Gene therapy trials shut down at University of Pennsylvania following patient death

regina1934 at regina1934 at
Mon Mar 13 07:45:30 EST 2000

Taken from the World Socialist Web Site of the International Committee
of the Fourth International at:

Gene therapy trials shut down at University of Pennsylvania following
patient death

By Tom Bishop
13 March 2000

The promising field of gene therapy was rocked by the September 17,
1999 death of 18-year-old patient Jesse Gelsinger. Gelsinger had
volunteered to participate in a gene therapy trial for the rare genetic
disease ornithine transcarbamylase deficiency (OTC) at the Institute for
Human Gene Therapy at the University of Pennsylvania in Philadelphia.
On January 21 the federal Food and Drug Administration (FDA) shut
down all gene therapy trials at the institute.

OTC occurs because the patient is born with a liver unable to rid the
body of the ammonia created during metabolism. Untreated, the
condition can rapidly lead to coma and death. The current treatment is a
special diet and medication. At the time, Gelsinger's death was believed
to be the first of a patient in a gene therapy trial.

Gene therapy is a 10-year-old field which holds the promise of finding
cures for many types of disease. It is part of the biological revolution
going on in all of the life sciences where scientists are on the verge
gaining control of the very mechanism by which all life forms reproduce.
The origins of this revolution date to the early 1950s when James Watson
and Francis Crick uncovered the structure of DNA. The next advances
were the cracking of the genetic code in the 1960s and the discovery of
restriction enzymes in the 1970s, which enabled researchers to isolate
specific genes from DNA and begin to develop gene-splicing technology.
In the 1980s, research began in gene transfer systems to find ways to
deliver the altered genes into organisms.

In addition to genetic disorders, gene therapy holds promise for making
advances against many forms of cancer, AIDS, and blood and heart
disorders. This would be done by supplying the patient with cells that
have healthy copies of missing or flawed genes. Instead of the patient
taking drugs to control or treat symptoms of a disorder, scientists
attempt to alter the gene makeup of the patient's defective cells to
a genetic or other deficiency.

One method takes cells from the blood or bone marrow of the patient
which are then grown in the laboratory under conditions which cause
them to multiply. The desired gene is then inserted into the nucleus of
cells with the help of a disabled virus. The altered cells are selected
encouraged to multiply, and then returned to the patient's body. In some
cases, disabled viruses are used to deliver the gene directly to nuclei
cells in the patient's body.

In the case of Jesse Gelsinger, the gene therapy trial was an ongoing
two-year trial being conducted by the Institute for Human Gene Therapy
at the University of Pennsylvania in Philadelphia. He began the trial on
eighteenth birthday, the day he became eligible to participate. His
was infused with trillions of genetically disabled cold viruses
the corrected OTC genes. The viruses, which were to be the delivery
vehicle for the needed gene, caused "an immune system revolt" causing
Gelsinger's immune system to go into overdrive and begin attacking his
lungs and vital organs. He died four days after the trial began. The
cause of his death is not understood.

On January 21, after a three-month study, the FDA shut down all gene
therapy trials at the Institute for Human Gene Therapy. The institute is
one of the largest academic gene therapy centers in the world, with an
annual budget of $25 million, a staff of 180, and links to many private
biotechnology companies. The FDA said they found numerous violations
of federal research regulations and shortcomings in the protection of
human subjects at the Institute.

In closing down eight active or pending gene therapy studies at the
institute, the FDA found 18 specific violations of FDA rules and
regulations in the OTC trial. It found the institute had admitted 18
into the study of which Gelsinger was a part without documenting that
any fit the eligibility requirements for the study. It found some should
have participated because they were too sick. The FDA suspension
affects studies involving cystic fibrosis, lung cancer, melanoma, breast
cancer, muscular dystrophy and brain cancer.

The FDA also found that patients in the OTC study had not been given
informed consent of the risks involved in the trial. These procedures
patient consent have developed as a result of the ethical questions
by such experiences as the Nazi's medical experiments during World
War II and the Tuskegee experiment in which African-American men
were purposely denied medical treatment for syphilis for decades.

The FDA found that the Institute consent form had been altered to
eliminate mention that monkeys had died in similar tests and the FDA had
not been immediately informed of this development. The forms for half
the patients were not properly signed and did not disclose that four
previous volunteers had suffered serious side effects. Nor had the
Institute properly monitored the health of volunteers after the
began, and it lost track of several lots of the experimental genes that
been infused into patients' livers.

The FDA raised questions about the institute's, and its key researcher
James Wilson's, ties with the biotechnology industry. Wilson is
considered one of the world's leading gene therapy researchers and was
involved in all eight gene therapy trials. A former president of the
American Society for Gene Therapy, Wilson founded Genovo Inc., a
suburban Philadelphia company, and both he and the university own
stock in the company.

The company and its corporate sponsor, Biogen, contributed one-fifth of
the institute's annual budget, and in return have exclusive rights to
the institute's discoveries into commercial products. Trials funded by
private companies do not have to obey federal guidelines if the patient
does not use facilities receiving federal funds. As a result, companies
tailor information released to the public not only to hide information
corporate competitors but to publicize good news, while keeping bad
news as a "trade secret", in order to encourage stock holder investment
in the company.

