Outlier: Takeda Scores Chinese Clinical Trial Authorization For Diabetes Agent In Record 7 Months

It’s not an anticancer therapy, and it has only Phase II data from overseas, but Takeda has managed to cut the average clinical trial authorization time for Class 1 new drugs in China by two months.

BEJING – Taking advantage of a special review process commonly known as the “green channel” in China, Takeda Pharmaceutical Co. Ltd. scored a clinical trial authorization for anti-diabetic agent TAK-875 in record speed, which even took the company by surprise.

TAK-875 is a novel treatment for type-2 diabetes that works on GPR40, a G-protein-coupled receptor that appears in insulin-secreting cells in the pancreas. The compound activates GPR40 to stimulate insulin secretion only when glucose levels are rising, said James Garner, general manager for the Takeda R&D Asia Center in Singapore, during the annual ChinaTrials conference in Beijing Nov. 7.

A Phase II trial conducted in the U.S. found that blood sugar in 303 patients who received TAK-875 was significantly reduced by a similar amount to those in the group taking glimepiride. However, 19% of patients who received glimepiride reported hypoglycemia, compared to only 2% on TAK-875.

Encouraged by the result, Takeda was eager to initiate a global Phase III study, but the company was also determined to include China, which has the most diabetes patients in the world, in the study. A clinical trial application was submitted in December 2011, and in July, Takeda received the go-ahead from China’s State FDA.

In China, TAK-875 is defined by SFDA as a Class 1 drug, meaning it has not been marketed elsewhere in the world. Another category more commonly used by multinationals in China is a Class 3 drug, which has never been marketed in China.

Although China has officially set 145 working days for CTA approval, compared to 30 days in the U.S. and Japan, and 60 days in the European Union, the actual time is much longer. According to the R&D-based Pharmaceutical Association Committee (RDPAC), a trade association representing Big Pharma in China, the CTA benchmark timeline for chemical compounds in 2011 was 15-19 months, and 18-22 months for biologics. Only Class 1 drugs fare better, with 9.5 months average CTA approval time.

To speed up the process, SFDA introduced a special review process in January 2009 that formally established a consultation system in which sponsors can request meetings with SFDA at each stage of new drug development. Prior to the introduction, consultations took place only after a new drug application had been submitted.

Four kinds of drugs qualify for such status: Class 1 drugs; Class 3 drugs; new treatments for AIDS, cancers and other rare diseases with greater efficacy over current treatments; and new drugs targeting diseases without available treatments (Also see "China Issues Fast-Track Registration Procedure For Drugs To Balance Innovation And Risk: SFDA Press Conference" - Scrip, 12 Jan, 2009.).

The so-called “green channel”, even with rolling submissions and pre-submission consultations, has not significantly reduced approval times, said an RDPAC official during the DIA China conference in May (Also see "China Enhances Data Management, Communication For IND Approvals" - Scrip, 4 Jun, 2012.). A study sponsored by RDPAC found that CTA timelines for both multi-regional clinical trials and green-channel drugs was around 10 months (roughly 50% of MRCTs enjoy green-channel status).

Nothing Beats Preparation Except A Good Compound

So what makes Takeda’s TAK-875 an outlier? Three factors aligned well, Garner said: a good compound, a well-prepared submission and a good relationship with regulators.

“First in class, never before registered and treating a prevalent disease affecting a large population in China has significant priority to other me-too drugs,” Garner noted.

Aiming to develop new products to spur innovation in the pharmaceutical industry, the Chinese government has set ambitious goals in its 12th Five-Year Plan. Despite a broader definition for new drugs, which are defined as not marketed in China instead of new chemical entities, the government has showed its willingness to bring more NCEs to the market.

SFDA approved a record five NCEs in 2011 (Also see "Five NCEs Approved In China In 2011: A Closer Look At SFDA’s Progress Report" - Scrip, 11 Oct, 2012.). Still, the number is merely a fraction of the average 30 NCEs approved each year in the U.S. and Japan.

