Are China’s regulations too lax?

China in November became the first country to have approved two drugs based on gene therapy. The approvals have fueled quick growth in the field, but they may be a sign that China’s drug regulation is too lax, experts caution.

China’s State Food and Drug Administration in October 2003 approved Gendicine to treat head and neck cancers. The drug uses an adenovirus to deliver the tumor suppressor gene p53 into tumor cells. Ins November 2005, the agency approved Shanghai Sunway Biotech’s H101, also an adenovirus, which targets cancer cells that lack p53. More than 50% of all cancers have abnormal expression of p53 (Oncology 13, 148–154; 1999).

In the West, the approach to gene therapy has been cautious since the death in 1999 of 18-year-old Jesse Gelsinger in a gene therapy trial at the University of Pennsylvania. More recently, French researchers used the technique to treat ten children with the so-called ‘bubble boy’ disease, but that trial was put on hold in 2003 after two of the children developed leukemia.

In China, however, both the government and the public have embraced the technology. The success of the two approved products has boosted the number of gene therapy trials in China from 5 in late 2003 to 19 in 2006.

“The huge numbers of highly cooperative patients, the low cost for research and clinical trials and the positive support from the government has enabled China to lead the world in certain areas of biotech research, such as gene therapy,” says Zhaohui Peng, chairman and chief executive of Shenzhen SiBiono GeneTech, Gendicine’s maker.

The government invested about 20 million yuan (US$1.2 million) into research toward Gendicine and government-backed firms put in about $40 million into H101. The government also offers tax-free imports for research equipment.

But the government’s open support for the controversial therapy does not mean that its standards are lax, Chinese scientists say. “I know there are many doubts among overseas scientists on China’s drug regulation, but the fact is China’s regulation of data is as strict as in the US,” says Peng. Until recently, the Chinese agencies were reluctant to approve anything that is not approved by the US Food and Drug Administration, he says, but he and others have been able to persuade them to take more chances.

For example, the agency took 23 months to approve H101 after some Western scientists criticized China for approving Gendicine, adds Fang Hu, president of Shanghai Sunway Biotech. The average approval time in China, including for generic drugs, is about 18 months; Gendicine was approved in a year.

When setting criteria for evaluating new drugs, China has closely followed standards used in the US and the EU, says Guowei Sang, director of the Beijing-based National Institute for the Control of Pharmaceutical and Biological Products, the agency that evaluates new products.

Scientists in China also take their cue from their American counterparts. Peking University’s Shanwen Zhang, who led Gendicine’s trials, says he carefully studied the research on Advexin, another p53-based drug made by Austin-based Introgen Therapeutics, which is in phase 3 trials.

In evaluating Advexin, US agencies will rely on its effect on five-year survival. But China based its approval of gene therapy products on the rate at which they caused tumors to shrink, notes Yong Liao, assistant professor of molecular and cellular oncology at the M.D. Anderson Cancer Center in Houston. The gene therapy trials have also enrolled fewer participants than trials in the US. Compared with 217 people in Advexin’s phase 2 trial, Gendicine’s combined phase 2/3 trial enrolled 135 individuals.

In that trial, 63 individuals given a combination of radiotherapy and weekly injections of Gendicine showed a tumor-regression rate that was three times that of the 72 individuals given radiotherapy alone.

Gendicine’s trial was designed to make the product look good, says Jack Roth, chairman of thoracic and cardiovascular surgery at the M.D. Anderson Cancer Center. Because p53 increases sensitivity to radiation, giving p53 in combination with radiotherapy would naturally improve the response rate over radiation alone, Roth says. In the trial for Advexin, for example, researchers gave the gene therapy in combination with chemotherapy.

The Gendicine trial also did not evaluate the efficiency of delivering the product and the level of immune response at the molecular level against the adenovirus. “We have been aware of this problem, and now we have obtained a state grant to do research in this field,” says Zhang.

Chinese agencies consider short-term safety, but generally do not pay enough attention to a drug’s long-term effects, says Zailin Yu, chief scientist of the Beijing-based Bioway Biotech Group. The agencies’ criteria for evaluating drugs are based mainly on the clinical trial rather than on molecular studies and long-time follow-up, he says.

The lack of regulation has had one unexpected benefit.

In the trial for H101, an immune response caused up to one-half of the participants to develop a fever of more than 37.5 degrees Centigrade. In the US, scientists would be required to take immediate measures to lower any fever above 38.5 degrees Centigrade. “But in China, there is no such requirement,” says Hu. In the H101 trial, it turned out those with a fever actually saw better results with the therapy. “This gives us an inspiration that heating helps the better function of H101 against tumor cells,” says Hu. There is some evidence to suggest that heating tumors could enhance the benefits of treatment (Cancer Cell 6, 611–623; 2004).

Reliable or not, China’s regulatory structure is attracting international drug makers to conduct their clinical trials in the country. “Most of Chinese patients do not have medical insurance, so that we can easily enroll the required number of patients within very short period of time,” notes Hu.

Although the US does not accept data from trials conducted in China, the safety and efficacy information collected in the Chinese trials could help design trials in the US, experts say.

“When Chinese companies make money using the technology that has been originally developed in the West, the US government will reconsider the situation of gene therapy in US companies,” says Masatoshi Tagawa, a researcher at Cancer Center Research Institute at Chiba University in Japan. “I would imagine that the commercialization [in China], when it makes money, will bring finance and science into gene therapy.”