When gene therapy trials began in the early 1990s, they were under
stricter federal regulation than those for pharmaceutical research
of the risks involved. Since the first trial, about 4,000 patients have
part in some 400 gene therapy trials, most treating patients with
cancer. Unlike basic drug research which the FDA supervises in private
to protect "company secrets" from other pharmaceutical companies as
well as the stock market, federally funded gene therapy is overseen by a
committee at the National Institutes of Health whose activities were
to public scrutiny. Three years ago, in a controversial move, the NIH
back its oversight due to pleas by desperate victims for a speed-up in
research and complaints about restrictions from the biotechnology
industry. Until Gelsinger's death, the industry had been agitating for
less scrutiny. Increasingly, the agency had relied on scientists
to follow the rules they had agreed to.

In the last 20 years the genetic revolution has brought ever closer ties
between medical schools and biotech corporations. Academic scientists
who do not have ties to the industry are now very rare. The trend began
in 1980 with the passage of the Bayh-Dole Act by Congress. This law
was designed to speed up commercialization of academic discoveries by
encouraging universities to patent inventions and then reassign those
patents to private companies that could develop them as products. Many
scientists raised their own venture capital and started their own
companies and now have a financial stake in the companies testing their
discoveries. Some doctors even enroll and treat patients in clinical
that are paid for by companies they own.

The FDA report prompted the National Institutes of Health to begin its
own investigation at Penn since it had awarded the Institute seven
grants making up nearly half of the institute's budget. The NIH has
suspended biomedical research on a number of campuses in the last year,
including Duke University, the University of Illinois at Chicago, and
University of Colorado Health Sciences Center, after finding they did
have adequate systems for monitoring patient safety. The Muscular
Dystrophy Association and Cystic Fibrosis foundation have also recently
suspended gene therapy trials at Penn and other medical centers. MDA
had given $1.6 million to Wilson and other researchers at Penn for their

As a result of Gelsinger's death, the NIH last fall requested agencies
send information on "adverse events" in gene therapy trials. At the end
January, the Washington Post received the reports through a Freedom
of Information Act request and reported that the NIH has been swamped
with reports of previously unreported serious adverse events during gene
therapy trials. Since 1993, 652 of 691 reports had never been filed.
Many patients suffered fevers, clotting abnormalities and serious drops
blood pressure. They included several unexplained deaths raising the
possibility that Gelsinger was not the first to die during a gene
trial. These deaths were usually attributed to underlying illnesses or
causes, but autopsies were rarely done.

On February 2, the Senate Health, Education, Labor and Pensions
subcommittee held hearings to investigate the crisis. It found that in
addition to scientists not reporting problems in a timely way, the NIH
FDA were not coordinating efforts and lacked adequate staff to monitor
experiments forcing them to rely on written reports from scientists
than on-site inspections to monitor clinical trials. Amy Patterson, head
the NIH office overseeing gene therapy, said the situation may be far
worse because the 691 "adverse events" involved only the 25 to 30
percent of gene therapy experiments that rely on the gene-altered cold
virus used in the Gelsinger experiment. Forty other adverse events in
other areas of gene therapy had already been reported.

On February 14, Penn officials issued a 34-page response to the FDA
report. The report said the FDA requirements were ambiguous, allowing
differing interpretations of requirements. It said they did not believe
of the lapses detailed by the FDA led to Gelsinger's death. On March 3,
the FDA rejected this attempt to lift the freeze on clinical trials at
institute and test programs have been shut down in other parts of the
country since January. The strongly worded letter all but accused Wilson
of lying to the FDA.

However, on March 7 the FDA and NIH issued new guidelines for gene
therapy experiments which fell short of what critics say is needed. The
new guidelines require researchers to appoint someone not involved with
the experiments to monitor safety, such as another research group or
scientists from another hospital or university. The FDA would also make
surprise inspections at the more than 350 gene therapy experiments
under way. The monitors, however, would be hired by the researchers
doing the experiment.

Alan Milsten, the attorney representing Gelsinger's father, said it was
little, too late." He added, "The FDA and the NIH have yet to address
their own mistakes with respect to Jesse's death-particularly and most
glaringly their approval of Penn's study, which had the prospect of very
little benefit and tremendous risk for patients."

On February 16, the University of Pennsylvania fired William Kelly from
his $1.2 million job as chief executive officer of the Health System and
dean of the Medical School, which he held for 11 years. Officials
the gene therapy crisis had no bearing on their decision.

The Medical School, which ranks second in NIH funding, has lost $300
million in the past two years due to medical reimbursement cutbacks from
Medicare, Medicaid and private health insurers. It laid off 2,800
employees last year, 20 percent of its workforce. The University of
Pennsylvania is considering joining other universities in establishing
medical practice as a separate nonprofit or profit corporation. This
be done to cut medical costs and would have a major impact on medical
research. Kelly is expected to take a position at Merck Pharmaceutical
and Health Care where he sits on the Board of Directors.

At the Congressional hearings on February 2, Jesse's father, Paul
Gelsinger, a handyman from Tucson, Arizona, testified that he now
believed he had been "misled" by the Penn scientists. Until the FDA
report he had been a strong supporter of the Penn team. Gelsinger said,
"It looked safe. It was presented as being safe. Since it would benefit
everybody, I encouraged my son to do this. I was misled, that's what
the most." He told the committee that Penn researchers told him that a
previous volunteer in the study experienced a 50 percent improvement in
liver function, when in fact no such improvement had been documented.

Gelsinger criticized the FDA for conducting its business in secret and
being unduly influenced by "business interests," the NIH for failing to
investigate adverse events in gene therapy trials, and scientists in the
for putting money and fame ahead of patient safety. "Guys want to own
this [technology] ... they want to have the patents on it," Gelsinger
said. "I
thought this was all about people. I'm very disappointed to find that it
not all about people."

See Also:

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