Novel drugs for major and rare diseases will particularly benefit from the government’s drive for innovation. Oncology therapies are obvious beneficiaries – Beta Pharma Inc.’s icotinib, for example, was cleared for clinical trials within six months (Also see "Meet China’s New Innovators: Beta Pharma Redefines Innovation With “Me-Too, Me-Better” Strategy" - Scrip, 3 Aug, 2012.).

For non-cancer treatments such as diabetes agents, the story can be different. SFDA gave TAK-875 the green light because the compound showed high efficacy of lowering glucose but also low risk of hypoglycemia, Takeda said.

China has an estimated 90 million people with type 2 diabetes, and the number is growing. Largely relying on old-line therapies such as metformin and insulin, the country is in need of novel treatments with new mechanisms that control blood sugar without the risk of hypoglycemia, particularly for patients resistant to insulin.

According to a Nov. 13 Citi research note on China’s oral diabetes market, metformin is the second-biggest selling diabetes drug, accounting for 13.5% market share, after acarbose (36.2%), and slightly ahead of repaglinide (13.4%). As the manufacturer of the China blockbuster Glucobay (acarbose), Bayer AG dominates the oral diabetes market with 30% share, followed by Novo Nordisk AS (12.3%), maker of Novonom (repaglinide) and Bristol-Myers Squibb Co. (10.4%).

Growing 20% in the past decade, the diabetes market in China is expected to generate $3.2 billion by 2016 (Also see "China Diabetes Cases Continue To Mount, Creating $3.2 Billion Market" - Scrip, 5 Nov, 2012.).

Taking note of the demand, SFDA values novel products and is willing to work with drug makers to bring them to the market faster, said Takeda. The agency is also changing its review process to be more science-driven, instead of checklist-based, Takeda Regional Regulatory Affairs Director Angela Yan said during the forum.

It also helped that SFDA has established several communication channels, Yan added (Also see "China SFDA Encourages Regulatory Consultations In New Communication Guidelines" - Scrip, 19 Jul, 2012.).

Well-prepared submissions are another key to success, Garner observed. “For multinational companies, the requirement from colleagues at Chinese SFDA seems to be too much on detail, especially in terms of CMC [chemical, manufacturing and controls] data, which can be unnerving.”

“So make sure that dossier contains as much detail as possible, really comprehensive, to avoid questions and pressure later in the process,” he emphasized.

Moreover, a good relationship with the regulatory agency is essential, he said, noting that Takeda held pre-submission interactions with SFDA and took advantage of the Center For Drug Evaluation’s weekly open meetings, held every Wednesday, to gain a better understanding of the review process (Also see "China SFDA Encourages Regulatory Consultations In New Communication Guidelines" - Scrip, 19 Jul, 2012.).

The special review status accelerates the process, Garner noted, allowing sponsors to hold meetings with CDE prior to and during the review process, and supplemental materials are also allowed.

When CDE requests face-to-face meetings, companies should respond quickly, Garner advised. In Takeda’s case, the center sent requests on June 13 and June 26, and those meetings ironed out remaining issues and paved the way for clinical trial authorization in July.

Local Corporate Commitment Required

To ensure faster trial approval and successful drug development in China, MNCs need to demonstrate a strong corporate commitment and provide full support to local teams, Takeda said.

In the case of TAK-875, the China Phase III trial is part of a five-country Asia-Pacific study in parallel with the rest of the world, a first for Takeda. The other four countries are South Korea, Taiwan, Australia and New Zealand. Getting China on board was no small accomplishment.

The extension study in China will be important in getting local data to bridge Takeda’s global study and erase SFDA concerns over study design, Takeda’s Yan stressed, adding that the efforts will add extra workload and require full support from the global study team.

To prepare, the company has not only involved its China and Asia-based clinical and regulatory teams, but also experts from the U.S. to coordinate efforts, Takeda said.

Demonstrating a newfound openness, CDE recently made the rare move of posting a public notice on its website explaining why the review process has been slow, and encouraging study sponsors and applicants to provide feedback (Also see "China’s Sunshine Plan: Clinical Trials Registry, English Website" - Scrip, 31 Oct, 2012.).

Despite the progress, Garner said the speed Takeda enjoyed is likely a case-specific story. But it is welcome news given Takeda’s ambitious 29% growth goal for China.