The four new coronavirus vaccines launched on the market are all “conditionally approved” - what are the conditions?

As an important tool for preventing and controlling the COVID-19 pandemic, COVID-19 vaccines have received widespread attention at home and abroad. On February 25, the National Medical Products Administration approved the registration applications of Sinopharm Wuhan Institute's COVID-19 inactivated vaccine (Vero cells) and CanSino Biologics' recombinant novel coronavirus vaccine (adenovirus type 5 vector), of which the latter is the first domestically produced adenovirus vector COVID-19 vaccine approved in my country.

In addition to the previous approval of the COVID-19 vaccines of Sinopharm Beijing Institute of Biological Products and Sinovac Biotech, as of now, my country has 4 COVID-19 vaccines approved for conditional marketing. This will not only further strengthen my country's health and epidemic prevention barriers, but also contribute more Chinese strength to the global affordability of COVID-19 vaccines.

As COVID-19 vaccines are approved and used one after another, people are paying attention to a hot word while getting vaccinated, namely conditional approval for marketing. So, what is conditional approval for marketing?

Fast track for new drug launch

Generally speaking, the safety and effectiveness of new drugs need to be verified through clinical trials. The vast majority of new drug marketing applications must be approved based on the clinical endpoint results of Phase III confirmatory clinical studies. However, for some drugs that treat serious life-threatening or inadequately treated diseases, such as tumors and rare diseases, in order to speed up the launch of new drugs, the drug regulatory authorities will temporarily approve the drug for marketing based on alternative indicators in Phase II or Phase III key clinical studies to meet clinical needs. However, this approval is conditional, that is, the company needs to continue to complete confirmatory clinical studies after the drug is launched to confirm the benefits of the drug, and then apply for full approval. This is "conditional approval."

Conditional approval is not the first of its kind in my country, and it is largely based on the "Accelerated Approval" established by the U.S. Food and Drug Administration (FDA) in 1992. As a fast track to accelerate the launch of new drugs, my country supports conditional approval of clinically urgent drugs and drugs for rare diseases, and has issued a number of relevant policies and regulations.

Articles 26 and 78 of the new version of the Drug Administration Law of my country, which came into effect on December 1, 2019, have corresponding provisions for "conditional approval". Article 26 stipulates that for drugs that are used to treat diseases that are seriously life-threatening and for which there is no effective treatment, as well as drugs urgently needed in public health, if the clinical trial data of the drug show efficacy and can predict its clinical value, they may be approved conditionally, and the relevant matters shall be stated in the drug registration certificate. Article 78 stipulates that for drugs approved conditionally, the holder of the marketing authorization shall take corresponding risk management measures and complete the relevant research as required within the prescribed time limit; if the research is not completed as required within the time limit or it cannot be proved that the benefits outweigh the risks, the drug supervision and administration department of the State Council shall handle it in accordance with the law, up to and including revoking the drug registration certificate.

According to the first paragraph of Article 20 of my country's "Vaccine Management Law", for vaccines urgently needed to respond to major public health emergencies or other vaccines identified by the health and health authorities of the State Council as urgently needed, if it is assessed that the benefits outweigh the risks, the State Council's drug supervision and administration department may conditionally approve vaccine registration applications.

As a drug regulatory system of "approval first, verification later", "conditional approval" brings some positive early benefits, but also faces many challenges. For example: how to select appropriate alternative indicators to accurately predict or reflect clinical efficacy and benefits; how to ensure that companies complete Phase III confirmatory clinical trials as required within the specified time after listing. It should be emphasized that "conditional approval" does not mean leaving it alone after approval, but continuing clinical research until the drug is proven to be beneficial.

Emergency situation "take the task in time of crisis"

As we all know, vaccine development needs to go through several processes, including basic research and exploration, preclinical, clinical (including phases I, II, and III), production, and market distribution. It takes about 8 to 15 years, or even longer, to develop a vaccine. Historically, the development of the measles vaccine took 9 years, the polio vaccine went through 20 years of trials, and the human papillomavirus (HPV) vaccine went through more than 20 years of research before entering the market. However, in the current global pandemic of the new crown pneumonia epidemic, humans obviously cannot wait for ten or twenty years. Therefore, in an emergency situation where people's health is seriously threatened and there are no effective drugs available, the new crown vaccine is conditionally approved for marketing. This is the motivation for the "conditional approval" of the new crown vaccine.

The COVID-19 vaccine developed in my country has been conditionally approved for marketing in China, which also has certain reference value for the use and registration of the vaccine in other countries. Since my country has better controlled the COVID-19 pandemic, the Phase III clinical trial of the COVID-19 vaccine has encountered certain difficulties due to the lack of a large number of clinical cases and can only be conducted abroad. Therefore, most of our clinical data comes from abroad, and these data have also been recognized by most countries. Some countries believe that clinical trials can no longer be conducted based on the test data that has been obtained. Some countries will also conduct "bridging" trials, which is equivalent to simulating the relevant part of the trial again, so that the test results can be obtained faster.

Continue to study and improve

Conditional approval has two meanings: one is that it means that the approved vaccine has met the basic requirements of safety, effectiveness and accessibility; the other is that it indicates that the vaccine is developed under emergency circumstances, and there are still some shortcomings in some aspects that need further improvement. In principle, additional conditions must be added before it can be put on the market.

Specifically, additional conditions are mostly due to the relatively short time for vaccine development. Only the completed part of the test data can be taken out for approval, and it can be put on the market as soon as possible if it meets the conditions. For example, during the development of the new crown vaccine, clinical trials were conducted in various age groups, but the age group of 18 to 59 years old was the first to obtain data. Therefore, when the vaccine is approved for marketing, restrictions must be imposed on the age of the vaccine recipient. For another example, there are no results for clinical trials on pregnant women, and there is a lack of data support. Therefore, it is recommended that pregnant and lactating women postpone the new crown vaccine.

From the above, we can see that the "conditional" requirement is mainly based on the consideration of the integrity of the test data. The data and basis for the vaccine to be marketed must come from clinical trials. Some clinical trials have not been completed and the data has not been obtained, so this part cannot be made public and must be limited to the open part.

The epidemic is raging and people's health is seriously threatened. In the absence of effective drugs, emergency use is the main motivation for conditional approval of vaccines. Only in emergency situations, such as the outbreak of a major infectious disease such as COVID-19, can vaccines be conditionally approved for marketing.

It is the responsibility of the national drug regulatory authorities to conditionally approve the marketing of vaccines. The specific additional conditions are determined by the national drug regulatory authorities based on the review results. After conditional approval for marketing, the drug regulatory authorities will also require the vaccine marketing license holder to continue to conduct relevant research on the vaccine in accordance with the recognized additional conditions, complete the conditional requirements and submit subsequent research results in a timely manner.

Author: Yaohuluwa Medical Biotechnology Science Popularization Group