This article is written by No Longer
On February 10, 2022, the U.S. FDA held an oncology advisory committee (ODAC) online for the listing application of the PD-1 antibody sindilizumab jointly developed by Innovent Biologics and Eli Pharmaceuticals.
Surprisingly, the final vote of this expert committee was 14:1, arguing that sindilizumab needed to be supplemented with additional clinical trials to prove its suitability in the United States.
Source: ODAC review document
Most notably, the FDA cites data disclosed by the Chinese Food and Drug Administration in 2016: 80% of Chinese clinical trials are not standard.
The listing application of xindiliumab is the first time that domestic PD-1 drugs have been shipped to sea. But after enjoying silkiness in the early stage, the later stage ushered in the FDA's first blow - why is it stuck in the audit pass? And why is there such a huge disparity in voting? Worth a look.
Sails of the domestic PD-1
In December 2018, Cindili Monoclonal Antibody Injection (Daboshu) jointly developed by Innovent Biologics and Eli Lilly Pharmaceuticals was approved for marketing in China for the treatment of relapsed or refractory classical Hodgkin lymphoma (R/R cHL).
In November 2019, sindilizumab became the first PD-1 product to enter the national health insurance directory at a price reduction of 63%.
Benefiting from medicare access, the coverage of sintilizumab expanded from about 2,000 hospitals and 300 pharmacies at the end of 2019 to about 4,000 hospitals and 900 pharmacies as of December 31, 2020. Thanks to this, the annual sales of sindili monoclonal antibody reached 2.290 billion yuan in 2020, an increase of 125.4% over the previous year.
Source: PDB, Guojin Securities Research Institute
In March of the following year, Innovent Bio submitted an application to the FDA for the listing of Sindili maclizumab.
On May 17, 2021, the U.S. Food and Drug Administration (FDA) formally accepted the marketing application of sindilimab combined with pemetrexed and platinum for first-line treatment of non-squamous non-small cell lung cancer (NSCLC). This is also the first bio-innovative drug in China that has been independently developed and whose market application has been accepted by the FDA and has entered the formal review stage.
However, the hot bench has not been sitting for long, and when the acceptance of the listing application is fast-forwarded to the review stage, the result is an overwhelming "14:1" failure.
Folding
First, from the official perspective, on this folding of Cinda and Eli Lilly, the FDA gave three explanations.
The first is a change in the clinical landscape.
The FDA believes that Keytruda (pambolizumab) combined chemotherapy was approved for the treatment of nonsquamous NSCLC on August 20, 2018, and that clinical data on K-drug were widely publicized prior to approval, but the ORIENT-11 experiment with sindilizumab was initiated after this.
At the time of initiation, the standard of care for first-line metastatic lung cancer had changed, and the clinical first-line therapy had changed from chemotherapy to "immunotherapy + chemotherapy" combination therapy. Given that Keytruda (pambolizumab) chemotherapy has shown a significant clinical and statistical benefit for overall survival, researchers should not include patients in the chemotherapy control group.
The second thing is that the FDA believes that single-country clinical study data do not apply to patients in the United States.
The FDA said the STUDY population for ORIENT-11 consisted entirely of Asian patients from one country. Although China is a multi-ethnic and multi-ethnic country, the ORIENT-11 study population did not reflect the racial and ethnic diversity of lung cancer patients in the United States.
"Accepting such and similar studies conflicts with an industry-wide commitment to fair representation of clinical trials."
The third reason is that it chose progression-free survival time (PFS) as the endpoint of the clinical trial, but did not choose the overall survival endpoint (OS).
To date, all FDA approvals for first-line immunotherapy regimens for metastatic non-small cell lung cancer have been statistically OS-based improvements. Overall survival is considered the most reliable cancer endpoint and is preferred when it can be reasonably assessed.
Therefore, the FDA expressed concern about continued use after PFS, saying that ORIENT-11 shows a lack of diversity in design.
In addition, the FDA noted that the applicant had not consulted the FDA on a "study design or trial." If the FDA is consulted, head-to-head studies of sindilimab with FDA-approved PD-1 drugs with an overall survival endpoint (OS) may be recommended.
FDA with a sudden change in wind direction
Let's pull the timeline.
In fact, as early as 2019, Richard Pazdur, director of the FDA Center of Excellence in Oncology, publicly called on Chinese pharmaceutical companies to introduce domestic PD-1/PD-L1 inhibitors into the US market.
"This can be a good thing for everyone because we haven't seen Western pharmaceutical companies adjust prices yet." He said.
He also said at the time that Chinese companies imitating the FDA's approval of product development of new PD-1/PD-L1 drugs would not be much suspense, "Obviously, they may give very similar results, so we will be very smooth in approving these drugs."
Since then, Cinda, Junshi, Kangfang, and BeiGene have submitted listing applications to the FDA.
Domestic PD-1 product sea time forecast
Source: Caixin Monita Research Data Report
In 2021, however, Pazdur suddenly changed its attitude.
On December 15, 2021, Pazdur published an article in NEJM, The Wild West of Checkpoint Inhibitor Development, stating that 45% of the indications for PD-1/PD-L1 drugs on the market were approved through Accelerated Approval, usually only one-arm trials, after which randomized clinical trials may show inconsistent results.
"Drugs developed in China in a way that are lower than U.S. clinical control standards are not worthy of the FDA's care to market in the United States."
A week before the conference, on February 4, 2022, Pazdur published an article on The Lancet titled Importing oncology trials from China: a bridge over troubled water.
