Wen 丨 Cai Jian Dao, Author 丨 Yan Rui, Editor 丨 Yang Zhongxu
Christmas Eve, December 24, 2021. Innovent Biotechnology (HK.01801) announced that the State Drug Administration (NMPA) has officially accepted the marketing application for a new indication of sindilizumab. This was probably the first time in 10 days that Cinda had breathed a sigh of relief.
Previously, China's pharmaceutical market has been hit hard, so much so that Cinda has had to issue a public statement to calm negative sentiment - on December 15, the Financial Times said that the US Department of Commerce added several Chinese biotech companies to the entity list, dampening the stock price of the pharmaceutical sector; on December 16, Richard Pazdur, director of the FDA's Center of Excellence for Oncology (OCE), once again hit the A/H-share innovative drug sector.
The domestic "cabbage price" of China's innovative drugs and the pursuit of "going to sea" for profit are the most respected development logics in recent stages. Since the opening of the New Drug Fast Track in 1982, the U.S. FDA has become one of the premier options for innovative drugs. However, since 2014, 7 antibodies to the PD-1/PD-L1 target have obtained approval for more than 85 tumor indications, and some commentators have said:
"The monoclonal antibody/double antibody of 7 antibodies, and the continuous 'permutation and combination' between various combination treatment options and various tumor indications, have departed from the original intention of innovation - perhaps after that, the pharmaceutical company's own PD-1/PD-L1+xxx dual antibody will be 'rolled up' first."
In this regard, relevant professionals commented: "Of course, the permutation and combination of the argument is somewhat one-sided, but (pharmaceutical companies) do go public in order to meet the various alternative endpoints, and invest a huge amount of resources." ”
Since 2016, Pazdur has expressed dissatisfaction with the "carve-up tide" of new indications. As Director of the FDA Center for Oncology Excellence and Director of the Office of Hematology and Oncology Products (OHOP), he is directly responsible for leading the development and implementation of a comprehensive regulatory approach to cancer drugs and therapeutic biologics.
Since the end of 2019, the FDA has begun to issue clearer clinical trial guidelines and re-examine to replace tumor treatment drugs that have been approved at an accelerated endpoint. "Empty cheques" that were listed as "alternative endpoints" but could not pass the corroborative review were withdrawn from the market because the medical sector could not withstand a bubble-hit "subprime mortgage crisis".
01, Pazdur spoke, the Chinese market shook three times
On December 16, Richard Pazdur, director of the FDA's Center of Excellence for Oncology (OCE), spoke in an interview with Premier Policy, "sprinkling salt" on the wounds of innovative drugs:
"New drugs are approved on clinical data from just one country, such as China, which is clearly problematic – contrary to the principle of the United States' efforts to increase patient diversity in clinical trials."
Pazdur is not only the "number one" of the FDA's innovative drug approval system, but also has a close relationship with the Chinese innovative drug market.
In 2018, Pazdur "urged" China to introduce qualified, low-priced PD-1/PD-L1 inhibitors to the U.S. market. During a visit to the Shanghai Pudong Zhangjiang Hi-Tech Park in April of that year, he said in an interview that as long as the quality is good, the FDA will definitely accept applications that rely solely on Clinical Data generated from China; although it will not use price as the standard, it will welcome low-priced products.
Speaking during a Q&A session at the American Association for Cancer Research called "East meets West: Chinese Pharmaceuticals Explore Western Markets," Pazdur also said during a Q&A session: "It may be a good thing for everyone that Chinese companies are competing for PD-1 prices in the United States — so far, we have not seen major Western pharmaceutical companies change prices."
