Regulatory approval for COVID-19 across the globe.

Introduction

The COVID-19 pandemic has changed the global regulator working on approval of drugs as a fast track process and involved in mutual agreement in bringing a drug of importance for the public. This is a major challenge as the safety and efficacy of novel therapies is not fully established but ways to bring about a difference to the COVID-19 pandemic response is the need of the hour. Regulators have been striving hard in order to bring flexibility in the regulations so as to accelerate various approval and adaptive licensing mechanisms. Various institutions have been working together in collaboration to fight this pandemic. The World Health Organization has always promoted such collaborative approaches as these enhance the efficiency of regulatory authorities and also avoids duplications. This editorial covers the perspective in relation to different regulatory agencies across the globe and their regulatory flexibilities amid COVID-19. We have also focused on details of clinical trials and different classes of drugs that are approved to treat SARS-CoV-2 infection.

Regulatory Approval for COVID-19 in the European Union

Like any global regulatory in medicines, the European countries European Medicines Agency (EMA) is entrusted with approval or rejection of drugs being submitted for approval.[1] Only after careful scientific examination of its quality, efficacy, and safety can a new medicinal product be advertised or recommended and used by its people. All marketing authorization is issued on the basis of the EMA's evaluation of medicines or goods that have shown a positive risk-benefit profile. However, these processes in general take several time period to be followed step by step. However, the current pandemic brought several changes in the EMA in screening and scrutinizing the application for the immediate availability of drugs for the public welfare. They have been keenly interacting with multiple developers for bringing out probable COVID-19 treatment and vaccines. Two medications namely Remdesivir and dexamethasone have already been approved by the EMA for COVID-19. The details for their approval will be detailed in subsequent headings.

Rapid assessment of Remdesivir

Remdesivir is a viral RNA polymerase inhibitor used to treat SARS-CoV-2 infection since July 2020. Its stipulated use is in patients with pneumonia who need supplemental oxygen.[2] 1063 patients hospitalized with SARS-CoV-2 infection (120 had mild-to-moderate disease while 943 had severe disease) were included in the National Institute of Allergy and Infectious Diseases (NIAID)-Adaptive COVID-19 Treatment Trial (ACTT-1) study which revealed accelerated recovery in patients on Remdesivir thus reducing their duration of hospital stay and total duration of treatment.[3] The EMA, concluded that the benefits of the drug outweigh its risk. Remdesivir was granted a “conditional marketing authorization” in the battle against COVID-19, thereby forcing the company that markets the medicine to produce more concrete evidence. The information thus generated will be continuously reviewed by the regulatory authority.

EMA's Committee for Medicinal Products for human use (CHMP) has assessed the application in a limited timeframe yet meticulously evaluating the data on the medication's risks and benefits. The assessment began on June 8, 2020. EMA's Pharmacovigilance Risk Assessment Committee finished an evaluation of the preliminary Risk Management Plan for the medication, and the company's Pediatric Investigation Plan (PIP) was evaluated promptly by the Pediatric Committee (PDCO).

European Medicines Agency and Rapid Assessment Strategies in Common for COVID-19

In cooperation with the responsible scientific committees and the European Commission, the EMA is implementing quick measures to ease the development and assessment of treatment and vaccines to treat COVID-19. The COVID-19 EMA Pandemic Task Force (COVID-ETF) aids rapid regulatory action to develop, authorize, and monitor the safety of therapies within a timeframe that is appropriate for the public health emergency. The activities of COVID-ETF include (a) offering direction on the development plans of COVID-19 medications where formal scientific advice is not possible; (b) guiding the Scientific Advice Working Party (SAWP); and (c) CHMP [Table 1].

Table 1

Difference in time frame at various regulatory procedures in COVID-19 pandemic

Procedures	Description	Standard timeline	Fast-track timeline (days)
Rapid Scientific Advice	Study designs - scientifically robust evidence Safety, effectiveness and efficiency of COVID-19 treatments and vaccines in the quickest time frame	40-70 days	<20
Rapid Agreement of PIPs	PIP Speeds up the analysis of PIP approval requests	<120 days	≥20
Rolling Review	The rolling review of the public health emergency continues to analyse details as the progress is still underway The formal evaluation procedure can take place within a very short timeframe for a MAA	210 days after MAA validation	14
Accelerated Assessment	To review applications for marketing authorisations for items of substantial public health concern within a shorter period Rolling review is not applicable Timelines for the assessment would be shortened to an absolute minimum	210 days	<150
Extension if the marketing authorisation is indicated and expanded	Medicines already approved for other diseases can work against COVID-19 as well In order to shorten approval times for applications, EMA is prepared to apply more flexibility to expand indications for already licensed medicinal products that are in the process of establishment or repurposed for treating or preventing of COVID-19
Compassionate use of potential treatments for COVID-19	Compassionate use programs can be developed by individual EU Member States to grant access to developing therapies which have not been approved for marketing purposes Provides guidelines on how to use these drugs to treat COVID-19 in order to facilitate a harmonized approach across Europe

