[Press Release, Jan 4, 2021 / unofficial translation ]

MFDS begins review of Astrazeneca’s COVID-19 vaccines
- MFDS aims to assess the safety and efficacy of the vaccine thoroughly and swiftly within 40 days -

□ The Ministry of Food and Drug Safety (MFDS, Minister Kim Ganglip) received the application from AstraZeneca Korea Co Ltd. for the approval of AstraZeneca’s COVID-19 vaccine (codename: AZD1222) on Jan. 4, 2021. Regarding the review and approval process of the COVID-19 vaccine, MFDS provides clarifications as follows.

1. Product Overview
□ The vaccine candidate, developed as a new drug by AstraZeneca, is a viral vector vaccine manufactured by inserting the spike protein gene of a pathogenic virus into the chimpanzee adenoviral vector.
○ Viral vector vaccines are made by adding the antigen gene of the pathogenic virus into the gene of another virus used as a vector for large-scale production.
○ The AstraZeneca vaccine uses an adenovirus that infects only chimpanzees as the vector to deliver the genetic material of SARS-CoV-2 spike protein to human cells. The genetic material enables the synthesis of antigens that trigger the production of neutralizing antibodies in a human body, leading to the neutralization of the virus for destruction.
- For reference, the U.S. company Johnson & Johnson (Janssen) also developed a COVID-19 vaccine using the viral vector mechanism.
○ AstraZeneca vaccine is indicated for use in adults aged 18 years and older. As for the proposed dosage, the second dose is to be given 4 to 12 weeks after the first dose, which is the same as the route of administration and dosage approved in the U.K. for emergency use. The vaccine should be kept at 2∼8℃.

2. Development Process
□ AstraZeneca is currently conducting Phase III clinical trials in 10 countries including the U.K., Brazil, the U.S.
○ AstraZeneca conducted clinical trials of the vaccine in healthy adults aged 18 or older. The clinical trials conducted in the U.K. and Brazil additionally included participants aged 65 and over.

○ The clinical trials had been suspended on Sep. 6, 2020, when a volunteer experienced an unexpected serious adverse event (1 case of transverse myelitis*) during the clinical trial. Since no direct relationship was found in the safety review, the trial resumed in the U. K. and other countries on Sep. 12, 2020 and in the U.S. on Oct. 23, 2020.
* transverse myelitis: an inflammatory syndrome that affects the spinal cord which may be caused by a viral infection. No direct correlation has been found in the clinical trials.

○ The U.K. granted emergency use authorization for the vaccine on Dec. 30 after the vaccine’s efficacy was verified in a clinical trial on 11,636 participants. The European Medicines Agency (EMA) has been conducting a rolling review* of the vaccine since October 2020.
* Rolling review: Unlike the regular review for marketing approval for which the whole dossier must be submitted at once, rolling review allows applicants to begin submitting data for review as they become available.

○ AstraZeneca is also seeking Emergency Use Listing (EUL) from the World Health Organization (WHO) for the global supply of the vaccine.

3. Filing of Application and Dossier for Review/Approval

<< Filing of Application >>
□ AstraZeneca Korea submitted the application and relevant dossier according to the drug approval process through the Ministry’s drug safety website (e-government service platform, nedrug.mfds.go.kr).
○ AstraZeneca Korea applied for the manufacture and marketing authorization of products manufactured by its contract manufacturing organization in Korea, SK Bioscience and the import authorization of products manufactured outside of Korea, including those from Italy.

