Reflections on Pending Technical and Legal Issues in the R&D of COVID-19 Medical Products

A. The production of inactivated vaccines is very large, but the technology is the most traditional, and most products have lost their practical value

The technical principle of inactivated vaccines is to extract the virus from an infected person’s body and cultivate it in the laboratory, then inactivate it to reduce virulence, and vaccinate to stimulate the protective antibodies. In the field of inactivated vaccines, China is the most active. China has launched five inactivated vaccines, among which the earliest one is the “CoronaVac” vaccine from Sinovac Biotech. In June 2020, CoronaVac was approved for emergency use in China, and subsequently approved for use in more than 60 countries. In 2021, sales exceeded $15 billion, and by 2023, the global cumulative supply exceeded 2.9 billion doses. With the passage of time, the demand for CoronaVac has declined significantly. In January 2024, Sinovac Biotech announced that CoronaVac have been stopped production and selling.

Inactivated vaccines have a history of several decades. They are a mature technology with fast preparation speed, and because they kill the active ingredients in the virus, they have high safety. The COVID-19 inactivated vaccine played an important role in the most serious stage of the epidemic, protecting many infected people from developing into critically ill and death. But inactivated vaccines have obvious technical shortcomings. Firstly, their immunogenicity is weak, and the neutralizing antibodies formed after vaccinations are much lower than those of mRNA vaccines and recombinant protein vaccines using highly effective adjuvants. For example, the efficacy of Sinovac’s CoronaVac in the mid-term analysis of phase III clinical trials in Brazil was 51%, ¹ while that of Sinopharm’s inactivated vaccine in phase III clinical trials was over 70%. ² In contrast, the efficacy of Pfizer and Moderna’s mRNA vaccine was around 95%.^3,4 (Of course, this was a small-scale clinical trial result and does not represent the real-world situation.) Secondly, the protection period is short. A Chinese research team conducted a 2-year longitudinal cohort study, which demonstrated that 60% of individuals who received three doses of inactivated vaccines did not have reinfection within 5 months, but the protective effect of the vaccine gradually decreased after 5 months. Thirdly, inactivated vaccines must be inoculated twice to maintain antibody levels. Fourth, the inactivated vaccine will not have a great effect on the SARS-CoV-2 variants. The Chinese government proposed different strategies for cross vaccination and sequential vaccination after 2022. Since most people have been fully vaccinated with inactivated vaccines for three times, it is no longer protective to continue to vaccinate, so it is recommended that residents should be vaccinated with recombinant protein vaccines.

B. Adenovirus vaccines have significant safety hazards and low economic benefit, and have therefore been abandoned in a short time. Some vaccines also trigger liability

Adenovirus vaccine uses the harmless transformed adenovirus as the carrier, and loads the S protein of SARS-CoV-2 for antigen expression, so as to trigger humoral immunity, cellular immunity, and mucosal immunity. The process of producing an immune effect in the body is similar to that of natural infection. In the global market, there are mainly three types of adenovirus vaccines, produced by Oxford-AstraZeneca, J&J, and CanSino. When adenovirus vaccines were first listed, they were popular due to their ability to generate immunity with just one injection and low storage requirements. However, the good times did not last long, and this vaccine exposed technical and legal issues.

Oxford-AstraZeneca’s “Vaxzevria” adenovirus vaccine was launched in 2020 and sold 2.5 billion doses in 2021, with sales reaching $4 billion. At the beginning, the side effects of Vaxzevria mainly included discomfort at the vaccination site, gastrointestinal discomfort, fever, and general fatigue. But it was later discovered that it may lead to thrombosis and low platelet counts. Due to safety concerns, the Australian Medicines Agency stopped using the Vaxzevria in April 2023, and AstraZeneca voluntarily withdrew the vaccine globally. ⁵ However, the vaccine’s troubles have not ended, and some vaccine recipients have started suing the company for compensation. AstraZeneca has admitted in lawsuit documents that Vaxzevria may cause a rare but fatal thrombosis.