PIP=Paediatric investigation plan, MAA=Marketing authorisation application, EMA=European Medicines Agency, MAA=Marketing authorisation application, EU=European union

The rapid formal reviews of the EMA are outlined in 7 headings, including quick scientific advice, speedy approval of the PIP and swift compliance verification, ongoing review, marketing authorization, extension of the indication as well as marketing authorization, compassionate use and other considerations.

Rapid scientific advice

The EMA offers prompt scientific advice which the CHMP and COVID-ETF will later follow. Prespecified deadlines for submission do not exist and enhanced flexibility is given to the form and content of the briefing dossier, that is, reviewed on a case-by-case basis. Through the intervention of the SAWP, CHMP, and COVID-ETF, the scientific validity of the advice is assured. The CHMP often adopts the final guidance. From the beginning to the final letter of advice, the overall review duration is 20 days, when compared with the normal 40–70 days.

Once the developers have contacted the agency and the suitability of the project has been reviewed, the project manager will be assigned. Further assistance and support would be offered by the scientific advice office of EMA.

Pediatric investigation plans

Applications for approval of PIPs, deferrals or waivers for COVID-19 treatment and vaccines would be revised considering applicable legislative requirements. The PDCO would perform scientific evaluation of such submissions and the COVID-ETF would provide scientific input. The total evaluation time beginning from the adopted PDCO opinion has been reduced to minimum 20 days, compared with usual 120 days. Once PDCO opines, the EMA verdict is approved within 2 days. Sponsors would then be asked to outreach to different regulators (e.g., Food and Drugs Act [FDA]) to enable such exchange.

Rolling review

Rolling review (RR) is an ad hoc procedure, where the EMA continuously assesses data of upcoming applications prior to the official submission of a whole application for new marketing authorization (or extending of indication with respect to authorized medications). Every RR is submitted in e CTD (electronic common technical document) format comprising an application form, an overview of module 2 and responses to the combined list of all unanswered issues from prior evaluation periods. When the committee determines that the documentation is adequately complete to progress with a formal regulatory request, the company submits a formal marketing authorization application, which, after validation, will be expedited. Finally, an EMA Product Lead is appointed for procedural guidance. If the application has been submitted and the eligibility has been authenticated, the petitioner asks the Rapporteurs for a rolling evaluation to be evaluated by the COVID-ETF. In the absence of a RR, the applicant applies for an accelerated assessment where the evaluation of the application starts only after authentication of whole application, reducing the cumulative time of active review from 210 days to 150 days.

Extension of indication and marketing authorization

For extension of indication and marketing authorization for already authorized products, with the plan of repurposing the medications, Marketing Authorisation Holder (MAHs) exchange details on their proposed production with the EMA and the Rapporteurs, using rapid scientific guidance and rapid PIP approval. The EMA Product Lead is contacted for expediting such processes. Member States Applicants shall approach EMA through the National Competent Authority for any requests for a compassionate use program. Following a proper channel through CHMP recommendations, EMA then collects data from applicants periodically, on the basis on which CHMP updates its opinion.[4]

The priority medicines scheme

It is a voluntary scheme that enables enhanced support for the development of treatment during the earlier stages.[5] If needed developers are directed to the Orphan Medicines office for procedural guidance.

Dexamethasone taw

Taw Pharma is designing Dexamethasone Taw as an injectable hybrid drug. Dexamethasone Taw is currently being assessed by CHMP of the EMA for treating admitted adult patients with COVID-19. The Dexamethasone Taw has been tested since August 31, 2020. A clinical trial called “RECOVERY” was performed with dexamethasone[6] as an interventional medication for COVID-19 hospitalized patients seeking respiratory assistance. As per the guidance of the EMA Executive Director under Article 5 (3) of Regulation 726/2004, the CHMP initiated this review on July 24, 2020. After the full analysis is completed by EMA, further contact will be carried out.

