Risky business
It's not the technology of gene therapy but the regulation of clinical trials that we should be most afraid of, says Apoorva Mandavilli.
Almost exactly seven years after the first death in a gene-therapy trial, another unexpected death hit the field late last month - followed quickly by panic, outrage and some calls for an end to gene therapy altogether.
But to blame and ban all gene therapy because of this would be rash and misguided. And it might risk missing the point. What we should be most outraged and scared by is the way this trial took place — and the similar mis-steps that seem to accompany a vast number of clinical trials, gene therapy or no gene therapy.
Comments
Compliments on such a clearly written article!
There are two points that I have some differences with, however.
As I had commented in my blog, there is no FDA requirement that a patient take a consent form home and review it. That is also an impossibility on many trials dealing with acutely ill patients, for example. Nor is there any requirement that the investigator not present the consent form to the volunteer. In fact, some times there is no one else capable of explaining the trial in detail and answering the volunteers questions. To avoid this type of question regarding the adequacy of consent, I try to have family members present when I review the consent, so I can address their concerns as well, and also try to include an impartial witness.
It sounds as though the consent form for this trial was inappropriately technical. Consents are generally pitched at an 8th grade level. Obviously, this is harder to do with a sophisticated gene therapy trial, but should be the goal.
It is disturbing and unusual to have an early phase trial include patients who are on multiple medications likely to cause serious side effects. The decision to allow this is now shielded from public review; there must be transparency, public review and accountability of the approval process.
I hope that there will be a thorough, thoughtful and very public review of this and other gene therapy trials, in particular.
However, articles in the popular press, such as the one in the Washington Post, often seem to dwell on the costs of clinical trials, and to ignore the benefits those trials have brought. Before the development of antibiotics, for example, an infection was often a death sentence, most cancers were considered incurable, and there was no way to control the disastrous effects of diabetes, heart arrhythmias, and many other common illnesses. While clinical trials are not perfect, and do sometimes injure those they are supposed to help, we have come a long way in the past 50 years, in terms of our abilities to develop useful interventions while providing reasonable protection to study participants. Every medicine goes through this sort of trial process. We need new medicines for serious diseases, such as infections, urgently.
Protections need to be in place, but they should not incapacitate research nor scare volunteers unnecessarily. Since many of the issues here revolve around potential conflicts of interest, the first step would be greater transparency, public discussion, and debate.
Judy Stone, MD
jstone@conductingclinicalresearch.com
Author of Conducting Clinical Research:
A Practical Guide for Physicians, Nurses, Study Coordinators, and Investigators
www.conductingclinicalresearch.com
Posted by: Judy Stone, MD | August 22, 2007 02:18 PM
Dear Apoorva
I would like to make a few points related to the article above. The first is related to the informed consent process. There are always inherent problems with consent forms. They are long as to be inclusive of all the pertinent information. Although the attempt is to make them simple (about an 8th grade level is the target), it is sometimes hard to provide information to a patient where there may still be some scientific uncertainty and even mixed results in the literature, in such a way that an individual can truly understand the debate. Since the experts might disagree on specific details, how can we expect the patients who are not experts to fully appreciate all these different parameters? Nonetheless, we as the experts do have a responsibility to explain the information to patients in the best possible and impartial manner so that true consent can be given. Clearly the informed consent process is a topic that crosses all medical trials and perhaps is better addressed by others. In general and as a whole, the gene therapy community has been diligent in making sure such consent forms are inclusive. I know at our institution they are updated on a regular basis as needed when new information becomes available.
The second point is related to conflict-of-interest. In the post J. Gelsinger era, there have been pretty good guidelines put forward to avoid financial conflict-of-interest, and the gene therapy community as a whole, to the best of my knowledge has followed these very well.
The third point is related to the stated cause of death. The implication in the article was that the cause of death was similar to that of J.Gelsinger who had participated in an adenovirus trial and died of "multi-organ failure". First to make it clear the two vectors, adenoviral and adeno associated viral vectors are not the same. The toxicity profiles when compared are very different. The viruses they were derived from while having some similarities in their name are very different and do not even belong to the same family. To the best of my knowledge an official cause of death has not been released in the case being discussed. Assuming the media reports are correct, it is important to point out that multi-organ failure (the point used to infer a similar cause of death) can be the end point of a serious medical disease or condition regardless of the disease process itself. To make it more clear, it would be similar to saying that two deaths were similar because at the time of death there was no heart beat. The underlying disease processes that can result in multi-organ failure can be very different.
There is one final point that I would like to mention. I do want to state with my deepest sympathy and sincerity to the family that this was indeed a tragedy. No one other than the family can begin to imagine what they are going through. However, in our current society, we tend to want to jump to a conclusion and find blame for a tragedy when it involves the loss of human life. But until all the analyses are completed, we should not jump to conclusions. I hope the media will continue to report the facts and not overly speculate until we have as much information as possible. It is easy in retrospect to question whether or not this was an appropriate disease to attempt to treat with gene therapy because as stated it is not considered a life threatening illness. But keep in mind that people do die from common drug therapies to treat diseases that are not immediately life threatening. There are numerous examples. One such example is a life-threatening complication that can occur from common lipid/cholesterol lowering medications. In every one of these scenarios, careful risk benefit analyses are carefully considered based on the best knowledge base available at that time. When it is your own loved one that has a bad outcome, it is understandably hard to appreciate the greater good that these therapies have or will have on all of society. We need to continue to protect the rights of patients and make sure they are not subjected to medical trials based on sloppy scientific practices. But even with the best medical science as unfortunate as this may sound, we will not be able to eliminate all adversity.
Posted by: Mark Kay MD, PhD Stanford University | August 22, 2007 09:57 PM