[Press Release, Jan 11, 2020 / unofficial translation ]


Updates on the approval and review of COVID-19 therapeutics and vaccines (1)


□ The Ministry of Food and Drug Safety (MFDS, Minister Kim Ganglip) provides the following clarifications regarding the marketing approval of a COVID-19 therapeutics Regkirona Inj. and AstraZeneca COVID-19 Vaccine Inj.


[1] Overview of the approval and review
□ MFDS is conducting reviews of COVID-19 therapeutics and vaccines according to the approval requirements and review criteria set out in the “Pharmaceutical Affairs Act” and other relevant regulations.
○ MFDS is a member of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), which is a governance forum that establishes the global approval standards of the most advanced pharmaceuticals. MFDS’ approval requirements, and our review criteria are equivalent to those of advanced countries including the U.S., Europe, and Japan.


[2] Therapeutics review/approval status
①Receipt of Application → ②Preliminary Review → ③Reviews and Inspections → ④Advisory Committee → ⑤Approval

□ Following the ①receipt of Celltrion’s application for the approval of its antibody treatment Regkirona Inj., MFDS conducted ②preliminary review to check on the document requirements. Then, the Ministry set about conducting the ③document reviews and inspections.

<< Document review (clinical trials) >>
□ The Ministry received clinical data from 3 trials conducted in Korea and abroad and other data on Regkirona Inj. MFDS is currently conducting a focused review of the validity of clinical data.
○ Two phase I clinical trials were conducted in 32 healthy individuals and 18 mild COVID-19 infected patients, respectively. MFDS is reviewing data that confirms the safety of the dosage administered to a person for the first time.
○ 1 Phase II clinical trial was conducted to verify the safety and efficacy in 327 mild-to-moderate COVID-19 infected patients.
- Phase II clinical trial generally focuses on the evaluation of a drug’s mechanism of action such as decrease in the virus reduction time. The above-mentioned phase II clinical trial, additionally includes the indicators for the amelioration of clinical symptoms or other effects.
- The Phase II clinical trial additionally included the proportion of patients with clinical symptom requiring hospitalization, oxygen therapy which is normally evaluated in the phase III clinical trial of COVID-19 therapeutics.
- The phase II trial aimed to verify whether the virus actually binds with to the therapeutics instead of a human cell to diminish the infectability of the virus within the human body.
- Virus tests were conducted using nasopharyngeal specimen collected* from subjects in the treatment group to measure the timespan from positive-to-negative SARS-CoV-2 RNA detection. The reduction in the positive-to-negative conversion time in the treatment group was assessed in comparison to the control group.
* Specimen was collected once every day for 7 days and then 14, 21 and 28 days from the date of administration.
- Also, the trial focused on the assessment of the time of recovery from 7* COVID-19 symptoms in the treatment group and whether the treatment actually provides clinical effects. Clinical symptoms were observed twice a day for up to 14 days. The severity of all symptoms were recorded and the recovery time was evaluated.
* fever, cough, breathing difficulty or shortness of breath, sore throat, body aches (myalgia), fatigue, headache
- The clinical trial also evaluated the proportion of patients with clinical symptoms requiring hospitalization, oxygen therapy or mechanical ventilation.
- Such phase II clinical trials are deemed to have the same design and objective as phase III clinical trial. If the phase II trial confirms the therapeutic effect, MFDS may consider granting the marketing authorization, provided that the company later submits the phase III clinical data.

<< Inspection (GMP compliance evaluation) >>
□ To assess whether the company has the manufacturing facility and management system that allows the manufacturing in consistent quality, MFDS conducted an on-site inspection of Celltiron’s two manufacturing facilities. The inspection was carried out last week by two teams of reviewers from MFDS, each comprised of three or four reviewers.
○ The antibody treatment candidate is a recombinant treatment. Unlike chemical drug production, the manufacturing of recombinant drugs requires recombinant cell culture and the purification of antibodies produced by the cultured cells. Thus, MFDS focused on assessing whether the cell culture facility and the cell culture separation/purification facility have been properly managed.
○ The candidate product is a sterile injectable medication. Therefore, the product’s manufacturing site must have facility and environment that are necessary to prevent contamination with fine particles and microorganisms and maintain the required level of cleanliness.
- Naturally, MFDS conducted the inspection of cleanliness level according to the characteristics of the operation and process, appropriateness of the configuration and management, matters related to the maintenance of equipments including those for appropriate air handling, solutions for the manufacture of pharmaceuticals, and other equipments and facilities.
○ MFDS also reviewed the actual batch records, quality inspection records and supporting evidence of the 3 batches of finished products for GMP inspection and bulk product and assessed the reliability of the data.
○ Through the on-site inspection, the Ministry also verified the quality assurance system data and validation data created before the company submitted the application for review.

