China’s Food and Drug Administration has introduced sweeping reforms that are likely to be a game changer for pharma companies that want a piece of the huge China market.
CFDA issued draft guidelines in mid-March that would allow multinational pharma companies to run Phase I trials in China for the first time. Currently, a company can only run a Phase I trial in China for a product that has already been tested in humans in other countries.
The change would mean that China should be considered much earlier in a company’s global development plans.
If the draft is implemented, it would mean that China could truly participate in global development for early phase trials, Dan Zhang, CEO of Beijing-based CRO Fountain Medical Development, told BioPharma Dive.
"Under the new guidelines, foreign sponsors could start Phase I studies in China simultaneously with Phase I studies conducted outside China," Zhang said.
Editor's Note: Since this piece was originally published in April 2017, the draft guidance has been finalized.
Multiregional clinical data accepted
CFDA would also allow foreign companies to use multi-regional clinical trial data to support new drug applications in China as long as the trial design fits China’s technical guidelines. This means that companies would no longer need to conduct a second local trial in China after running their global trials.
The change removes an additional bureaucratic layer, and companies would only have to file two applications rather than three applications for registering a drug in China, Zhang said. Industry has long awaited clarity on this topic, and the news should bring a sigh of relief.
Moreover, even if a product is not manufactured in China, a company could apply for an NDA in China. Previously, if a product was manufactured in the U.S., the sponsor would have to get U.S. NDA approval first before it could export the product to China.
"Now, companies wouldn’t have to get NDA approval in the U.S. first; they could directly apply for an NDA or importation to China even if the product is manufactured outside of China," Zhang said.
If the guidelines are approved, global companies should automatically include China in their clinical development plans, Zhang said, adding that China would no longer be a drag on companies’ timelines, and it would be feasible that China could approve an NDA ahead of other countries, particularly in areas of high unmet need in China such as liver cancer.
Zhang noted that global companies should revisit new products to include China sites in their ongoing studies. One word of caution was that China has limited clinical sites, so competition for high quality sites will be fierce.
The draft guidelines indicated the CFDA's general direction of encouraging innovative assets to come to China earlier, said Katherine Wang, partner in the law firm Ropes & Gray, based in Shanghai. "However, this policy can be deemed in conflict with certain provisions in the Implementing Rules of the Drug Administration Law," she said, warning that it may take some time to finalize the draft.
CFDA reform seeing big payoffs
In July 2015, China’s State Council made changes to its regulations that pushed CFDA to dramatically improve its review process for drugs. The agency issued a number of technical guidelines that have brought the agency on a more level playing field with other global regulators.
CFDA recruited top-notch technical leaders from U.S. Food and Drug Administration, including He Ruyi, a former U.S. FDA reviewer for 17 years. He became the first chief scientific officer in CFDA’s Center for Drug Evaluation. Following his appointment, CFDA began to issue numerous technical guidelines that are more aligned with ICH guidelines.
One of the most important changes was that CFDA more than quadrupled the headcount for its drug review team, recruiting 600 more reviewers. Prior to 2015, there were only 120 reviewers.
Green Channel Expanded
Another policy intended to speed up the timeline to approval is the expansion of China’s fast-track pathway. Previously the pathway, known as the "green channel," was available for drugs that have not been marketed anywhere in the world. The CFDA expanded the pathway to allow more types of drugs to access the green channel, said Wang.
For example, drugs that target high unmet needs in China, innovative drugs using advanced technology, imported innovative drugs manufactured in China, as well as pediatric and geriatric drugs, to name a few, all have access to the green channel.
"To some extent, the green channel forced foreign pharmaceutical manufacturers to revisit the strategic value of China as a market, because previously foreign companies would benefit from the quasi new drug status by launching a drug that is already approved outside of China but not in China yet," Wang said.
Now if companies want to benefit from the accelerated approval status, they have to "take China more seriously by launching the product sooner."
Wang said that companies are already seeing results since the reforms were announced in terms of faster approvals of NDAs and clinical trial authorization.
For example, the CFDA has accelerated the time to market to an average six to nine months, she said.
Clinical trial authorization can be as short as six months, said Zhang, noting that one drug was cleared for trials in as short as four months. Previously, it took 12 to 18 months to get clinical trial authorization.
The country is also making headway in clearing out the huge backlog of drug applications, most of which are generics.
During a February press conference, CFDA Commissioner Bi Jingquan said that in 2015 the backlog was 22,000 cases, and now it’s only 8,000 cases, Wang said.
"This year or the beginning of next year the backlog could even be eliminated," Zhang added.
Focus on Quality, Data Integrity
Over the next five years, CFDA will shift its focus from pre-approval supervision to day-to-day operational supervision, said Wang. She explained that the CFDA is trying to use regular inspections as a tool to make sure companies comply with the regulations.
"For example, the U.S. FDA has always focused more on post-approval requirements through regular inspections for compliance to verify data," Wang said, "and this is what CFDA is aiming for with more rigorous and regular post-approval inspections."
"That philosophy has not really been implemented by the CFDA until maybe two years ago," she said, noting that Bi wanted to use the FDA as a model to learn from, so his regulatory philosophy is probably more aligned with the U.S. FDA philosophy.
"That is a very good thing. On the one hand, he has increased the number of reviewers and has simplified the approval process for innovative products even if they are developed outside China." Those measures are intended to "increase the transparency of the review process and to shorten time to market with innovative products."
CFDA’s current plan is to inspect 300 to 400 pharmaceutical manufacturers every year in China, and 40 to 60 imported drug manufacturers outside China. In addition, blood products and vaccine manufacturers will be inspected every year, according to Wang.
The agency will also conduct random sampling of products and is aiming for 120 to 140 inspections for high risk drugs. Provincial FDAs will conduct inspections of essential drugs every year.
A top priority for CFDA is to focus on quality consistency for generics, Wang said. To that end, the agency is requiring companies to redo pharmacokinetic and bioequivalence studies for generics approved before 2010.
"This is quite a dramatic request," Zhang said, noting that more than 90% of manufacturers in China are generic manufacturers, so this affects tens of thousands of approvals that will need to be revisited.
"On the positive side, companies can expect the CFDA to prioritize their resources for innovative drugs, which is good news for multinational companies," Wang said. But the CFDA is also focusing on enhancing the quality of generic drugs, which can also be a challenge for multinational companies because the Chinese government is very keen to encourage hospital procurement of generic drugs.
"Even if you can get approval from the CFDA faster, it doesn’t mean your market access path is smoother," Wang said, stressing that CFDA has no control over reimbursement and the hospital tendering process.
"The older strategy of extending the lifeline of generics in China, will need to be revisited," Wang said. "There is still a preference for drugs made in China, so the more companies can localize their operations in China, the better they may be treated during the market access stage."