J&J’s “Ad26.COV2.S” vaccine uses the adenovirus Ad26 vector, which is a common virus that often causes symptoms such as colds and pinkeye disease. The modified adenovirus cannot replicate in the body but can trigger an immune response against SARS-CoV-2. This vaccine was approved by the Food and Drug Administration (FDA) for emergency use in the United States in February 2021. Not long after that, in April 2021, the United States reported several rare cases of severe thrombosis due to vaccination. ⁶ The FDA and the Centers for Disease Control and Prevention (CDC) issued a joint statement, suggesting that the vaccination of Ad26.COV2.S should be suspended. ⁷ But 10 days later, the two health authorities withdrew this suggestion. ⁸ In July 2021, FDA also added a warning in the information note of Ad26. COV2.S, saying that the data showed that the risk of Guillain-Barre syndrome increased within 6 weeks after vaccination. ⁹ The sales revenue of this vaccine in 2021 was $2.385 billion, and production was suspended at the end of 2021. Later, some vaccinated individuals also filed lawsuits.

The type 5 adenovirus vector vaccine, “Convidecia” developed by China CanSino, was conditionally approved for marketing authority in China in February 2021. In May 2022, Convidecia was approved by the WHO to enter the Emergency Use List (EUL). In order to produce more vaccines, CanSino built a vaccine factory with an annual production capacity of 200 million doses and transferred technology to Mexico, Pakistan, and Malaysia for local filling and production. However, in April 2023, Convidecia was announced to be discontinued, due to the fact that most people have been infected with adenovirus type 5 during their growth process; thus, there may be antibodies in their bodies that neutralize the adenovirus vector, which can develop resistance to the vector and affect the effectiveness.

C. The technical limitations of recombinant protein vaccines are also evident, and they are not popular in the market

The technical principle of recombinant protein vaccine is to isolate B cells from the serum of patients recovered from COVID-19, find some neutralizing antibodies, neutralize them with the receptor binding region (RBD) of spike protein on the surface of SARS-CoV-2, so that the virus cannot replicate, then implant the genetic code of spike protein into host cells (such as Chinese hamster ovary cells) for gene recombination, express in vitro to form dimers, combine them to make vaccines, and then add aluminum hydroxide adjuvant to improve immunogenicity. Compared with the inactivated vaccine, the recombinant protein vaccine only intercepts the protein fragment of SARS-CoV-2 and does not use the live virus, so it is safer. Moreover, hamster ovary cells have strong reproductive capacity and high vaccine production. But the disadvantage is that the adjuvant added to the recombinant protein vaccine may cause side effect, such as redness, swelling, fever, chills, and pain at the injection site. Another disadvantage is that the recombinant protein vaccine requires three doses and the full immunization course takes 6 months.

The R&D of recombinant protein vaccines is quite popular in China, and pharmaceutical companies have launched six vaccines, among which the most well-known is the ZF2001 vaccine from Zhifei Biological Products Co., Ltd (ZFSW). This vaccine was included in emergency use by the National Medical Products Administration (NMPA) in March 2021 and approved for conditional marketing in March 2022. According to phase III clinical trials conducted in multiple countries such as China, Pakistan, and Uzbekistan, after completing the full course of vaccination, the protection rate of the vaccine against the Delta variant was 81.4%, and the protection rate against the Alpha variant was 92.7%. ¹⁰ ZFSW has built one raw material line, four formulation lines, and seven packaging lines for this vaccine, with a daily production capacity of over one million doses and an annual production capacity of 500 million doses. But later on, the situation showed that with the overwhelming dominance of the Omicron variant, vaccines originally designed based on the original strain had limited effectiveness, and the market sales of this vaccine were impacted. The company can only rely on the ZF2002 vaccine, which is still under development, to regain market share.