"I can see a very simple development strategy," he says, "for example, in terms of lung cancer, you can simply do some of the research that big pharmaceutical companies have done." You already know the effect size, you don't even have to do non-inferior studies to get started, and statistical plans are easy to write—you don't even need to be a statistician. ”
He also believes that China's imitation of drugs that have been approved by the FDA will also be approved smoothly: "Obviously, they will produce very similar results, so we have very little to say about approving such drugs." ”
These previous statements seem to run counter to those made in an interview with Prevision. Pazdur's views in recent reports are three:
1. You can't just do a single country single ethnic clinic;
2. The "me-too" target is flooded, and international management should be carried out;
3. PD-1/PD-L1 homogenization competition is serious (for international leading innovative pharmaceutical companies).
The first two points will undoubtedly trigger a huge earthquake in China's innovative drug market. Because China's tumor immunotherapy is basically maintained at the "me-too" level, and many clinical trials have relied on Chinese patient data for verification. Previously, the successful sea launch of BeiGene (688235) zebutinib and the recent announcement by the CDE that it intends to include it in breakthrough therapies undoubtedly fuel this logic.
As one of the seeded players who mainly rely on Chinese clinical data for applications, Innovent's Sindili monoclonal antibody is the first to bear the brunt. In the minutes of the subsequent meeting, Cinda explained in detail the enrollment rate of patients in the subgroup: although the enrollment ratio of Chinese patients was the highest among the four drugs, it was still within the reasonable scope of clinical guidelines and did not conflict with the FDA's rule that clinical trials were multi-center; at the same time, the enrollment rate of terminally ill patients ranked second among the four drugs and was more in line with real-world conditions.
Still, the debate over whether the drug is "the best" hasn't stopped. Some medical related people said that Sindilly did not exceed Merck K drug (Keynote189) in the risk indicators of each alternative endpoint.
Because of the general lack of head-to-head trials, data such as clinical trials of tumor drugs, the total survival (OS) after enrollment of many pairs of patients, and the progression-free survival (PFS) of tumor control were used to predict the effectiveness of treatment options.
The smaller the risk ratio (HR) data resulting from the model, the greater the likelihood that patients will benefit from it. For example, the PFS trial HR=0.76 represents a 24% reduction in patient enrollment without progression mortality. In general, the higher the PD-L1 expression in patients, the better the immunotherapy effect. In clinical trials, low expression rates such as PD-L1 >
In the minutes of the meeting, the K drug used by Innovent Biologics is not squamous cell carcinoma PD-L1>
Then, in terms of OS HR data, sindilizumab also seems to rank first, at 0.60, better than merck K's 0.608. However, in the K drug data released by the American Society of Clinical Oncology (ASCO) Annual Meeting in May 2020, its OS HR was 0.51, far exceeding the data taken in the minutes of the Cinda Biological Conference. With this data alone, it is difficult for Sindilly to argue for the so-called "best".
The logic of China's innovative drugs going to sea has plunged into a controversial "Rashomon".
02. Does the FDA only target Chinese pharmaceutical companies?
Not against China, of course. The FDA targets any company that exploits the substitute endpoints of clinical trials and "shoddy" companies for profit. If the "shoddy" bubble floods, the medical field will never be able to withstand a "subprime mortgage crisis"-style disaster.
The reason why pharmaceutical companies dare to call themselves "me-better" or "the best" is related to the FDA approval system. Beginning in the 1980s, the FDA began using alternative endpoints and accelerated approvals to help bring on-market oncology treatment drugs, opening up the possibility of various risk analysis pathways.
Although in general, the higher the rate of PD-L1 expression in patients, the greater the effectiveness of immunotherapy. However, the mechanism of immune onset can not be determined by only one expression rate criterion, and there are many cases in which the expression rate is 90% but the immunotherapy is ineffective, and the expression rate is 1% but the efficacy of single-drug therapy is good. According to relevant people in the industry, to some extent, the PD-L1 expression rate is not entirely a scientific standard for clinical judgment, or one of the prediction model dimensions used by pharmaceutical companies to go public.