Potential Therapies and Vaccines under Investigation

EMA has remained in discussion with the producers of 38 new COVID-19 vaccines and 158 probable COVID-19 therapies as of September 1, 2020. Immunomodulatory, antiviral, and hyperimmune serums are the treatment choices. EMA has been actively working to provide developers with instructions for future COVID-19 medicines on the most suitable methods and study designs. Seventeen such projects have been finalized so far, and 22 projects are pending. The International Coalition of Medicines Regulatory Authorities (ICMRA) is leading regulatory authorities for medicines worldwide to streamline the production of vaccines and treatments for COVID-19. With unpredictable timeline, EMA is under the process of making Vaccine for COVID-19 as soon as possible but it might take at least until the beginning of 2021.[7]

Clinical trials

A total of 305 trials have been registered with various phases of trials. Out of which 296 are ongoing including one observational study, 6 completed and 3 restarted [Figure 1]. The completed trial included Remdesivir, hydroxychloroquine, and oral selinexor.[8]

Figure 1

Ongoing clinical trial

Regulatory Approval for COVID-19 in the United States of America

The nodal agency for the evaluation of safety and efficacy of marketed medicines in the USA is FDA. The Center for Drug Evaluation and Research under FDA reviews drugs, postmarketing surveillance, etc. Pharmaceutical companies will apply for Investigational New Drug (IND) to FDA before commercial marketing for its approval. The application of IND can be investigator IND, treatment IND, or emergency use IND. Investigator IND proposes approved or unapproved drugs for new patient populations or new indications. Emergency use IND permits for emergency use of the experimental pharmaceutical product in an emergency like the COVID-19 pandemic. Treatment IND permits in case of serious or immediately life-threatening conditions.[9]

In New Drug Application (NDA), IND data from animal and human studies will be submitted for approval. NDA application is critically reviewed by FDA reviewers for safety and efficacy in a proposed use, risk-benefit analysis, appropriateness of package insert, and quality and purity of drug during manufacturing, maintenance, and preservation. The generic drug product receives approval under Abbreviated ANDA. The generic drug product can be safe and effective or a low-cost alternative for the intended disease and marketed with an alternative brand name.[10] Therapeutic biologics application deals with cytokines, monoclonal antibodies, enzymes, thrombolytics, growth factors, immunomodulators, animal-derived proteins, or their recombinant version and other nonvaccine therapeutic immunotherapies.[11] Expedited approval mechanisms for new drug products: in this category, pharmaceutical companies can propose their product under various categories for faster approval for drugs. Different mechanisms for faster approval of drugs are discussed below.[12]

Fast track procedure

Under this, the development and review of drugs is expedited for the treatment of serious or unmet medical conditions. This process enables access to new drugs to the patient. An unmet medical need is defined as “providing a therapy where none exists or providing a therapy which may be potentially better than available therapy,” Drugs under this category will conduct clinical trials using specific biomarkers to prove their efficacy.[1314]

Breakthrough therapy

Under this category, drug products fill the gap in the treatment of a serious condition designed for development. The efficacy of these products is derived from the early clinical trial outcomes related to clinically significant endpoints. The drug products under this category receive benefits of fast track approval along with senior mentors of FDA from the Phase 1 trial.[1315]

Accelerated approval

Under this pathway, a surrogate endpoint is used instead of clinical endpoints to fill an unmet medical need for serious conditions. The pharmaceutical agents received approval under this category need to complete phase 4 confirmatory trials to the actual benefit for which drug was approved. In 2020, FDA proposed withdrawal of hydroxyprogesterone caproate injection from the market for the prevention of recurrent preterm birth. The neonatal outcomes in treatment group showed that there was no significant improvement.[1617]

Priority review

This shortens the duration of the FDA's review. Priority review is given for serious conditions for which the pharmaceutical product is shown to be safe and effective from the available treatment.[18]

Total 53 drugs approved in the year 2020 are enumerated in Table 2.[19]