D. The live-attenuated vaccine has a novel idea, but the final effect is unsatisfactory

Live-attenuated vaccines use laboratory cultured bacteria or viruses that have been repeatedly passaged and attenuated in toxicity, or use other safer live bacteria that are very similar to the original pathogenic bacteria. In the field of COVID-19 vaccine, the live-attenuated vaccine is mainly mucosal vaccine. Its design idea is that the current intramuscular vaccine mainly produces IgG antibodies after inoculation, which can protect the lower respiratory tract and lungs, but there are relatively few IgA antibodies produced by intramuscular injection, while the upper respiratory tract needs IgA antibody protection. Therefore, if mucosal immunity can be achieved, it can protect healthy populations. At present, there are about 100 mucosal vaccines against COVID-19 in the world under development, ¹¹ but it is not ideal in terms of commercialization. For example, the nasal spray vaccine produced by China Wantai BioPharm inserts the RBD gene sequence of the protective antigen of SARS-CoV-2 into the double attenuated seasonal influenza virus (CA4-DelNS1) vector, vaccinates through nasal spray, simulates the natural infection path of COVID-19, generates T cell immune response in respiratory system tissues, and forms a barrier to prevent virus invasion in the respiratory tract. At the beginning of 2021, Wantai BioPharm began purchasing land and factories to build a production line with an annual capacity of 100 million doses. In December 2022, this vaccine was approved for emergency use by the NMPA. But this project has not been completed yet and has been abandoned. The reason is likely that the actual protective effect of this vaccine is not outstanding. Inhaling the vaccine does not produce a large amount of IgA immune protein, and serum IgA reactions are also rare and low in magnitude.

E. mRNA vaccines represent the highest level of vaccine technology and are popular in the market, but the legal disputes they face cannot be resolved in the short term

mRNA is a natural component responsible for transmitting genetic information stored in DNA and guiding protein synthesis in cells. mRNA vaccines utilize this characteristic to introduce antigens expressing mRNA into the body through a special delivery system. They use human cells to synthesize S protein, induce B and T cell immune responses, and activate the immune response in the body, fighting against various pathogens. mRNA vaccines can achieve standardized production, and the required vaccines can be produced within 10 days.

The mRNA vaccine “Comirnaty” (BNT162b2) jointly developed by BioNTech and Pfizer announced phase III clinical trial results in November 2020. ¹² It was approved for emergency use by the United Kingdom, United States, and European Medicines Agency (EMA) in December 2020, and by the WHO on December 31, 2020. Moderna’s “Spikevax” (mRNA-1273) vaccine followed closely. At present, Comirnaty vaccines have been authorized for emergency use in 145 countries, and Spikevax vaccine has been approved for EUA in 116 countries, with a cumulative global use of more than 5 billion doses. Later, the two companies also developed a bivalent mRNA vaccine against the Omikron variant BA. 4/BA. 5. In 2021, Spikevax vaccine sales amounted to $17.7 billion. Pfizer’s vaccine sales amounted to $36.781 billion. BioNTech’s annual revenue was 18.8 billion euros. In 2023, Pfizer’s vaccine sales still reached $11.5 billion.

In China, there are more than 10 companies planning to research COVID-19 mRNA vaccine, but their R&D speed is not very ideal. The fastest progress is the CSPC PHARMA’s SYS6006 bivalent vaccine, which was announced for emergency use in China on March 2023. It is the first domestic mRNA vaccine, with an annual production capacity of 240 million. Another mRNA vaccine developed by Stemirna has obtained emergency use authorization (EUA) in Laos. Stemirna has built vaccine production bases in China and Laos, with an annual production capacity of 20 million doses. In July 2023, the company announced the shutdown of its vaccine factory.

Since their launch, mRNA vaccines have faced endless patent disputes. In August 2022, Moderna filed patent infringement lawsuits against Pfizer and BioNTech, claims that Comirnaty infringes the patent on basic mRNA technology submitted by Modena. The scope of infringement includes mRNA structure patents and full-length spike protein encoding patents. The two companies replicated two key features of patent in vaccines and continued to use them without permission. Subsequently, Pfizer and BioNTech denied infringement and insisted that the two companies independently developed vaccines. They filed a counterclaim in the U.S. federal court, claiming that Moderna’s patent far exceeded its actual contribution to the field and demanded that Moderna’s patent be ruled invalid. In July 2024, the High Court of England ruled that Comirnaty infringed a patent right of Moderna and should pay corresponding damages. ¹³ At the same time, the European Patent Office have found that some parts of the patents obtained by Moderna are invalid. ¹⁴ In April and October 2024, GSK filed lawsuits against Pfizer, BioNTech, and Moderna, alleging that the development of mRNA vaccines infringed upon GSK’s patents.^15,16 The patent lawsuits related to the aforementioned companies also include Northwest University suing Moderna in October 2024, Arbutus Biopharma and Genevant Sciences suing Moderna in February 2022, Alnylam Pharmaceuticals suing Moderna and Pfizer in March 2022, and CureVac suing BioNTech in July 2022. All controversies point to the patent layout in the popular field of mRNA.