The alternative endpoint cannot really replace the clinical endpoint, just like the credit crisis of the year, the bubble can never replace the real gains. For example, tumor shrinkage can certainly be used as a substitute endpoint to support the marketing of drugs, but whether it can improve the overall survival rate of patients still needs to be verified by confirmatory experiments. It's like the difference between "gold water" and "silver water" in the werewolf killing, not to mention that "golden water" is not always correct.
Therefore, as a drug marketed as a "possibility", as long as it reaches a certain level, in the absence of real data and confirmatory tests, each drug can always find an analytical model to prove that it is valid.
Since the effect is uncertain, why support the accelerated approval of drugs for marketing? Because it is too difficult to develop tumor treatment drugs. If the "gold standard" of the clinical trial endpoint, that is, the only criterion for the overall survival rate of patients, it will be extremely difficult for cancer treatment drugs to pass the approval.
At the end of the last century, the FDA recognized that in terms of serious or rare diseases, few drugs, few trials, and few approvals are likely to create a vicious circle. Therefore, making patients as available as possible becomes the starting point for the alternative endpoint of innovative drug use and accelerating the approval of marketing.
Acceleration and substitution, combined with the huge market for tumor treatment drugs, will inevitably bring about the phenomenon of drug accumulation. As a result, Pazdur has been expressing dissatisfaction with innovative oncology companies led by the United States since 2016, two years after the first PD-1/PD-L1 drug was launched.
However, Pazdur's ideal of low price and innovation orientation has not been realized. China's innovative pharmaceutical companies not only did not reduce prices, but also hoped that drugs could "go to sea" to recover the profits that had been beaten in the domestic medical insurance negotiations.
On December 15, 2021, the day before his interview with Prevision, he and colleague Julia Beaver continued to express this disappointment in the New England Journal of Medicine, "The Wild West of Checkpoint Inhibitor Development."
"Over the past seven years, the FDA has approved seven antibodies against the PD-1/PD-L1 pathway and more than 85 indications for these drugs." [1] The article begins seven years ago, when Merck K and Bristol Squibb O were approved in 2014.
As of August 2021, according to relevant media statistics. Out of this approved indication, search for "PD-1" on the official website of the ClinicalTrials.gov, there are still 2903 related clinical trials in progress, and 1343 clinical trials that are still under recruitment.
In thousands of studies, there are very few new indications or breakthrough therapies, most of which are combination treatment regimens of 7 existing antibody components, which can be understood as the "permutation combination" of existing antibody drugs and different indications.
Pazdur believes that this greatly reduces the marginal effect of investment in cancer immunotherapy research. First, there are no studies to compare the accessibility and economy of different therapies; second, although the design and treatment plan of this drug have been "streamlined", the research and development and approval expenditure of the new "permutation" scheme remains high. It is equivalent to doing the work of "generic drugs", but investing in the resources required by the "original research drugs" and earning the money of the "original research drugs".
At the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) in 2016, Pazdur said, "People should ask themselves... Should we make better use of those resources to develop more innovative drugs? ”。
Based on this, there was Pazdur's speech at the "East meets West" conference. He directly said that he very much welcomes Chinese companies to "imitate" PD-1/PD-L1 to break the deadlock of homogeneous competition in the "Wild West" in the United States and unwilling to reduce prices.
However, homogeneous competition is not a particular flaw of a particular country. The phenomena slammed in the Wild West article — such as the rush of sponsors, the development of approval strategies based on non-randomized, one-arm trials, the recruitment of patients with unmet medical needs for accelerated approval, and so on — have emerged and will continue to be frequent worldwide (including China, of course).
At this point, even if we completely leave aside the data analysis of drug research, we can understand why Pazdur's few anti-homogenization and focus on the validity of clinical data can shake the market's confidence in China's innovative pharmaceutical companies:
For China's innovative drug market, "me-too" is still the ceiling for most companies, and most of the competitors are people who know that the "inner volume" has entered the white-hot stage, but has not retreated. They understand that if they want to make a profit in the "subprime mortgage crisis", they must of course face a big gamble.
