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.”