COMMENTS TO THE FOOD AND DRUG ADMINISTRATION, BIOLOGICAL RESPONSE
MODIFIERS ADVISORY COMMITTEE
October 10,
2002
Who We Are
The Council for
Responsible Genetics (CRG) is the nation’s oldest organization committed
to educating the public on issues of biotechnology. Founded in 1983, CRG
works to raise public awareness and promote debate on the social, ethical,
and environmental implications of new genetic technologies. Our Board of
Directors consists of scientists, physicians, lawyers, educators and
public advocates, each of whom have been involved in these issues at the
community, national, or international levels. Our central concern is that
of public involvement and accountability. The public must have access to
clear and understandable information on technological innovations, and it
must be able to participate in governing the applications of technological
developments.
Ever since proposals were first made to use gene modification
techniques for potential human therapies CRG has fought to prevent the
premature application of these treatments. Our Board members and advisors
with experience in the relevant areas were concerned that genetic
modification could produce severe and unintended side effects. This has
been borne out in recent trials and therefore we are renewing our
recommendation to adopt a different approach from the one currently in
place. As a first step we propose a moratorium on all human gene
modification trials.
The Present Risks
Overall, the
effects of both viral and non-viral gene therapy vectors continue to be
poorly understood. After over a decade of human trials and more than two
decades of animal research, gene therapy is still more of a theoretical
concept than a sound medical course of treatment. Techniques for making
genetic changes in mammalian somatic tissues are still primitive. The
death of 18-year-old Jesse Gelsinger as a result of a University of
Pennsylvania trial on in vivo viral intoduction of genes was followed by
reports of the resounding lack of success of hundreds of other such
attempts.
Using ex vivo techniques the Necker Hospital protocol to
treat ADA deficiency hoped to circumvent the potentially fatal
complications associated with in vivo methods. Nonetheless, there is
insufficient ability to precisely direct gene transfer through the vectors
chosen. Retroviruses are difficult to target effectively and, as a result,
they often may not reach the intended DNA location. This becomes a safety
hazard in two primary ways. First, these viruses integrate randomly into
the genome of the host cell. After the transgene is introduced,
inappropriate integration could disrupt important gene and cell
functioning, precipitating cancer or other forms of biological damage.
Second, retroviruses may infect non-targeted cell types. Which of these is
responsible for the leukemia-like disease seen in one of the Necker
patients is unclear.
Data from model organisms does not justify
continuing human gene modification experiments at this time. Indeed the
NIH report on the Gelsinger incident acknowledged that there were no good
animal models for the viral vectors used in that in vivo trial. With
regard to ex vivo protocols animal studies provide a strong basis for
precaution. For example, in the April 19 issue of Science this year, a
team of researchers led by Zhixiong Li showed that the insertion of
foreign genes into mouse bone marrow cells using a replication-defective
retroviral vector caused the animals to develop leukemia.
Why, in
the face of potential cancer risks (which could have been anticipated, and
were by us and other commentators), were retroviral gene therapy trials
allowed to proceed? This is a question that the committee will have to
answer for any adequate review of the recent adverse event. At this stage,
many of the scientists who are pushing the gene therapy agenda forward
have financial stakes in moving the trials forward. Careful attention
should be paid to the potential conflicts of interest that could lead to
premature applications of these techniques and thereby compromise the
safety of research subjects.
During the months that followed the
Gelsinger incident, under improved reporting procedures, 691 reports of
“serious adverse events” in gene therapy experiments were sent to the NIH.
Over 98% of these incidents had not been previously disclosed. It should
be clear that trials cannot responsibly proceed under conditions of
secrecy, commercial or otherwise. Regulatory mechanisms should be put in
place to ensure the open distribution of data so that investigators can
learn from each other’s experience.
Furthermore, that case
highlighted the lack of adherence by university researchers to principles
of informed consent and to existing Recombinant DNA Advisory Committee
(RAC) and FDA recommendations. In many cases, patients in gene therapy
trials had not been made fully aware of the risk of severe immune system
response, cancer, and other adverse events. As Abbey Meyers, President of
the National Association for Rare Disorders and a past member of the NIH
Recombinant Advisory Committee, aptly stated, “In the years that I sat on
the RAC, I would see these documents time after time, sometimes eight or
ten of them would come in front of us at a meeting, and I saw lies, I saw
omissions, I saw exaggerations. Patients were not being told the truth in
the informed consent documents.” What is also not being clearly
communicated to research subjects is that Phase 1 trials hold out no
promise of efficacy—they are solely for safety and toxicity
evaluation.
A main purpose of FDA oversight is to maintain controls
over research to protect the safety and integrity of human experimental
subjects. Genetic modification raises questions qualitatively different
from previous drug treatment regimes. As a result, these studies should be
reviewed with added care. The implications of gene therapy go far beyond
the immediate medical context, potentially changing the relationship of
humans to their permanent biological makeup. Such issues make it
imperative that the FDA take into account larger ethical questions before
permitting gene therapy to move forward.
A
Proposal
Faced with new evidence of risk, it is our position
that the FDA should establish a moratorium on all future gene therapy
trials, awaiting clearer evidence of safety and efficacy. Reevaluation
should be undertaken of the Phase 1/Phase 2 framework for gene
modification trials.