Meanwhile, although mRNA vaccines are currently the most-advanced third-generation vaccines, they also face huge vaccine hesitancy. On the one hand, based on the safety of vaccines, common side effects of mRNA vaccines include fever, nausea, and diarrhea. For most people, these symptoms can be relieved in a short period of time, but for patients with serious underlying health problems, these side effects may be fatal. Some journals reported that a few patients who received mRNA vaccine developed myocarditis and were discharged after receiving treatment.^17,18 This indicates that there is definitely a certain level of risk associated with vaccination, because the heterologous proteins produced by vaccines may cause allergic reactions or other side effects in patients, exacerbating their underlying diseases. Secondly, since the outbreak of the epidemic, there has been no interruption in the voices of vaccine skepticism. The vaccination rate in some countries has not reached a satisfactory level. Various media publicity and the statements of some public figures tend to shake the people who have not yet been vaccinated. There are different opinions on what COVID-19 is, and what is the difference between COVID-19 and influenza. The debate on whether COVID-19 vaccine is effective has also exceeded any previous vaccine.

In general, during the epidemic, these vaccines of the above five categories were developed synchronously and shared the market. On technical perspective, the main indicators for measuring the effectiveness of vaccines are protection rate, neutralizing antibody value, and protection time. mRNA vaccines produce the highest neutralizing antibody values after vaccination, and the protection rate is usually higher than 90%. According to Moderna’s report, vaccines maintain an efficacy rate of over 90% after 6 months of vaccination. ¹⁹ From these data, mRNA vaccines are undoubtedly leading, while recombinant protein vaccines, adenovirus vaccines, and inactivated vaccines are weaker in neutralizing antibodies. If vaccines can induce immune responses in cells, it will make the protective effect more long-lasting. mRNA vaccines also have advantages in this regard. From a commercial perspective, inactivated vaccines, adenovirus vaccines, and recombinant protein vaccines are not as popular as mRNA vaccines. In terms of safety, some side effects of vaccines have been disclosed, while others hidden side effects require longer time to verify, and these technical myths cannot be solved at present. ²⁰

On the other hand, the R&D of the COVID-19 vaccine is full of hardships. According to the statistics of the WHO, by the end of 2024, there were 199 COVID-19 vaccines under preclinical development, 183 COVID-19 vaccines under clinical development, and more than 50 COVID-19 vaccine products approved for conditional marketing or emergency use. There are still a large number of companies that have not been successfully developed or have not been able to commercialize their products. Even the products on the market are facing problems, such as diminishing vaccine protection effectiveness, declining market demand, and entanglement in legal proceedings. The COVID-19 vaccine for early mutants, developed using the traditional technical route has lost its market value. The speed of vaccine development and production cannot keep up with the speed of virus mutation, making vaccine development always shrouded in high risk. However, people should know that billions of people worldwide must have vaccines. Compared with protective measures such as masks and social distancing, only vaccines can save more lives.

A. The effectiveness of traditional medicines used in emergency during the early stages of the epidemic is questionable, and drug authority agencies are not fully confident in their efficacy

At the beginning of the epidemic, the medical community urgently searched the drugs already on the market, analyzed whether they had the potential to inhibit COVID-19, and combined with the experience of treating SARS and other infectious diseases, put some drugs into clinical use, including chloroquine/hydroxychloroquine, convalescent plasma, lopinavir/ritonavir, IL-6 inhibitor, corticosteroids, and later added baretinib.

Chloroquine has been used as an anti-malaria drug in the past. At the initial stage of the COVID-19, some scientists found that it can inhibit SARS-CoV-2 through in vitro tests. ²¹ Then clinical trials were carried out in some countries to verify whether the patients who took drugs could reach the expected concentration in their bodies. However, more research has found that the initial clinical trial results were not reliable, ²² and the inherent toxicity of chloroquine can lead to serious arrhythmias, posing significant risks for long-term use.

