China, Unhampered by Rules, Races Ahead in Gene-Editing Trials
China, Unhampered by Rules, Races Ahead in Gene-Editing
Trials
U.S. scientists helped devise the Crispr biotechnology
tool. First to test it in humans are Chinese doctors
By Preetika Rana, Amy Dockser Marcus and Wenxin Fan Jan.
21, 2018 2:19 p.m. ET
HANGZHOU, China—In a hospital west of Shanghai, Wu Shixiu
since March has been trying to treat cancer patients using a promising new
gene-editing tool.
U.S. scientists helped devise the tool, known as
Crispr-Cas9, which has captured global attention since a 2012 report said it
can be used to edit DNA. Doctors haven’t been allowed to use it in human trials
in America. That isn’t the case for Dr. Wu and others in China.
In a quirk of the globalized technology arena, Dr. Wu can
forge ahead with the tool because he faces few regulatory hurdles to testing it
on humans. His hospital’s review board took just an afternoon to sign off on
his trial. He didn’t need national regulators’ approval and has few reporting
requirements.
Dr. Wu’s team at Hangzhou Cancer Hospital has been
drawing blood from esophageal-cancer patients, shipping it by high-speed rail
to a lab that modifies disease-fighting cells using Crispr-Cas9 by deleting a
gene that interferes with the immune system’s ability to fight cancer. His team
then infuses the cells back into the patients, hoping the reprogrammed DNA will
destroy the disease.
In contrast, what’s expected to be the first human Crispr
trial outside China has yet to begin. The University of Pennsylvania has spent
nearly two years addressing federal and other requirements, including numerous
safety checks designed to minimize risks to patients. While Penn hasn’t
received final federal clearance to proceed, “we hope to get clearance soon,” a
Penn spokeswoman said.
“China shouldn’t have been the first one to do it,” says
Dr. Wu, 53, an oncologist and president of Hangzhou Cancer Hospital. “But there
are fewer restrictions.”
In traditional drug development, too, human-trial rules
can differ among countries. But China’s foray into human Crispr trials has some
Western scientists concerned about the unintended consequences of using the
wholly new tool—such as harm to patients—which could set back the field for
everyone.
Western scientists the Journal interviewed didn’t suggest
America’s stringent requirements should be weakened. Instead, many advocate an
international consensus on ethical issues around a science that makes
fundamental changes to human DNA yet still isn’t completely understood.
Out of the Gate
China has gotten a jump on the U.S. in human trials of
Crispr-Cas9. It is the only country known to have conducted tests on humans.
“How do we make sure everyone is under the same tent?”
says Jeffrey Kahn, director of the Berman Institute of Bioethics at Johns
Hopkins University. With Crispr science still uncertain, “we need to be talking
to each other internationally.”
There is little doubt China was first out of the block
testing Crispr on humans. Nine trials in China are listed in a U.S. National
Library of Medicine database. The Wall Street Journal found at least two other
hospital trials, including one beginning in 2015—a year earlier than previously
reported. Journal reporting found at least 86 Chinese patients have had their
genes edited.
The trials align with China’s industrial policy. As part
of its drive to place China on the global stage in a multitude of industries,
Beijing in a 2016 five-year plan highlighted gene editing. Many of the Crispr
trials emerged after that call-to-arms.
Carl June, lead scientist for the Crispr research team at
Penn, says China could beat the U.S. to apply medical technologies such as
Crispr pioneered in the West. “We are at a dangerous point in losing our lead
in biomedicine,” he says. There is a “regulatory asymmetry” between America and
China, Dr. June says, but Crispr science is so new “it is hard to know what the
ideal is between moving quickly and making sure patients are safe.”
In Europe, too, trials haven’t started. Crispr
Therapeutics AG , whose founders include a scientist associated with the tool,
announced in December it had filed with the European version of the U.S. Food
and Drug Administration to open a clinical trial in Europe. Regulators are
reviewing the application, and the company plans to start this year, a
spokeswoman says.
Crispr emerges
Crispr, for Clustered Regularly Interspaced Short
Palindromic Repeats, serves as the immune system in bacteria. In 2012, a team
led by scientists in the U.S. and Austria published a paper demonstrating how
they reprogrammed a particular Crispr system to enable gene editing.