<< Dossier for Review/Approval >>
□ AstraZeneca’s dossier submitted for the marketing approval includes data on non-clinical and clinical trials, quality, risk management plan, GMP.
○ Non-clinical data demonstrate a drug’s toxicity and pharmacological activity verified under laboratory conditions before it is administered to humans.
○ Clinical data show the safety and efficacy of the drug evaluated through human trials.
- (Efficacy) While the clinical trials of general pharmaceuticals determine the therapeutic effects, those of vaccines focus on evaluating preventive effects in healthy individuals after vaccination.
- Vaccine efficacy (%) in a clinical trial is calculated from the proportion of the infected subjects within a vaccinated group and a control group, which would be given a placebo.For example, the occurrence of 10 confirmed cases among the vaccinated group and 100 confirmed cases in the control group in a Phase III clinical trial on 10,000 subjects for each of the two groups would mean that the vaccinated group’s probability of infection is one-tenth of the control group’s rate. In this case, the vaccine’s efficacy against COVID-19 would be 90%.
* Vaccine efficacy (VE) % = 100 x (1 - (Attack Ratevaccinated) / (Attack Rateunvaccinated))
- For reference, WHO’s “Considerations for Evaluation of COVID-19 Vaccines” recommends that the primary efficacy endpoint estimate of a COVID-19 should be at least 50%.
- (Safety) MFDS checks for any Adverse Events Following Immunization and assesses the safety through long-term follow-ups on various factors such as serious adverse events.
- WHO’s “Guidelines on clinical evaluation of vaccines” recommends a follow-up period of at least 6 months for general vaccines and at least 12 months for vaccines containing novel adjuvants.
- In the “Considerations for Evaluation of COVID-19 Vaccines,” WHO also recommends that the COVID-19 vaccines be followed up for at least 1 year.
○ Quality data involves the drug’s manufacturing process management and “Standards and test methods” for quality management.
○ Risk Management Plan (RMP)* includes data regarding a comprehensive safety management plan including risk mitigation steps such as patient information sheet and elements to assures safe use.
* Risk Management Plan (RMP): Comprehensive plan on safety management activities intended to ensure the collection of safety and efficacy data, investigation, testing, risk minimization throughout the life-cycle of drugs from pre-approval to post-marketing stage
○ Data on the evaluation of Good Manufacturing Practice (GMP)* compliance is comprised of 10 types of documents on facility/environment management, quality assurance system and other aspects related to the candidate product.
* Good Manufacturing Practice (GMP): Standards that a drug manufacturer must comply with respect to the whole manufacturing process, facility, and equipment to manufacture quality-assured pharmaceuticals.
- As for the AstraZeneca vaccine, MFDS will conduct assessments in addition to the regular GMP evaluation according to the characteristics that are unique to viral vector vaccines. The additional assessment items include matters related to the management of biological ingredients, living modified organisms and Biosafety Level.

<< Additional documents >>
□ The AstraZeneca vaccine will be manufactured by SK Bioscience in Korea and other companies in the U.S., the U.K, and Italy.
○ (Quality data) SK Bioscience has been additionally submitting quality data on the bulk and finished products manufactured in Korea under a consignment deal with AstraZeneca to the AstraZeneca Headquarters.
- Using the quality data from SK Bioscience, AstraZeneca Headquarters plans to analyze and assess the quality equivalence of the vaccines used in the clinical trials and the vaccines produced by SK Bioscience.
- AstraZeneca intends to include the quality equivalence report in the quality data, and AstraZeneca Korea will swiftly submit the report.
- MFDS plans to shorten the review period by commencing the review of other components of the quality data that have been already submitted while the quality equivalence report is being prepared.
○ (Clinical data) AstraZeneca will submit the data on adverse events following vaccination gathered and analyzed over 12 months through a premeditated follow-up, which is in line with the global practice.
- Generally, the data on adverse events following vaccination should be collected over a certain period after the administration. MFDS expects to receive the data from a 12-month-long follow-up.
- AstraZeneca submitted the clinical trial data obtained from Phase I, II, and III trials conducted in the U.K., Brazil and other countries. The trials are still underway to assess the vaccine’s safety and are scheduled to end in September 2021.
- As the same safety evaluation method applies to other vaccines, Pfizer and Moderna will also prepare their vaccines’ long-term safety data obtained from follow-up studies.