The plasma of recovered patients usually contains pathogen specific antibodies that can be used to combat viruses, but this blood product cannot be mass-produced through production lines and may also be unable to be imported into other patients due to the presence of other diseases in the donor.

Lopinavir is a protease inhibitor used to combat the HIV and was shown to inhibit the coronavirus during the SARS epidemic. Litonavir is often used in combination with lopinavir to increase its plasma half-life. However, clinical trials have shown that the combination of lopinavir/ritonavir did not reduce the viral load in the subjects’ bodies, nor did it significantly shorten the treat time, and the significant benefits to patients were not significant. ²³

IL (interleukin)-6 receptor inhibitor is a kind of monoclonal antibody, which was used to treat rheumatoid arthritis in the past. The most representative is Tocilizumab-Actemra of Roche Pharmaceutical. Researchers found that it can alleviate the cytokine storm that occurred in patients with severe COVID-19. ²⁴ In July 2021, the WHO recommended this drug can be used in patients with severe or critical COVID-19. It cannot function alone, but is used in combination with other conventional treatments and corticosteroids.^25,26

Corticosteroid hormone is a cheap drug, such as hydrocortisone, dexamethasone, etc. It was also used to treat respiratory diseases and tumors in the past. There have been differing views on its effect in treating COVID-19. In September 2020, medical journals extensively reported on the effectiveness of corticosteroids in treating infected individuals worldwide. In 2021, a study showed that when the ratio of neutrophils to lymphocytes of people infected with COVID-19 was high, corticosteroids would help reduce their risk of death, but not all patients can benefit. ²⁷ Another study believes that corticosteroids have inhibitory effects on acute lung injury and acute respiratory distress syndrome, but it also inhibits immune response and pathogen clearance, ²⁸ and it will cause many complications, such as diabetes, vascular necrosis, osteoporosis, and in other cases, the risk of invasive fungal infection and pulmonary aspergillosis is significantly increased in the treatment of COVID-19. ²⁹ In September 2020, the WHO recommended 7 to 10 days of systemic corticosteroid treatment for patients with severe COVID-19, and to not use corticosteroid treatment for noncritical patients. The FDA’s treatment guidelines do not recommend its use in noncritical patients. In September 2022, WHO further recommended the combination of baricitinib and corticosteroids in the treatment of severe COVID-19 patients.

Baricitinib is a Janus kinase inhibitor that regulates immune responses and reduces inflammation by inhibiting kinase activity in signaling pathways. When this drug was introduced, it was used to treat autoimmune diseases such as rheumatoid arthritis, alopecia areata, and atopic dermatitis. After the outbreak of COVID-19, some research teams found that the combination of glucocorticoid, IL-6 receptor inhibitor and baricitinib can provide more survival benefits for severe and critically COVID-19 patients. ³⁰ In November 2020, baricitinib obtained EUA from the FDA. In May 2022, the FDA officially approved its use for the treatment of hospitalized adult COVID-19 patients who require supplemental oxygen, noninvasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation. But some studies have also found that patients receiving treatment with baricitinib have an increased risk of developing severe bacterial, fungal, viral, and opportunistic infections.^31,32

The common characteristics of the above drugs are, first of all, although they are easy to obtain, they are not special antiviral drugs after all, so they cannot become the firstly and universal treatment choice for COVID-19. Secondly, their usage conditions are limited, often meeting the needs of specific patients, such as critically patients and adult patients, and the effect on other patients is not significant. Thirdly, the known and newly discovered side effects of these drugs are worthy of vigilance. Most importantly, these drugs have no essential breakthrough in technology, which is not enough to contain COVID-19, which was a new virus with strong infectivity and rapid mutation. In April 2022, WHO strongly recommended that any COVID-19 patients should not use drugs such as hydroxychloroquine, lopinavir/ritonavir, cassirivimab, and imdevimab. For doctors and patients, these drugs are far from enough. For pharmaceutical companies, they also hope to develop drugs with higher technology level that can better restrain COVID-19.