The new tool—called Crispr-Cas9 after the natural system
it uses—acts like molecular scissors, letting scientists cut or repair DNA. In
2013, U.S. scientists used it to edit the genome of human cells in the lab.
Rewriting the Code
Scientists can use the gene-editing technology called
Crispr-Cas9 to correct disease-causing mutations.
The technology is easier to use than other gene-editing
methods and less expensive. Lab experiments have shown it can correct some
glitches that cause incurable diseases. Crispr has spurred heavy investment and
a proposed Jennifer Lopez-produced television thriller.
Rewriting life’s building blocks, however, is fraught
with scientific and ethical quandaries. One: Crispr might make unintended
irreversible changes in people that may not emerge for years.
A new paper from Stanford University suggests many people
may have pre-existing immunity to Cas9 proteins and that some Crispr therapies
might not work or could spark a dangerous immune reaction.
Dr. Wu agrees risks could surface, calling Crispr “a
two-edged sword.” Some “see the potential damage,” he says. “We see the
potential benefits.” He says speed is critical because his patients face
imminent death. “If we don’t try, we will never know.”
None of the Chinese trials has published results. While
Dr. Wu and other doctors say some patients’ conditions improved, at least 15 of
the known 86 patients have died of what doctors in the trials say were their
diseases.
At first, it looked as if the U.S. would be out in front.
The Penn-sponsored Crispr trial was among the first to publicly surface in
2016. The trial targeted patients with multiple myeloma, sarcoma and melanoma.
Later in 2016, news reports said a Chinese hospital had
begun the world’s first Crispr trial. In fact, it wasn’t first—No. 105 Hospital
of the People’s Liberation Army in Hefei began testing Crispr on patients in
2015, says Liu Bo, who leads that trial.
A Chinese startup, Anhui Kedgene Biotechnology Co.,
pitched Crispr to the military hospital, say Dr. Liu and Kedgene, offering to
apply the tool in Kedgene’s lab. Doctors recruited participants, taking their
blood and reinfusing edited cells.
“The doctors don’t understand gene editing,” says Mandy
Zhou, who co-founded Kedgene in 2015 and trained medical students on how to use
Crispr. “We have to do this together.”
Early transfusions at the military hospital shrank some
tumors, Dr. Zhou says. She teamed with Anhui Provincial Hospital in Hefei for
another trial in 2016. There, participants such as Zhang Jianmin, 45, are
showing signs of improvement, says his doctor, Wang Yong. Years of chemotherapy
failed to stop his nasal cancer. Within months of receiving Crispr infusions,
his nasal tumor shrank, says Dr. Wang, who is involved in the trial.
“If I continue to get better, you have to believe in science,”
Mr. Zhang said from his hospital bed in September. He is alive and doing well,
Dr. Wang says.
Tale of two trials
Dr. Zhou last year approached Dr. Wu, proposing another
trial with Kedgene doing the gene editing in its lab 250 miles away.
Dr. Wu says he was eager. He needed approval only from
his hospital ethics committee. Its role is similar to U.S. institutional review
boards that examine proposals and assess risks.
In the U.S., investigators must also apply for FDA review
before a human trial can proceed. A regulation of China’s health ministry,
which is responsible for medical affairs, authorizes a hospital’s ethics
committee to approve research on humans. The ministry didn’t respond to
requests for comment.
Reviewing Dr. Wu’s proposal was a committee appointed by
his hospital, comprising nine people including doctors from the hospital, a
lawyer and a former cancer patient, Zheng Xiaomin. The seven who showed up
sifted through a roughly 100-page proposal and watched a PowerPoint
presentation, panel members say.
Ms. Zheng says the proposal, which she received a day in
advance, “was too much to finish reading.” She says she “didn’t understand the
academic details” but did ask about side effects and was told they were mild.
Deng Qinghua, a radiologist on the panel, says he voted
in favor because the gene that was going to be cut out had been targeted before
in successful cancer therapies—suggesting a lower risk. The application passed
unanimously in one afternoon.
Penn’s Dr. June was navigating a more rigorous process.