4. Approval/Review Plan
□ MFDS will thoroughly evaluate the safety and efficacy of COVID-19 treatments through the operation of the “COVID-19 Vaccine/Treatment Review Task Force” to ensure the distribution of safe and effective COVID-19 treatments in Korea.
○ (Overview of the review process) Pharmaceuticals intended for use or sale in Korea are regulated by the Pharmaceutical Act, requiring marketing authorization issued by the Minister of Food and Drug Safety.
- As with AstraZeneca’s vaccine, MFDS may refer to the decisions of other foreign regulatory authorities on approvals when reviewing products developed outside of Korea. In this case, MFDS considers the scientific data to be more important than the approval status.
- If such products have an issue related to approval outside of Korea, MFDS will look into the background of the situation and make decisions based on a comprehensive and scientific review.
- In this way, MFDS can seek consultation from external experts to ensure the scientific expertise and objectivity of the review results and swiftly make the final decision on the issuance of approval in Korea.
○ (Review of the submitted documents) MFDS will verify the vaccine’s preventive effect against COVID-19 through factors such as the infection rate within the vaccinated and the control groups. The Ministry will also focus on reviewing the safety and quality of the vaccines. In particular, MFDS will closely examine adverse events observed during non-clinical and clinical trials for safety assessment and risk management plan for safe vaccination.
○ (Investigation of Good Clinical Practice* compliance) As on-site inspections have been restricted due to the COVID-19 situation, MFDS has conducted a document review to assess the Good Clinical Practice compliance, including the reliability of clinical test results issued by foreign institutions.
* Good Clinical Practice (GCP) for pharmaceuticals
○ (Investigation of manufacturing facility) MFDS will conduct document reviews and investigations on the management of manufacturing facility, quality assurance system, and other items to evaluate compliance with the Good Manufacturing Practice.
○ (Expert consultation) seek consultation from external experts to ensure the scientific expertise and objectivity of the review results.
- Hold consultations with external experts such as the “COVID-19 vaccine expert panels” comprised of toxicologists, infectologists and other medical specialists to discuss the validity of the submitted data and its applicability in the clinical settings; and seek final advice from the CPAC.
□ MFDS aims to cut the regular processing period (180 days or longer) down to 40 days to step up the review and approval of COVID-19 vaccines and therapeutics including the AstraZenca vaccine.
○ MFDS has conducted the rolling review of the non-clinical and quality data according to the request of AstraZeneca Korea (non-clinical data: since Oct. 6, quality data: since Dec. 18) and requested the company to submit supplementary non-clinical data.

5. National Lot Release
□ Unlike other medicinal products, vaccines are used in healthy individuals to prevent infectious diseases. Therefore, vaccines need to be approved for national lot release in addition to the marketing approval.
○ The national lot release system allows MFDS to verify the product quality through tests and the review of the summary protocol on each individual lot.
* summary protocol: allows to evaluate manufacturing data and test reports according to GMP; comprised of elements including test results of the drug substance and drug product
□ AstraZeneca vaccines produced by SK Bioscience are first in line for the next national lot release.
○ (Establishment of test method) the detailed test methods of the vaccine’s manufacturing company was shared in late August 2020. After MFDS was provided with reference standards and other reagents in November 2020, the Ministry established test methods in late December.
○ (Tests and data review) MFDS will conduct thorough reviews of data and tests for each lot to ensure the safety and efficacy of the vaccine so that people of Korea can feel safe about vaccination.
○ (Timeframe for national lot release) Since vaccines against pandemic diseases are subject to expedited national lot release, they will be prioritized before any other medical products for national lot release. Although the lot release normally takes 2 months or longer, MFDS will strive to finish the expedited lot release swiftly within 20 days.

□ MFDS will do its utmost to expedite the approval process of COVID-19 therapeutics and vaccine candidates while closely evaluating their safety and efficacy.