If a drug of the same type has been approved for marketing, a controlled trial of a drug under study should use the marketed drug as a criterion for efficacy control, rather than a placebo test
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Text | Caijing reporter Xin Na
Edit | Sun Aimin
Anyone who wants to get a piece of the new crown special drug market must first pass the review level.
On February 17, 2022, the Drug Evaluation Center (CDE) of the State Drug Administration issued the Technical Guidelines for Clinical Trials of New Antiviral Drugs for Novel Coronavirus Pneumonia (Trial Implementation).
Six days ago, on February 11, the State Food and Drug Administration passed the emergency review and approval and conditionally approved the import registration of Pfizer's new coronavirus treatment drug nematvir tablets/ritonavir tablets combination packaging.
After approving the first imported special drug, how can many domestic pharmaceutical companies continue to carry out clinical trials to meet marketing requirements? The guiding principles chart a "runway" that gives guidelines for every step of the way, from research to clinical trials.
Among them, the industry has attracted much attention from the guiding principles for the formulation of standard treatment in clinical trial design: in the case of no positive control drug, it is recommended to use a randomized, double-blind, placebo parallel control, and efficacy comparison load design based on recognized background therapy; if there is a confirmed drug on the market, it can be used as a standard treatment, and the proposed development of a trial drug is similar to the standard treatment mechanism, and the positive control of the positive control can be considered as a good or non-inferior design.
In layman's terms, if the same type of drug has been approved for marketing, the controlled trial of the drug under development should use the approved drug as the standard for efficacy control, rather than a placebo test. This also means that if the efficacy of the "latecomer" is not as good as that of the drug that has been approved for marketing, it is most likely not approved for marketing.
According to an insider of the drug regulatory system, this has sounded a wake-up call for pharmaceutical companies with slow research and development processes in the same route: unless they are very confident in the efficacy of their own drugs, they must either accelerate the speed of research and development and clinical practice, or give up as soon as possible and choose a differentiated route.
The reporter of "Finance and Economics Health" combed and found that among domestic pharmaceutical companies, the relevant drugs of the development of pharmaceuticals, real organisms, and Junshi biology (688180.SH) have entered the clinical trial stage, and frontier biological (688221. SH), Zhongsheng Ruichuang, Simcere Pharmaceutical (02096. HK)), Genting Xinyao (01952. HK), Cerley Pharmaceuticals (01672. HK) and other related projects are in the preclinical stage.
Who can win the new crown special drug market, the competition has just begun.
Which businesses do the guiding principles have an impact on?
What clinical problems can be solved by drug candidates is the core idea of the guiding principles of this CDE release.
The Guiding Principles discuss both clinical trial protocol design and issues to focus on. Of particular note is the description of the expected standard of care: "If a confirmed drug is marketed as a standard of care, and the proposed experimental drug has a similar mechanism of action to the standard of treatment (e.g., both the standard treatment and the test drug are direct antiviral drugs), the positive or non-inferior design of the positive control can be considered."
This is the same as the "closing effect" mentioned by the drug regulatory authorities many times before, that is, if the same type of drug has been approved for marketing, other clinical trials of drugs under development need to conduct head-to-head trials with the listed drugs.
A person familiar with the drug regulatory system believes that the move is to "avoid everyone's clinical trial design from comparing the effect with the placebo." Otherwise, the approved drug efficacy data will not go up."
This means that if there is already an approved COVID-19 drug, other similar drugs need to be controlled clinical trials with the approved drug as the standard treatment. However, whether the approved drugs are imported drugs or domestic drugs, the specific policies are different.
If only imported drugs are approved for a certain indication, the drug regulatory authorities usually do not require clinical trials of other domestic drugs to go head-to-head with imported drugs. "This threshold is too high for Chinese pharmaceutical companies now." The above-mentioned drug regulatory system person said.
However, if there are already domestic drugs in the treatment in this field, and they are widely used, it is necessary to consider improving the clinical value of latecomers. This situation is like a race: someone has already run to the finish line, and it is not reasonable to allow people who have just reached the starting line to start, especially if there are already many runners on the track.
A typical example is the previous "inner-rolled" PD-1/PD-L1 drug track. Due to the excessive number of similar drugs on the market, the drug regulatory department has clearly proposed higher trial design standards for pharmaceutical companies that apply for clinical trials in the future, and even advised them to give up.
Who can win the Chinese market?
On February 11, the State Food and Drug Administration conditionally approved the import registration of Pfizer's new coronavirus treatment drugs, Nematvir tablets/ritonavir tablets combination packaging (Paxlovid).