B. Neutralizing antibody drugs were highly anticipated, but unforeseeable variables occurred during the approval process, resulting in their untimely demise

A neutralizing antibody is a humanized monoclonal antibody. First, we obtain protein macromolecular antibody from COVID-19 patients in convalescence, then apply bioengineering technology to reduce the risk of antibody mediated dependence enhancement and extend the plasma half-life to obtain more lasting therapeutic effect. After being injected, the neutralizing antibody can target different parts of SARS-CoV-2 spike protein RBD, giving play to the ability of noncompetitive synergistic neutralizing virus, thereby killing target cells and preventing viruses from entering human cells. Neutralizing antibodies are not metabolized by the kidneys or cytochrome P450 enzymes, and only require a one-time injection. However, neutralizing antibodies are expensive and may cause hypersensitivity reactions during or after infusion, requiring clinical monitoring of patients.

In 2020, REGN and Roche jointly developed REGEN-COV (ronapreve, casirivimab, and imdevimab) neutralizing antibodies, which were granted EUA by the FDA. Phase clinical trial results showed that REGEN-COV can reduce hospitalization or death by 70% and shorten symptom duration by 4 days. ³³ Other approved neutralizing antibodies include AstraZeneca’s Evusheld, GSK’s Sotrovimab, Eli Lilly’s Bebtelovimab, and Celltrion’s Regkirona. These products sold very well, with REGEN-COV achieving a global sales performance of $7.574 billion in 2021, GSK’s sotrovimab had sales of £2.3 billion in 2022. However, in November 2021, Regeneron Pharmaceuticals announced that preliminary testing had found that REGEN-COV was ineffective against the Omicron strain. The FDA has decided to restrict the clinical use of REGEN-COV and extend the review period for marketing approval. In April 2021, FDA revoked the emergency authorization of Eli Lilly’s bamlanivimab for independent use. In November 2022, FDA finally decided not to approve bebtelovimab for the treatment of COVID-19 because the antibody did not work on two new virus variants. In April 2022, FDA decided that the sotrovimab of GSK would no longer be authorized to be used for COVID-19 treatment in the United States. This is because sotrovimab has little effect on Omicron BA. 2. In January 2023, FDA decided to withdraw the EUA of AstraZeneca’s Evusheld, because this therapy may not be effective against the XBB, XBB. 1.5, BQ.1, and other variants of SARS-CoV-2 Omicron strain.

There are 30 projects in China to R&D neutralizing antibodies. Among them, the successfully player is ambarvimab (BRII-196) and romosevimab (BRII-198) developed by Brii Biosciences. The neutralizing antibodies are isolated and purified from the whole human immunoglobulin IgG1 of COVID-19 patients and approved for marketing in December 2021. It became the first approved COVID-19 drug in China and was included in the COVID-19 diagnosis and treatment program of the China National Health Commission. But in July 2022, Brii Biosciences decided to end the combination therapy project of anbimumab/romizumab, cease production work, withdraw the Biological Product License Application from the China National Medical Products Administration, and withdraw the EUA application from the FDA. After calculation, Brii Biosciences invested over $200 million dollars in R&D, but only sold in the market for 8 months, with sales of approximately $7.09 million dollars. The reasons for its failure are twofold: firstly, the virus mutation rendered the neutralizing antibodies synthesized from early original strains ineffective; secondly, the high price of this drug, which was priced at $1,400, caused the expensive neutralizing antibodies to lose their market competitiveness after the launch of oral small-molecule drugs.

C. Small-molecule drugs have made up for the shortage of drugs timely, but there are differences in the efficacy, and the prospects for approval are unclear

Compared with other drugs for COVID-19, small-molecule drugs have multiple advantages such as convenient use, good accessibility, and effective against mutants. The most famous small-molecule drug is Pfizer’s Paxlovid (nirmatrelvir and ritonavir). The nirmatrelvir component can inhibit key enzymes required for the production of functional viral particles by the SARS-C0V-2. After treatment with nimarivir, the virus released from cells can no longer enter uninfected cells in the body, thus preventing infection. Another ingredient is ritonavir, which can slow down the metabolism of nimarivir in the liver, allowing it to stay in the body for a longer period of time, thereby enhancing its ability. This medication is not only suitable for adults with mild to moderate COVID-19 but can also be administered to adolescents aged 12–17. Paxlovid can reduce the risk of hospitalization and death of high-risk COVID-19 patients by 89%. ³⁴ In 2022, Paxlovid achieved revenue of $18.933 billion, accounting for 90% of the global COVID-19 drug market.