□ Korea has demonstrated its competence in GMP evaluation and management on the global level through its member status in the Pharmaceutical Inspection Co-operation Scheme (PIC/S).
○ MFDS joined the PIC/S, a forum that leads international harmonization of the pharmaceutical GMP and inspections, in 2014 along with Japan. The Ministry’s level of GMP implementation has been acknowledged globally. The Ministry is committed to the international harmonization of GMP through the operation of GMP inspection data exchange system with other PIC/S member states.
- PIC/S member states have implemented the internationally harmonized GMP regulation. Therefore, they can refer to the GMP compliance evaluation results from another member state where the manufacturing facility is located if the two countries with the same regulatory maturity have signed a mutual recognition agreement. A case in point would be the Agreement on Mutual Reliance in GMP signed by Korea and Switzerland in June 2018.


[3] Vaccine review/approval status
①Receipt of Application → ②Preliminary Review → ③Review → ④Adviosory Committee → ⑤Approval → National lot release (Vaccines) Inspection

□ MFDS ①received the application for the COVID-19 vaccine approval from AstraZeneca Korea, conducted the ②preliminary review to check on the compliance with document requirements, and began the formal ③review of submitted documents.

<< Document Review (general process) >>
□ Application dossier for the marketing authorization of the AstraZeneca vaccine includes non-clinical, clinical and quality data, and Risk Management Plan.
○ Proposed AstraZeneca COVID-19 vaccines are those who are 18 or older. The vaccine is to be administered as a series of two doses (0.5 mL each) 4 to 12 weeks apart.
- The Ministry is reviewing the submitted data to determine the appropriateness of the indicated recipients, dosage and administration and is currently focused on the validity of non-clinical and clinical data.
○ Non-clinical data including toxicity and pharmacology required prior to first in human clinical trail submitted upon the company’s request for a rolling review on Oct. 6, 2020.
○ Quality data demonstrates the management of the vaccine’s manufacturing process and quality, among others, and includes data on the physicochemical and biological characteristics of the drug substance and the finished product, manufacturing methods, specifications and analytical procedures (including evidence), reference standards, containers, and packaging.

<< Document review (clinical trials) >>
□ AstraZeneca submitted clinical data from four trials underway in the U.K., Brazil and other countries. The data have been also published in The Lancet, a medical journal.
○ Phase II/III and phase III clinical trials that provides scientific evidence for the indicated dosage and administration were conducted in the U.K. and Brazil. The vaccine’s preventive effect is assessed based on the results of the trials.
- As for the phase II/III clinical trial in the U.K., the second dose was administered after the safety and immunogenicity after the first dose was verified through the comparison with placebo group and the number of clinical trial subjects were continuously increased.
- Phase III clinical trial in Brazil was designed to give two doses to approximately 10,000 persons aged 18 or older to assess efficacy and safety.
- Efficacy can be evaluated by 1) ending the trial when the number of confirmed cases in the subject population reach the previously defined threshold level and 2) analyzing the preventive effect by comparing incidence of confirmed COVID-19 cases between the vaccine group and the placebo group ≥ 15 days after the second dose.
- Also, the efficacy will be assessed through immunogenicity assessment that monitors the neutralizing antibody production and additional indicators including the proportion of severe cases.
* Vaccine Efficacy (VE) % = 100 x (1 - (Incidence vaccinated) / (Incidence unvaccinated))
○ The vaccine’s safety will be assessed based on the comprehensive review of the results from 4 clinical tests, in which subjects were vaccinated in the U.K. (2 cases), Brazil, and the Republic of South Africa.
- According to the evaluation method, the trial simultaneously monitors and compares the occurrence of solicited* and unsolicited adverse events in the vaccine group and the placebo group. The data submitted for this review had been collected and analyzed by Nov. 4, 2020.(The long-term safety follow-up is carried out until 1 year after the administration)
* pain at the injection site, nausea, fever, headache, muscle ache, joint pain, etc.
○ MFDS is verifying the candidate vaccine’s efficacy including the preventive effects (e.g. incidence) and dose interval based on the submitted clinical data and thoroughly assessing adverse events observed in the clinical and non-clinical trials.
- In particular, the vaccine’s safety and efficacy in the elderly who are 65 or older will be assessed separately from those in other age groups.


[4] Review/approval plans in the third week of January
○ (Therapeutics) The Ministry will also inspect the clinical trial sites (medical institutions) for Celltrion’s Regkirona Inj. in the 3rd week of January to verify GCP compliance throughout the entire clinical trial including the safety of the clinical trial subjects and the reliability of the trial results.
- Furthermore, the “Advisory Committee for the safety and efficacy assessment of COVID-19 Vaccine/therapeutics*” will hold a meeting to review the clinical data early next week.
* The advisory committee is comprised of external experts with sufficient knowledge and experience in clinical, non-clinical and quality evaluation, mostly specializing in infectology. It will assess the candidate product’s safety, efficacy, clinical significance, and the validity of subject composition, among others.
○ (Vaccine) As for the AstraZeneca vaccine, the Ministry will thoroughly assess the preventive effect and validity of indicated dosage and administration based on the clinical data and focus on the quality data assessment to expedite the national lot release.
- On-site inspection of the manufacturing facility (SK Bioscience) for the assessment of manufacturing and quality management will be conducted before the end of January.