03. FDA approval tightens, confirmatory review "accounting after autumn"
Perhaps, the previous few years were indeed the bonus period of PD-1/PD-L1, but the fast approval mechanism has never been a shortcut for speculators.
In February 2012, then-FDA Director Echenbach published an article in the Wall Street Journal titled "FDA Drug Approval Should Be Based on Safety, Effectiveness Should Be Left to Postmarket Research," advocating reform of drug regulation to encourage innovation, reduce drug prices, and benefit patients. This meant that the FDA at that time had an encouraging and wait-and-see attitude towards the tumor treatment drug market.
After all, if you want to innovate, you need to allow the existence of "bubbles" to a certain extent, like Deng Xiaoping's metaphor of "opening windows for ventilation and flies will come in". Therefore, Pazdur's criticism of innovative drugs began in 2016, which was completely disapproved by pharmaceutical executives.
Pharmaceutical companies that have been immersed in innovative research and development for decades are well aware of the difficulty of innovation, which not only needs the accumulation of resources, but also the favor of luck. Most of them believe that combination therapy, or "permutation combination", between different antibody drugs under existing targets, is the trend of cancer immunotherapy in the real world. From 2014 to the present, reality has confirmed their claims.
The 7 antibody drugs for PD-1/PD-L1 mentioned above can obtain more than 85 indication approvals, relying on alternative endpoints and accelerated approvals. This is the source of the so-called dividend period – since 1982, the fast-track approval channel has mostly been "occupied" by tumor treatment drugs; conversely, tumor treatment drugs are rarely excluded from the fast-track approval list.
However, the FDA announced in a 2018 study published in the Oncology Division of the Journal of the American Medical Association that only 55 percent of the 93 drugs that received accelerated approval confirmed their benefit after marketing; only 40 percent of the indications that received accelerated approval completed confirmatory clinical trials.
A 2019 study published in the Journal of the American Medical Association Internal Medicine[3] found that only 20% of cancer drugs that the FDA accelerated approval by using alternative endpoints improved overall survival in confirmatory trials. The study's authors also stated in a 2017 study[4] that a 38% increase in the rate of change in safety warnings on drug labels through a rapid review of approved drugs.
After a period of trials, the FDA began to use the "visible hand" of regulation to trim the "invisible hand" of the tumor immune drug market. Since December 2019, the FDA has begun to issue targeted guidelines to carry out data review of tumor treatment drugs listed at alternative endpoints, and slowly launch the "autumn accounting" offensive in a "slow gas" manner. Whether it is macro or industry, slow gas and no sharp turns are the signs of the level of supervision.
On December 20, 2019, the FDA issued an industry guideline titled "Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products."
In November 2020, senior FDA officials confirmed at the Preventive Policy/Friends of Cancer Research Biopharmaceutical Conference that a review of accelerated approval of drugs would be conducted.
On January 25, 2021, the FDA's Center for Drug Review and Research (CDER) released a plan for the development of guidelines for pharmaceuticals, including the "Meeting Substantive Evidentiary Standards Based on a Well-Controlled Clinical Study and Corroborating Evidence," which was derived from the title of Subsection IV.B of Draft Guidelines in December 2019.
Three months later, the FDA officially announced that it would hold an Expert Advisory Committee on Oncology Advisory Committee (ODAC) meeting on April 27-29 to discuss the future of six unconfirmed clinical benefits for accelerated approval of three cancer immunotherapy PD-1/PD-L1 drugs. The Federal Register announced that the meeting was requested by the Center for Oncology Excellence (OCE) as part of its "accelerated approval of unproven clinical benefits from industry-wide confirmatory trials of oncology products."
Drugs at risk of review and revocation include two indications for Genentech's atenizizumab, three indications for Merck's pambolizumab, and one indication for Bristol-Myers Squibb's navulilizumab.
Earlier in March, Bristol-Myers Squibb, AstraZeneca, Merck and Roche had actually reached an agreement with the FDA to revoke accelerated approvals for four other new indications because the confirmatory test did not meet post-market requirements (PMR).