Data suggest that Paxlovid can reduce the risk of COVID-19-related hospitalizations and deaths by nearly 90%. This oral small molecule CORONAVIRUS treatment is used to treat adults with mild to moderate coronavirus pneumonia (COVID-19) with a high risk factor for progression to severe disease, such as patients with high-risk factors for severe illness such as advanced age, chronic kidney disease, diabetes, cardiovascular disease, chronic lung disease and other high-risk factors for severe illness.
Pfizer Paxlovid was approved in China only 50 days after the U.S. Food and Drug Administration (FDA) emergency use authorization. According to the official website of the State Food and Drug Administration, the approval was "carried out in accordance with the relevant provisions of the Drug Administration Law and in accordance with the special drug approval procedures" for emergency review and approval.
A relevant person from a pharmaceutical company believes that such a short period of time to enter the Chinese market shows that the regulatory authorities recognize its overseas clinical trial data. However, China now has few new crown patients, the vaccine has basically achieved national vaccination, and the market demand for new crown drugs is not large, "for Pfizer, the momentum to promote the listing and supply of this drug in China in the short term is not so strong."
In any case, Pfizer's new crown drugs have taken the lead in the Chinese market, how many opportunities are left for other new crown drugs under development? Judging from the above guidelines issued by the Drug Review Center of the State Food and Drug Administration, the slower the research and development process of the new crown special drugs of the same technical route, the higher the standards for clinical trials, and correspondingly, higher investment is required, and it is more difficult to be approved for listing.
From the perspective of the research and development process of domestic pharmaceutical companies, the research and development progress of VV116 of Junshi Bio and the pukluamine of the pioneering pharmaceutical industry is relatively fast.
VV116 is an oral nucleoside that inhibits replication of the new coronavirus. According to junshi bio-announcement, VV116 is currently conducting global multi-center clinical studies, of which three phase I studies in China have been completed in January this year, preliminary results show that the clinical safety is good, and international multi-center Phase II/III clinical trials for patients with mild to moderate covid-19 are underway.
Previously, at the end of 2021, VV116 was already authorized for emergency use in Uzbekistan.
Pioneering Biologics' pkrutamine belongs to the new generation of androgen receptor (AR) antagonists, originally a Class 1.1 innovative drug used to treat prostate and advanced breast cancer. According to the company's announcement on February 11, its global multi-center Phase III clinical trial for the treatment of mild and moderate covid-19 patients has completed the enrollment and administration of China's first subject at the Third People's Hospital of Shenzhen.
The technical route of both is to suppress viral replication. The other two technical routes of antiviral treatment drugs for the new crown virus are: blocking the virus from entering the cell and regulating the human immune system.
According to the analysis of the above-mentioned drug supervision system, different types of drugs and indications are often differentiated, which can provide different choices for the clinic. However, if it is a me-too drug that uses the same mechanism, is suitable for the same population, and only has a slight difference in structure, it needs to have a research and development order.
How to judge clinical advantage? The above-mentioned drug regulatory system gives some references: if there are differences in indications, adaptable populations, safety and tolerability, it can be not applied to the "closing effect" in research and development.
This means that if the development progress of the new crown special drug that adopts the exact same technical route is relatively backward, it will be more difficult to apply for approval and listing.
According to the statistics of Capital Securities in December 2021, among the representative varieties of China's new crown special drug research and development, the most fierce competition is neutralizing antibody drugs, including Junshi Bio/Eli Lilly, Tengsheng Bo Pharmaceutical/Peking University Shenzhen Third Hospital, Peking University/Danxu Biologics, etc.
In the neutralizing antibody drug track, the fastest progress is Tengsheng Bo Pharmaceutical, which cooperates with Tsinghua University and the Third People's Hospital of Shenzhen to develop the neutralizing antibody drug combination therapy, and has submitted an emergency use authorization application to the US FDA. The results of the Phase III clinical trial of the therapy showed that COVID-19 outpatients at high risk of severe illness had a 78% lower risk of hospitalization and death compared to placebo.
"The insufficiency of neutralizing antibodies is the need for intravenous injection, and patient compliance is not as high as oral medications. The pricing of oral small molecule drugs is also more advantageous, such as Merck's small molecule oral drug Molnupiravir, which is priced at about one-third of the cost of neutralizing antibody therapy. In addition, small molecule oral drugs are more advantageous in terms of production and transportation. Cheng Zengjiang, the founder of Tongyi, once analyzed.
The door to the approval of new crown special drugs has long been set, after Pfizer's products are approved, which domestic variety can successfully break through? For pharmaceutical companies, it is not only necessary to find customs clearance passwords according to the guiding principles of CDE, but also to consider the market space after approval.