China's first PD-1 to go overseas is a newborn calf that is not afraid of tigers?

The high-profile ODAC conference detonated the global live broadcast room

In the end, Innovent Bio and Eli Lilly's PD-1 antibody sintilimab ended in a 14:1 vote

The first domestic PD-1 to pass the FDA, the expert opinion does not recommend direct approval, and believes that additional clinical trials need to be supplemented before approval to prove its applicability in the American population and American medical practice

The approval of Biogen's Alzheimer's treatment drug Aduhelm (aducanumab) was a special case in which the FDA did not accept the ODAC expert opinion, but in general, the FDA will follow the voting results of the ODAC expert committee

Figure 1 FDA Expert Committee voting results

Under the dual dilemma of domestic PD-1/PD-L1 extreme involution and increased medical insurance negotiation, going overseas to open up new markets is undoubtedly a potential commercialization path

This "trial examination" is an outpost for domestic innovative drugs to go overseas, and it is also a landmark case worthy of study

The focus of the Cinda/Lilly PD-1 "big test", let's briefly review together:

From "Welcome" to "Strict Judgment",

Does it make going to sea a "hell mode"?

During the 2019 AACR meeting, Dr.

As long as the quality is good, the FDA will accept applications that rely solely on Chinese clinical data, and the FDA welcomes products that are more cost-effective

The official statement of FDA officials once made the market believe that China-Only clinical data does not pose a substantial problem for the drug's application for marketing in the United States

In fact, there are indeed Chinese pharmaceutical companies that have successfully launched their drugs in the United States with clinical trial data mainly completed in China

In November 2019, BeiGene’s zanubrutinib was successfully applied for at the FDA mainly using Chinese population data (with several overseas patients)

On May 18, 2021, Innovent and Eli Lilly jointly announced that the US FDA has officially accepted the PD-1 inhibitor sintilimab injection combined with pemetrexed and platinum for non-squamous non-small cell lung cancer The New Drug Marketing Application (BLA) for the first-line treatment of (NSCLC) is also understood to be a signal of support from the FDA

Until the second half of 2021, the >

Especially at the Biopharma Congress virtual meeting in December 2021, Dr.

In February of this year, Dr.

Figure 2 Commentary on the article "Importing oncology trials from China: a bridge over troubled waters?"

Screenshot of the official website

In an interview before the ODAC meeting, Dr.

The 180-degree change in attitude means that the "disruptive pricing strategy" can no longer become a bright sword and gold medal for domestic innovative drugs to go overseas
.

Criteria for judging clinical efficacy

Is it getting higher and higher?

The ORIENT-11 clinical study confirmed the efficacy and safety of sintilimab combined with pemetrexed and platinum-based chemotherapy for the first-line treatment of nsqNSCLC
.

The median progression-free survival (PFS) of the patients reached 8.
9 months, which was nearly 4 months longer than the placebo group, and the risk of tumor progression decreased by approximately 52%
.

Figure 3 PFS analysis of clinical efficacy of ORIENT-11

Source: BLA 761222 ODAC: Sintilimab BLA in non-squamous NSCLC

The excellent PFS data of ORIENT-11 was questioned by the FDA, and its non-inferiority was basically bombarded in this case;

He even asked with the smell of gunpowder: "How many times has Eli Lilly conducted trials that have deprived patients of therapies with known survival advantage?"

(How many trials has Eli Lilly conducted that deprived patients of a therapy with a known survival advantage?)

Taking the head-to-head comparison with the marketed PD-1+ chemotherapy and using the OS endpoint is the second major signal released by the FDA experts at this ODAC conference
.

PFS no longer complies with U.
S.
medical practice for varieties/lines declared together
.

It is basically the same as the "Clinical Value-Oriented Clinical Research and Development Guidelines for Antitumor Drugs" issued by CDE last year
.
For products with serious involution, if they do not have the characteristics of "more effective curative effect, safer medication, and faster onset", it is basically impossible to do it in China or overseas
.

Or, sprinting first-in-class, breakthrough therapy, emerging treatment methods, etc.
, may better take the lead
.

Adequate communication and compliance with local national regulatory standards

will be required?

At the ODAC meeting, Eli Lilly/Cinda stated that the project had already communicated with the FDA before the project was launched, and the sponsor also emphasized maintaining communication with the FDA and giving positive feedback when stating its views
.

Figure 4 ORIENT-11 Regulatory Communication Timeline (Source: BLA 761222 ODAC: Sintilimab BLA in non-squamous NSCLC)

But they were quickly "slapped in the face".
FDA experts sorted out their own timelines.
They were tit-for-tat and full of gunpowder.
They said that they did not equate the communication with the FDA before the NDA with the communication with the FDA before the start of the trial
.

Figure 5 Timeline of FDA regulation of ORIENT-11

Source: Screenshot of the live broadcast of the ODAC conference

Without sufficient communication with the FDA, the ORIENT-11 trial did not fully consider principles such as E5 & E17, and did not update the informed consent guidelines in a timely manner, and informed the enrolled patients of the more effective Keytruda combination chemotherapy that already existed
.

FDA believes that obtaining data in an environment that is easy to operate and has a relaxed approval environment is used to challenge the FDA's bottom line without adequate respect for regulatory rules
.

This heavy hammer basically affected the wind direction of the entire vote, and also established the possibility of basically no direct approval
.

Drugs are a special commodity that relies heavily on regulatory access.
To become a global pharmaceutical company, you must first understand the medical conditions, regulatory policies, social conditions, public opinion, and environmental trends of the target market
.

The development, registration and approval of drugs is not only a science, but also an art to some extent
.

The "Waterloo" encounter of Innovent Bio's PD-1 also explains the complexity and difficulty of the process of China's innovative drugs going overseas
.

Cinda PD-1 died at sea?

China's first PD-1 to go to sea, not only is a newborn calf who is not afraid of tigers, but also explores an international warrior in the "spiral scroll" situation, providing a useful reference for the latecomers to go to sea
.

This is a battle for the entire industry to share the same fate, and it is also a milestone node
.

This setback does not mean the premature death of Cinda PD-1
.

Sintilimab has a wide range of indications, and there are currently more than 30 clinical trials in progress, many of which are international multi-center clinical trials in many countries around the world
.
In the future, it is also possible to promote the application of sintilimab for the treatment of other indications in the United States
.

Innovent Bio also issued a statement quickly, and it is believed that the impact on short-term financial statements is relatively limited
.

Figure 6 Innovent Biological Statement

On the other hand, under the support of FDA regulatory rules and obvious guiding principles, some review loopholes adopted opportunistically in an attempt to get approval quickly, a little bit of knowing that there are tigers in the mountains
.

When Chinese innovative drugs go overseas, they must carefully study the regulatory framework of foreign data, including the review of ICH and the determination of SOC, as well as communication with regulatory authorities
.

summary

There is no doubt that the exploration and development of Innovent Bio will accumulate valuable experience for domestic innovative drugs to go overseas, and will eventually be internalized into China's differentiated ability to go overseas, and will eventually be transformed into the common ground of China's pharmaceutical industry.
wealth
.

This is the only way for China to turn from a "big pharmaceutical country" to a "powerful pharmaceutical country".
It is precisely the "battles" of big and small, winning and losing, that can "be at the top of the mountain and see all the mountains and small"
.

China's naval regiment, come on!