On June 18, the FDA released its first evaluation of the use of patient experience data in regulatory decisions. As part of the 21st Century Medicine Act of 2016, Section 3004 requires fda to publish patient data evaluation reports in 2021, 2026, and 2031, respectively.
The report notes that patient experience data should be central to patient-reported outcomes (PRO) and clinical outcome evaluation (COA). This means that cancer treatment drugs that accelerate the approval of marketing according to the alternative endpoint will be required to conduct post-marketing confirmatory experiments and face the risk of withdrawal at any time.
On December 8, 2021, the FDA released draft guidance on Considerations for Using Real-World Data and Real-World Evidence to Support Regulatory Decisions on Drugs and Biologics. Of course, it is all in order to continue to observe, study, and most importantly, supervise after the drug is listed.
04, "settle accounts after autumn", but there is a measure
Can Chinese pharmaceutical companies really break into the U.S. market at a large number of low prices, as Pazdur said? As long as immunotherapy is at the forefront of technology, it is difficult.
No matter how tight the FDA's "visible hand" is, it cannot interfere with market prices, especially for the innovative drug market. Since the listing of K drugs and O drugs, the price of tumor immunotherapy drugs has not changed.
Ellis Unger, director of the FDA's Office of Cardiology, Blood, Endocrinology, and Nephrology, believes that assuming a drug has a 70 percent chance of clinical benefit, 30 percent of drugs approved in that pathway should be withdrawn from the market. But it's actually hard to ask for drugs to be withdrawn, because the FDA can't dominate market decisions.
To some extent, the confirmation review conference, the withdrawal of the market, and the introduction of new guidelines are all professional efforts made by the FDA to deal with the problem of "internal volume" in the market. Making a fuss about professionalism is basically the best effort it can make.
For the FDA, new drugs can only apply for accelerated approval if professionalism is guaranteed. Since the establishment of the accelerated approval route for new drugs in 1982, the FDA drug review time has dropped from nearly 3 years in the 1980s to about 1 year now, with remarkable results. However, the total average time from clinical trials to formal approval of innovative drug research and development has not changed significantly, that is to say, the difficulty of development has not decreased but increased. [5]
The faster the approval curve, the higher the requirements for clinical data of the drug. For example, breakthrough therapy certification (i.e., BTD) requires the drug to prove at the beginning of the clinical trial stage that the drug can be significantly improved over existing therapies on one or more clinically significant indicators. If a drug application for a breakthrough drug fails, the FDA will not cancel its fast-track accreditation process, and the R&D unit will need to reapply.
To date, Bristol-Myers Squibb's Opdivo has achieved 10 BTD certifications, while Merck's Keytruda has received 9 BTD certifications, leading the way. But the FDA's corroborative review of the drugs was not "benevolent." Of the six indications reviewed at the Review Conference above, 2 have been withdrawn.
Therefore, although the business community has different views on FDA regulation, it is unanimous in its professional capabilities. Many FDA examiners are master's or doctoral degrees, with multiple identities such as "doctor, lawyer, analyst, scientist," or adjunct professor at a university or scientific institution.
A person in charge of Merck once said: "Although we do not necessarily agree with the FDA's decision, we must respect the FDA's decision." ”
Of course, even if there is no stricter corroborative review, the pharmaceutical company's justified "permutation and combination" trick has already reached its limit.
Taking in the controversial sindilimab as an example, the application is for the first-line treatment of sindilizumab combined with pemetrexed and platinum for non-squamous non-squamous cell lung cancer (NSCLC).
This indication is simply the biggest of all — first, lung cancer is the most mortal malignant tumor in the world, and the incidence is second in the world; second, non-small cell lung cancer patients account for about 80% to 85% of all lung cancer patients; finally, about 60% of the more than $25 billion in PD-1 sales in the United States in 2021 will come from non-small cell lung cancer indications, and mainly in the first line.