Monolavir produced by Merck & Co., Inc. (MSD) is an RNA polymerase inhibitor with broad-spectrum antiviral activity. It can combine with the RNA polymerase of SARS-CoV-2 and introduce the wrong nucleotide into the newly synthesized RNA molecule, thus terminating virus replication. In November 2021, Monoclavir was approved by the British Medicines and Healthcare Products Regulatory Agency for the treatment of adults infected with mild to moderate COVID-19 with high risk of severe illness and hospitalization. In December 2021, Monoravir obtained EUA in the United States. In December 2022, Monupivar was granted emergency conditional approval by the National Medical Products Administration of China for the treatment of adults with mild to moderate COVID-19 accompanied by severe high-risk factors. Monoravir achieve sales of $5.7 billion in 2022.

Remdesivir is a nucleoside analogue that can mimic the nucleosides required for virus replication, leading to misidentification and integration into its replication chain, thereby interfering with the virus’s replication process. Different from other small-molecule oral drugs, it is an injection dose. Doctors at the initial stage of the COVID-19 outbreak used “Compassionate use of investigational drugs” and found that remdesivir can delay disease progression and reduce the risk of severe death. In April 2020, the first clinical study of remdisivir showed that among severe and critical COVID-19, remdesivir brought clinical improvement. ³⁵ Also in April 2020, the results of remdesivir’s clinical trial in China were released and showed that remdesivir did not achieve the expected efficacy of the research scheme design, and the trial was terminated later because the number of subjects was insufficient. ³⁶ In May 2020, the FDA granted remdesivir EUA for COVID-19. In October 2020, remdesivir was approved by FDA for marketing approval. The attitude of the WHO is more ambiguous. In October 2020, WHO conditionally did not recommend remdesivir to patients with COVID-19 of any degree. In April 2022, WHO changed to conditionally recommend remdesivir to nonsevere patients with high risk of hospitalization. In 2022, remdesivir achieved sales revenue of $3.9 billion dollars.

Japan’s SHIONOGI developed ensitrelvir, which is similar to Paxlovid. It inhibits the replication and proliferation of SARS-CoV-2 in vivo by inhibiting the 3CLPro target. Moreover, it is an independent component and does not need to add ritonavir as an enhancer. In September 2022, SHIONOGI announced the results of the Phase III clinical trial for mild/moderate COVID-19, which showed that ensitrelvir could significantly reduce the duration of symptoms after Omicron infection. ³⁷ Ensitrelvir was approved for listing by the Japanese Ministry of Health, Labour and Welfare in November 2022.

In China, there have been 13 small-molecule drugs in clinical or application stage. At present, there have been five drugs on the market, namely XIANNUOXIN (simnotrelvir/ritonavir) from Simcere Pharmaceutical, Mindevi (etesevimab) from Junshi Bio, Azvudine from Genuine Bio, Leruiling (leritrelvir) from Raynovent Biotech, and TAZOVID (atilotrelvir/ritonavir) from Cosunter pharmaceutical. The China National Medical Products Administration has frequently adopted special approval procedures for drugs and medical equipment to promote the emergency marketing of domestic COVID-19 drugs. The most typical is Azvudine, which is a broad-spectrum RNA virus inhibitor, and was first used for HIV. As a synthetic nucleoside analog, it is metabolized into a 5′- triphosphate metabolite with antiviral activity in cells, which can specifically act on SARS-CoV-2 polymerase (RdRp), embed viral RNA in the process of RNA synthesis, and lead to the stop of viral DNA chain synthesis, thus inhibiting virus replication, and achieving the effect of treating COVID-19. In July 2022, the China National Medical Products Administration approved the use of it to treat adult patients with common COVID-19. Azvudine has accumulated sales of over 10 million bottles.

