Wow, this really works", he stated yes and that it would be for those for whom this therapy was designed, not kids like Jesse with mild otc, but newborns with the almost always fatal form. We totally dropped our guard and Jesse made arrangements to participate.
Three months ffter his death we discovered that there was never any efficacy, that the 50% improvement that the patient showed was not related, that the researchers had multiple toxicites at 1/10 the dose that Jesse received that were each a stop sign for the protocol (and the FDA knew of these), and that animals had died in the research. I had been very supportive of these men and their institution after his death, but with this new knowledge I was no long able to support them. Jesse had been doing very well (he was virtually normal except he had to take medication) on the standard drug therapy, and he only wanted to help those less fortunate than himself. You can not imagine how disillusioning it was to discover the lapses by the researchers and the government.
The financial conflicts of interest for both the sponsor (James Wilson) and the University were basically ignored by the University's Conflict of Interest Committee. This led to a blindness on the part of all parties to the dangers they were seeing. These were not bad men doing evil. They were men blinded by ambition and greed. They have told me that they could not have foreseen Jesse's death, yet their data was screaming at them to stop. We trusted a system that was untrustworthy, one that didn't even pay attention to its own stops. So we sued and settled within 6 weeks. The quickness of that should tell how badly the other side wanted this to go away.
The government in the form of the FDA criminal division and the Department of Justice did a 5 year investigation at the end of which they fined the institutions involved a combined total of a little over a million dollars. They decided not to press any criminal charges and slapped the docs on the wrist with retraining and supervision. Wilson was not allowed to be a sponsor for 5 years and could only be involved with one trail at a time as an investigator for a specified period. The other docs were permitted to go about their business. We didn't support the settlement... all we ever really wanted was an apology that wouldn't be granted. As part of the deal, Wilson was to write a paper on "Lessons Learned" with my family having space in the same journal for a say on how we felt. It is now 3 years after the settlement and no "Lesson's Learned" paper has been issued but he is editorialing on the issues surrounding what he did. Repeated efforts by my lawyer, Alan Milstein, and myself to get the DOJ to follow up have basically gone nowhere.
So, my son, doing the right thing, was killed by a sytem and people rife with conflicts of interest, and real justice has been found to be very lax. It's essentially business as usual. You may think that I am bitter, but I am not. My son gave me the best possible example on how to be. The system showed me what everything is really all about. Hopefully, given enough time they'll fix this, but I'm not holding my breath. Anyone considering joining a clinical trial needs to be aware that they are dealing with a system that is seriously flawed.
- by Paul Gelsinger on Jan 31, 2008 at 1:50 PM | link