The FDA changed its face two years after the domestic drug went out to sea: 80% of Chinese clinical research is not standard

On February 10, 2022, the US FDA held an online Oncology Drug Advisory Committee (ODAC) for the marketing application of the PD-1 antibody sintilimab jointly developed by Innovent and Eli Lilly
.

Surprisingly, the final vote of the expert committee was 14:1, arguing that sintilimab needs to be supplemented with additional clinical trials to prove its applicability in the United States
.

Source: ODAC Review Document

Most notably, the FDA cited data disclosed by the China Food and Drug Administration in 2016: 80% of Chinese clinical trials are substandard
.

Source: ODAC Review Document

The listing application of sintilimab is the first time that a domestic PD-1 drug has gone overseas
.

But after enjoying the silky smoothness in the early stage, the FDA ushered in a blow in the later stage-why is it stuck in the audit level when going overseas? Why is the vote so disparate? Worth a look

The sailing of the domestic PD-1

The sailing of the domestic PD-1

In December 2018, sintilimab injection (Daboshu), jointly developed by Innovent and Eli Lilly, was approved for marketing in China for the treatment of relapsed or refractory classical Hodgkin lymphoma ( R/R cHL)
.

In November 2019, sintilimab became the first PD-1 product to enter the National Medical Insurance Catalog at the cost of a 63% price reduction
.

Benefiting from the entry into medical insurance, the coverage of sintilimab has expanded from approximately 2,000 hospitals and 300 pharmacies at the end of 2019 to approximately 4,000 hospitals and 900 pharmacies as of December 31, 2020
.

Thanks to this, the annual sales of sintilimab in 2020 reached 2.

Source: PDB, Sinolink Securities Research Institute

In March of the following year, Innovent Bio submitted a marketing application for sintilimab to the FDA
.

On May 17, 2021, the U.
S.
Food and Drug Administration (FDA) officially accepted the marketing application of sintilimab in combination with pemetrexed and platinum for the 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 marketing application has been accepted by the FDA and entered the formal review stage

However, the hot bench has not been on the bench for a long time.
When the acceptance of the listing application is fast-forwarded to the review stage, the result is an overwhelming "14:1" failure
.

Broken Halberd

Broken Halberd

Let’s first look at the official point of view.
In the failure of Cinda and Eli Lilly, the FDA gave three explanations
.

The first is a change in the clinical landscape
.

The FDA believes that Keytruda (pembrolizumab) combined with chemotherapy was approved for the treatment of non-squamous NSCLC on August 20, 2018, and the clinical data of K drug have been widely publicized before the approval, but the ORIENT of sintilimab -11 The experiment starts after this
.

At the time of launch, the standard of care for first-line metastatic lung cancer has changed, and the clinical first-line therapy has changed from chemotherapy to "immunotherapy + chemotherapy" combination therapy
.

Given the clinically and statistically significant benefit of Keytruda (pembrolizumab) chemotherapy on overall survival, investigators should not include patients in the chemotherapy control group

Source: ODAC Review Document

The second thing is that the FDA believes that the single-country clinical study data is not applicable to US patients
.

The FDA said the ORIENT-11 study population consisted entirely of Asian patients from one country
.

Although China is a multi-ethnic and multi-ethnic country, the ORIENT-11 study population does not reflect the racial and ethnic diversity of lung cancer patients in the United States

"Accepting this and similar studies conflicts with industry-wide commitments to fair representation in clinical trials
.

"

Source: ODAC Review Document

The third reason is that it chose progression-free survival (PFS) as the clinical trial endpoint, but not overall survival (OS)
.

To date, all FDA approvals of first-line immunotherapy regimens for metastatic NSCLC have been based on statistical improvements in OS
.

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 medication after PFS, saying that ORIENT-11 showed a lack of diversity in design
.

Image credit: ODAC review document

In addition, the FDA noted that the applicant has not consulted the FDA regarding the "study design or trial
.

" If the FDA is consulted, a head-to-head study of sintilimab with an FDA-approved PD-1 drug with an overall survival endpoint (OS) may be recommended

FDA in sudden change

FDA in sudden change

Let's pull the timeline
.

In fact, as early as 2019, Richard Pazdur, director of the FDA Oncology Center of Excellence, publicly called on Chinese pharmaceutical companies to introduce domestic PD-1/PD-L1 inhibitors into the U.
S.
market
.

"This could be a good thing for everyone because we haven't seen a price adjustment from Western pharma,
" he said
.

He also said at the time that Chinese companies imitate FDA-approved products to develop new PD-1/PD-L1 drugs, and there will be no suspense to get FDA approval.

"Obviously, they may give very similar results, so we When these drugs are approved, it will be smooth
.
"

After that, Cinda, Junshi, Kangfang, and BeiGene successively submitted marketing applications to the FDA
.

Prediction of the time for domestic PD-1 products to go to sea

Source: Caixin Monita Research Data Report

In 2021, however, Pazdur suddenly changed his attitude
.

On December 15, 2021, Pazdur published the article The Wild West of Checkpoint Inhibitor Development in NEJM, pointing out that 45% of the indications for the marketed PD-1/PD-L1 drugs have passed the Accelerated Approval (Accelerated Approval).
Approved pathways are usually only single-arm trials, followed by randomized clinical trials that may show inconsistent results
.