At least 25 new applications for immunosuppressants from China are based almost exclusively on data from clinical trials done in China, reiterating that the idea that "a single foreign data does not represent the U.S. population" is very different from the public comments at that medical conference in 2019.
Whether it is the change of face of China's surgical masks in the early stage of the epidemic, or the previous "indiscriminate resistance" to domestic drugs, it is not the first time that the FDA has reversed. This "scumbag behavior" is undoubtedly a blow to pharmaceutical companies that want to go to sea, so even Eli Lilly has suffered a dark loss.
Fast-Follow Innovative Drugs
However, from the perspective of the innovation logic of the drug itself, although the FDA is not rude this time, it is rough and not so rough. Because most of the so-called innovative drugs in China are just the products of Fast-Follow.
Fast-Follow, called fast-tracking new drug model, refers to the molecular structure modification or modification of new drugs on the basis of existing targets and mechanisms without infringing on the patents of others, looking for new drugs with the same or similar mechanism of action and new therapeutic effects.
Fast-Follow includes drugs such as Me-too, Me-better, and Me-worse.
As the name suggests, Me-too drugs are similar in structure to the first drug, with only a small difference, and this smaller difference distinguishes between Me-too drugs and generic drugs.
Unlike generic drugs, generic drugs are completely copied from the original drugs and need to wait for the original drug patents to expire before they can be put on the market. However, because the Me-too drug bypasses the patent, even if the original drug is still in the patent period, it does not need to be authorized.
Me-better refers to improved imitation, that is, to innovate on the basis of the original drug to obtain a better effect than the original drug.
Me-worse refers to the fact that although the original drug patent is bypassed, the efficacy is not as good as the original drug, and it is now difficult to obtain NMPA approval.
If innovation is hair, then generic drugs are polished baldness, and Fast Follow is three hairs — bald, but not completely bald. The advantage is that it can develop new drugs with less time and money cost, and it can also avoid the patent protection of the first drug.
At present, all domestic PD-1 inhibitors belong to Me-too drugs. Although all domestic manufacturers claim that their drugs are Me-better drugs, that is, after the drug is modified, the clinical effect is better than that of the first drug, but unfortunately the results of clinical trials cannot be self-evidenced.
This is also a microcosm of the domestic innovative drug market - not innovative enough.
Most of the existing innovative drugs are based on the research of popular targets, following the "small fights" of the first drugs. In China, similar drugs want to beat the original drug, you can rely on the cost advantage of Fast-Follow, of which it is key to quickly seize the market and go to market faster.
Without the 2019 health care negotiations, in addition to eating meat in the "First-in-class" pharmaceutical factory, the Me-too pharmaceutical factory that followed in the footsteps of the former could also live very comfortably by drinking soup. But round after round of health insurance negotiations is like a "mirror", and the innovation ability of pharmaceutical companies is clear in front of the "mirror".
So the pharmaceutical company came up with another trick - to go to sea.
What no one expected this time was that the capricious FDA taught pharmaceutical companies a lesson.
Behind the market competition, the patient is the main body
As of Last December, NMPA had approved 12 PD-1/PD-L1 products covering 11 cancers and 44 indications. Among them, non-small cell lung cancer: MSD, Hengrui, BeiGene, and Xinda have all been approved for first-line squamous cell carcinoma and adenocarcinoma.
Number of domestic PD-1/PD-L1 clinical studies
Source: FIC Intelligence, Insight, Monita Research
The market competition of PD-1 has fully entered the white-hot stage.
Whether the domestic PD-(L)1 inhibitor market can avoid the harm of "inner volume" has become an urgent question to be answered.
Of the 44 indications currently approved, 25 are from domestic PD-(L)1 inhibitors, of which 16 are duplicate indications and only 9 are exclusive or the first approved indications of their kind.
In stark contrast, of the 19 indications approved for the 4 imported PD-(L)1 inhibitors, 18 are still exclusive or the first of their kind to be approved.
Number of domestically approved indications for PD-(L)1 inhibitors and the number of exclusive or first indications
"Statistical standards are subject to approved acceptance number"
Image source: Literature collation
Whether the new clinical studies carried out by domestic PD-(L)1 inhibitors that are not innovative enough to meet the previously unmet needs of patients will be the answer sheet that pharmaceutical companies need to submit most.
After all, the consultation draft released by the Drug Review Center (CDE) of the State Drug Administration on July 2, 2021 has the following paragraph:
"New drug development should aim at providing patients with better treatment options. Patient-centered drug development can realize the fundamental value of new drug development – to solve clinical needs and maximize patient benefits."
The "scumbag behavior" of the FDA's rough words this time is actually the same meaning conveyed by the mainland CDE.
Source: CDE website
At least for now, China's innovative drug research and development still has a long way to go.
Curated by: Carollero
Executive Producer: Gyouza
Title image source: Visual China
bibliography:
[1] Beaver J A, Pazdur R. The Wild West of Checkpoint Inhibitor Development[J]. New England Journal of Medicine, 2021.
[2] Singh H, Pazdur R. Importing oncology trials from China: a bridge over troubled waters? [J]. The Lancet. Oncology, 2022: S1470-2045 (22) 00071-7.
[6] Guidelines for Clinical Research and Development of Antineoplastic Drugs Oriented by Clinical Value[R].
Guidelines for the clinical application of novel antineoplastic drugs (2021 edition)[M].
[8] Monita - Biweekly Report of the Pharmaceutical and Biological Industry: Global Competitive Landscape of PD-1 and PD-L1 - 211227