To get a go-ahead from his hospital’s review board and
the FDA, he first sought an assessment by a U.S. National Institutes of Health
advisory committee. The NIH set up the committee 40 years ago in the wake of
public concern about new gene technologies.
At a June 2016 meeting, the NIH panel asked Penn’s team
to strengthen warnings to patients explaining that the procedure was
experimental and that ill effects might be irreversible, according to committee
members and a meeting transcript.
Mildred Cho, a Stanford University bioethicist on the
committee, requested Penn describe the trial as “gene transfer” instead of
“gene therapy,” which she says implied effective treatment, not
experimentation. The investigators complied.
“We want to make sure everyone knows this is an
experiment and not a cure,” says Laurie Zoloth, dean of the University of
Chicago Divinity School and a bioethicist on the committee. “Especially with
end-stage cancer, the intervention can be grueling. Experiments can fail, and
in ways that can be terrible.”
At the time of the NIH hearing, Dr. June’s lab had run a
variety of tests to see if Crispr made unintended cuts in cells. He says the
FDA wanted still more. The FDA declined to comment on the process.
Dr. Wu says he didn’t have the time to do such tests
because his terminally-ill patients needed treatment urgently.
The NIH advisory committee allowed the Penn team to
proceed. The researchers then spent over a year in discussions with the FDA,
providing information and answering requests. Penn’s ethics review was
completed in late 2017, and Penn is awaiting final FDA clearance, the Penn
spokeswoman says. Dr. June says he expects clearance as early as this month.
After the Penn trial begins, it will again face different
standards from Dr. Wu’s. In enrolling patients, Penn researchers must use
consent documents examined by the FDA and the hospital institutional review
board. Cases involving patients harmed during biomedical research “set in
motion a chain of events that ended up with the regulatory system we have,”
says Stanford’s Dr. Cho.
Dr. Wu’s consent letters briefly mention gene
engineering. He says he tells patients his trial is aimed at modifying their
immune systems and doesn’t dwell on the fact he is using an experimental tool.
His explanation to participants, he says, varies based on their education.
“The Chinese patients will sign the consent letter,” says
Kedgene’s Dr. Zhou. “But mostly they listen to what doctors tell them.”
Penn also must report deaths. An FDA spokeswoman says
investigators must immediately inform a trial’s sponsor of serious adverse
events, such as death, regardless of whether they are trial-related. The
sponsor must then notify the FDA.
Seven of Dr. Wu’s patients have died, among 15 known
deaths across Kedgene’s three trials, say Dr. Wu and other doctors involved.
Dr. Wu says the deaths in his trial were due to patients’ diseases and not
related to Crispr, so he wasn’t required to report them to his ethics
committee.
China’s health ministry requires researchers report
“adverse events” to their ethics committees. Dr. Wu says deaths unrelated to
the trial aren’t seen as adverse events. Wei Jia, who is leading a separate
Crispr trial at Nanjing University’s Drum Tower Hospital and isn’t involved
with Kedgene, says any fatality in a trial is considered an adverse event.
Dr. June says the Penn study will test whether Crispr is
safe and “isn’t designed to see if we can cure patients.” The researchers plan
to test Crispr on one patient, wait a month to make sure there aren’t adverse
reactions, then try it on two more.
Dr. Wu says he sees saving patients’ lives as paramount.
He began by testing Crispr on three patients and has modified genes of more
than a dozen. He says he is planning other trials with lung-cancer and
pancreatic-cancer patients.
Not all China’s Crispr trials were approved as easily.
Dr. Liu, the principal investigator in what appears to be the world’s first
experiment, says his ethics-committee reviewers took months to approve his
trial after asking for supplementary information.
More U.S. Crispr trials are expected to open in the next
18 months, led by publicly traded companies started by scientists associated
with the tool.
The University of Chicago’s Dr. Zoloth says she hopes
countries will devise international Crispr standards, sharing results and
ethics. “We need to talk collectively about what it means in science to prove
something,” she says, “and about what it means to protect someone, too.”
https://www.wsj.com/articles/china-unhampered-by-rules-races-ahead-in-gene-editing-trials-1516562360
Comments
Post a Comment