"A drug developed in China in a way that is lower than the US clinical control standard is not worthy of the FDA's care to be marketed in the United States
.
"

One week before the conference, on February 4, 2022, Pazdur published another article in The Lancet entitled Importing oncology trials from China: a bridge over troubled water
.

The article pointed out that at least 25 new drug applications for immunosuppressants from China were almost exclusively based on clinical trial data in China, reiterating the view that “single foreign data cannot represent the U.
S.
population”, and the medical conference in 2019.
Public comments on the website vary widely
.

Whether it is the face-changing of Chinese surgical masks in the early stage of the epidemic, or the previous "indiscriminate boycott" of domestic drugs, it is not the first time that the FDA has backtracked
.
The "scumbag behavior" this time is undoubtedly a blow to the pharmaceutical companies that want to go overseas, so even Lilly suffered a secret loss
.

Fast-Follow Innovative Drugs

Fast-Follow Innovative Drugs

However, from the perspective of the innovation logic of the drug itself, although the FDA is not kind this time, it is not so rough in its words and rationales
.
Because most of the so-called innovative drugs in China are just the product of Fast-Follow
.

Fast-Follow is called the fast-tracking new drug model, which refers to the molecular structure modification or modification of new drugs on the basis of existing targets and mechanisms without infringing the patents of others, looking for new treatments with the same or similar mechanism of action effect of new drugs
.

Fast-Follow includes Me-too, Me-better, Me-worse, and more
.

Me-too drugs, as the name suggests, are similar in structure to first-in-class drugs, with only minor differences that distinguish Me-too drugs from generic drugs
.

Unlike generic drugs, generic drugs completely copy the original brand drugs and need to wait for the patent of the original brand drugs to expire before they can be put on the market
.
However, because Me-too drugs bypass 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 research drug, and obtain better efficacy than the original research drug
.

Me-worse means that although the patent of the original research drug is bypassed, the efficacy is not as good as the original research drug, and it is difficult to obtain NMPA approval now
.

If innovation is hair, then generics are shiny bald heads, and Fast Follow is three hairs — bald, but not completely bald
.
The advantage is that it can not only develop new drugs with less time and money cost, but also avoid the patent protection of the first drug
.

At present, all domestic PD-1 inhibitors are Me-too drugs
.
Although all domestic manufacturers claim that their drugs are Me-better drugs, that is, after the drugs have been modified, the clinical effects are better than the first-in-class drugs, but unfortunately the results of clinical trials cannot be self-certified
.

This is also a microcosm of the domestic innovative drug market - not enough innovation
.

Most of the existing innovative drugs are based on the research of popular targets, following the "small fight" of the first drug
.
In China, if similar drugs want to beat the original research drugs, they can rely on the cost advantage of Fast-Follow.
Among them, it is crucial to quickly seize the market and launch faster
.

If there is no medical insurance negotiation in 2019, in addition to eating meat in the "First-in-class" pharmaceutical factory, the Me-too pharmaceutical factory, which follows the former's footsteps, can also live very comfortably by drinking soup
.
But round after round of medical insurance negotiation is like a "mirror mirror", in which the innovation capabilities of pharmaceutical companies can be seen at a glance
.

So pharmaceutical companies came up with another trick - going overseas
.

What no one expected this time was that the capricious FDA taught drug companies a lesson
.

Behind the market competition, patients are the main body

Behind the market competition, patients are the main body

As of December last year, NMPA has approved 12 PD-1/PD-L1 products, involving 11 cancer types and 44 indications
.
Among them, non-small cell lung cancer: MSD, Hengrui, BeiGene, and Cinda 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 completely entered the white-hot stage
.

Whether the domestic PD-(L)1 inhibitor market can avoid the harm of "involution" has become an urgent question to answer
.

Among the 44 approved indications so far, 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, 18 of the 19 indications approved for 4 imported PD-(L)1 inhibitors are still exclusive or the first of their kind to be approved
.

Number of domestically approved indications and exclusive or first indications for PD-(L)1 inhibitors

"The statistical standard is subject to the approval number"

Image source: Documentation

Whether the new clinical research conducted by domestic PD-(L)1 inhibitors with insufficient innovation can meet the previously unmet needs of patients will be the answer that pharmaceutical companies most need to submit in the future
.

After all, the draft for comments issued by the Center for Drug Evaluation (CDE) of the State Drug Administration on July 2, 2021 has the following paragraph:

"New drug development should be the highest goal of providing patients with better treatment options
.
Only by patient-centered drug research and development can the fundamental value of new drug research and development be realized—solving clinical needs and maximizing patient benefits
.
"

The FDA's "scumbag behavior", which is not rough, actually conveys the same meaning as China's CDE
.

Image source: CDE official website

At least for now, China's innovative drug research and development still has a long way to go
.

references:

references:

[1] Beaver JA, Pazdur R.
The Wild West of Checkpoint Inhibitor Development [J].
New England Journal of Medicine, 2021.

[1] Beaver JA, 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.

[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.

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