Take regenerative elements as an example. Its Libtayo also applied for first-line treatment for non-small cell cancer, as an example, and they needed to fight Against Merck, Bristol-Myers Squibb and Roche. According to industry insiders, analysts at SVB Leerink, a well-known analysis agency on Wall Street, predict that even if Libtayo is approved as a non-small cell lung cancer frontline, its share in all PD-1/PD-L1 markets will never exceed 5%.
In the saturated state, the market has its own ecological model. The broader the spectrum and the earlier the drug (such as Merck K drug) accounts for a larger proportion of commercial insurance payments, and the closer the relationship with insurance payers. Broad-spectrum immunotherapy drugs can often provide a higher proportion of rebates, forming a "rebate wall" and forming a certain degree of monopoly in the middle and lower reaches of the industrial chain.
Although many innovative Chinese pharmaceutical companies, including Hengrui, have chosen to start with large indications, this may not be a good thing. To compete with broad-spectrum immunotherapy drugs that take the lead, in addition to price barriers, it is actually quite difficult to prove "me-better" or even "the best" in clinical head-to-head trials.
There are no mature cases of unpopular indications to replicate, and it may be more difficult to do. In this case, the so-called price war cannot be discussed except for the pursuit of "the best", "me-too" and even "me-worse" cannot be seen.
"Most of China's innovative pharmaceutical companies that are currently moderately innovative still have to embrace the domestic market." A pharmaceutical analyst said that the fate of blindly "going to sea" can only be "losing money and making money". However, China's drug review and approval system also tends to be stricter.
On July 2, 2021, the Drug Review and Approval Center (CDE) of the State Food and Drug Administration issued the "Technical Requirements related to pharmaceutical common issues in the pre-marketing conference of innovative chemical drugs (Draft for Comment)" and the "Guidelines for Clinical Research and Development of Anti-tumor Drugs Oriented by Clinical Value (Draft for Comment)", especially for head-to-head clinical trials of tumor drugs and the latest treatment plans, and clarified the differences in product commercialization.
In this way, China's innovative pharmaceutical companies seem to be in a dilemma. But this "difficulty" is the meaning of innovation.
The "me-too" dilemma of China's innovative drugs is a three-foot freeze, not a day's cold – companies do not change to twist innovation into a seemingly easy imitation heat, because the bubble of the "subprime mortgage crisis" will eventually burst. Bi Jingquan, former director of the State Food and Drug Administration, told Caijian Dao: "The Review Center (CDE) needs to be bigger and stronger to encourage real innovation. ”
This requires a lot of long-term patience, which includes many aspects of institutional, financial and social concepts. It takes many years to find a truly innovative sprout.
Resources
【1】Beaver JA, Howie LJ, Pelosof L, et al. A 25-Year Experience of US Food and Drug Administration Accelerated Approval of Malignant Hematology and Oncology Drugs and Biologics: A Review. JAMA Oncol. 2018;4(6):849–856. doi:10.1001/jamaoncol.2017.5618
【2】Julia A. Beaver,M.D.,and Rechard Pazdur,M.D.:The Wild West of Checkpoint Inhibitor Development. (https://www.nejm.org/doi/full/10.1056/NEJMp2116863)
【3】Gyawali B, Hey SP, Kesselheim AS. Assessment of the Clinical Benefit of Cancer Drugs Receiving Accelerated Approval. JAMA Intern Med. 2019;179(7):906–913. doi:10.1001/jamainternmed.2019.0462
【4】Mostaghim S R, Gagne J J, Kesselheim A S. Safety related label changes for new drugs after approval in the US through expedited regulatory pathways: retrospective cohort study BMJ 2017; 358 :j3837 doi:10.1136/bmj.j3837
[5] Berlin,Fan Ping'an,Shi Luwen,Chen Jing. New drug development and approval trends from the approval of new drugs in the United States from 1985 to 2019[J].China Journal of New Drugs,2021,30(20):1830-1835.