The small-molecule drugs have greatly enriched the choices of COVID-19 patients, and most of them are oral drugs, which are convenient for patients to use. However, the biggest obstacle facing them is the price and accessibility. On the one hand, many patients in developing countries cannot afford the high price of newly developed drugs; on the other hand, relying only on the production capacity of original drug companies cannot meet the needs of patients in the epidemic. For this reason, legal negotiations on drug prices and generic drug were difficult. For Paxlovid, with the participation of the Geneva Pharmaceutical Patent Pool (MPP), Pfizer signed agreements with 35 companies around the world to allow the generic drug of one of the ingredients of Paxlovid, nimatrilvir, or nimatrilvir’s prodrug. The generic drugs produced by these companies can only be provided to 95 low-and middle-income countries/regions worldwide, covering approximately 53% of the world’s population. But these preferential conditions do not apply to China. Five Chinese companies have been granted permission to produce generic drugs but can only export them. In October 2021, MPP also signed a voluntary licensing agreement with MSD, authorizing 27 generic drug companies worldwide to produce molnupiravir or active pharmaceutical ingredients and supply them to 105 low-and middle-income countries and regions worldwide.

Stimulated by this preferential policy, India quickly replicated Paxlovid and named it “Primovir” and “Paxista.” In January 2022, two pharmaceutical companies in India replicated molnupiravir and named it “Molflu” and “Molulife.” The price of a course of medication is only 1,400 rupees. In February 2022, Myanmar successfully replicated molnupiravir and named it “MOLNUPAC 200,” with the price of each treatment reduced to 39,000 kyats. A replica in Laos is marketed as “Molavir,” and another replica in Bangladesh is marketed as “Emorivir.” Although this sharing policy helps developing countries to obtain COVID-19 drugs, there may be inconsistency between the composition, efficacy, and side effects of generic drugs and the original drugs. How to ensure that generic drugs meet the technical standards of the original drugs has not been consistent in all countries. If the quality of drugs is not good enough, it will definitely affect the therapeutic effect. Moreover, due to the significant price differences between the same drugs, black market transactions of drugs may arise, affecting the quality and supply of drugs.

Another legal issue is that during the epidemic, many drugs or vaccines were applied to clinical practice through EUA in various countries, including the FDA’s EUA, the WHO’s EUL, the EU Medical Products Agency’s EMA, and China’s special approval process. Taking the practice of the WHO as an example, in order to provide drugs, vaccines, and diagnostic tools as soon as possible in public health emergencies, the WHO organized three stages of review. Firstly, the emergency application will be accepted, and then it will be submitted to the WHO expert meeting for presubmission meeting review. Secondly, a clinical trial case review will be conducted. As it is difficult to complete all clinical trials for drugs and vaccines in a short period of time, the WHO can also accept some periodic clinical trial data. The applicant promises to provide further clinical trial data in the future, and the WHO will judge the safety and effectiveness of drugs or vaccines based on rolling data. In addition, for drug varieties that have already been approved for emergency use by regulatory agencies in countries such as the United States, the United Kingdom, the European Union, and Japan, the WHO can expedite the approval process. This is why a batch of COVID-19 vaccines can be recommended by WHO in early 2021.

But from a legal perspective, this EUA is temporary and has a deadline. However, after the emergency situation disappears, pharmaceutical companies should submit sufficient clinical trial data and safety data to regulatory agencies, and then seek routine authorization. This cycle takes several years. For example, Pfizer’s Paxlovid received EUA from the FDA in March 2021 and only received formal approval from the FDA in May 2023, more than 2 years later. In January 2023, the China NMPA conditionally approved Junshi Bio’s Mindev, but it was not until January 2025 that the China NMPA officially approved this drug for routine marketing. Some of the above vaccines and drugs have not yet been approved by regulatory authorities in various countries. It is unknown how long it will take to complete the entire approval process of these vaccines and drugs.

Also, EUA is reversible. For example, with the mutation of COVID-19, the FDA has revoked the EUA for AstraZeneca’s Evusheld, GSK’s Sotrovimab, Lilly’s Bamlanivimab, and so on. China Brii Biosciences has voluntarily withdrawn its emergency use applications for amubarvimab (BRII-196) and romlusevimab (BRII-198) from the U.S. FDA. In addition, according to U.S. law, foreign pharmaceutical companies applying for EUA from the FDA should also undergo on-site inspections by the FDA to check whether their R&D and production processes comply with regulations, in order to determine the final review. Due to the epidemic, the FDA is unable to conduct on-site inspections of some pharmaceutical companies.