Table 2

Novel drug approvals for 2020

Drug Class	Drugs Approved
Anti-cancer	Relugolix, Margetuximab, Gallium 68 PSMA-11, Naxitamab-gqgk Pralsetinib, Copper Cu 64 dotatate injection, Tafasitamab-cxix, Lurbinectedin, Fluoroestrdiol F18, Ripretinib, Selpercatinib, Capmatinib, Sacituzumab govitecan-hziy, Pemigatinib, Tucatinib, Selumetinib, Isatuximab, Tazemetostat and Avapritinib
Anti-microbial agents including COVID 19	Ansuvimab-ebola, Remdesivir, Atoltivimab, maftivimab, and odesivimab-ebgn, Fostemsavir, Artesunate
Metabolic disorders	Setmelanotide, Triheptanoin, Bempedoic acid
Others	Berotralstat, Lumasiran, Lonafarnib, somapacitan-beco, Satralizumab-mwge, Viltolarsen, Oliceridine, Risdiplam, Nifurtimox, Belantamab mafodotin-blmf, Abametapir, Decitabine and cedazuridine, Remimazolam, Inebilizumab-cdon, Flortaucipir F18, Opicapone, Ozanimod, Osilodrostat, Rimegepant, Amisulpride, Eptinezumab, Lactitol, Teprotumumab and Tirbanibulin

The USFDA along with NIH is involved in Accelerating COVID-19 Therapeutic Interventions and Vaccines for the development of therapeutic candidates and vaccines that can help end the COVID-19 global pandemic.[20]

A statutory requirement for emergency use authorizations

This is granted when a medical product shows effectiveness in serious or life-threatening diseases. While authorizing emergency use for any product, the probable benefit for the proposed use should outweigh its recognized and potential hazards.[21] As of December 18, 2020, total in vitro diagnostic products were 305 (molecular tests and sample collection devices-233, antibody tests-62, and antigen tests-10), Personal Protective Equipment and Related Devices were 24, and >100 Ventilators and accessories, and Drug and Biological Products were 10. In Table 2, details of drugs and biologics approved by the USFDA under Emergency Use Authorizations (EUA) are described [Table 3].[22] Shuren and Stenzel observed that molecular diagnostic tests for COVID-19 that received approval under EUA was a reasonable step accessing diagnostic steps during emergency situation-like COVID-19 pandemic. Initiatives such as international collaboration, large scale production of small number of well designed, well-developed, and validated tests along with reliable method of validation and its test performance are essential for molecular diagnostic test to beat the pandemic like COVID-19.[23]

Table 3

Drug and biological products approved by US Food and Drugs Act under emergency use authorization

Drug/biological agent	Indication
The mRNA-1273 vaccine	Individuals of 18 years and above To prevent COVID-19
SARS CoV 2 RNA vaccine	Individuals of 16 years and above To prevent COVID-19
Casirivimab and Imdevimab	Individuals of 12 years and above with minimum of 40 kg body weight To manage mild to moderate COVID-19 patients, those at high threat for advancing to severe COVID-19 and/or hospitalization
Baricitinib along with Remdesivir	A suspected/laboratory-confirmed COVID-19 patient in hospital Individuals above 2 years Patients who require supplemental oxygen, invasive mechanical ventilation, or ECMO
Bamlanivimab	Individuals of 12 years and above with minimum of 40 kg body weight To treat mild-to-moderate cases of COVID-19 Patients at greater risk for advancing to severe COVID-19 and/or hospitalization
Convalescent plasma of recovered COVID-19 patient	Only hospitalized patients
Fresenius Kabi Propoven 2%	Individuals of 16 years and above Either suspected/confirmed COVID-19 on mechanical ventilation
Remdesivir	A suspected or laboratory-confirmed COVID-19 patient Only hospitalized patients (adults and pediatric age group)
Fresenius Medical, multiFiltrate PRO System and multiBic/multiPlus Solutions	To offer CRRT for treating patients in an acute care setting

SARS-CoV-2=Severe acute respiratory syndrome coronavirus 2, ECMO=Extracorporeal Membrane Oxygenation, CRRT=Continuous Renal Replacement Therapy

Hydroxychloroquine sulfate (HCQ) and Chloroquine phosphate (CQ) received EUA for the treatment of COVID-19. However, scientific review of CQ and HCQ observed that potential benefits outweigh the known (serious cardiac adverse events) and other potential adverse effects.[24]

Canadian approval mechanism

Health Canada (HC) is a nodal agency that regulates the distribution and selling of medications in Canada as per the FDA and its food and drugs regulations. Under this act and its regulations, HC designs suitable policies and guidance. A pharmaceutical product can be marketed in Canada, from the manufacturer holding a Notice of Compliance from HC and the drug should be allotted a Drug Identification Number.[25] On May 23, 2020, an interim order (IO) was signed to clinical trials for medical devices and medicines associated with COVID-19 by the Ministry of Health. The IO streamlines the investigation of potential therapies and facilitates broader access for Canadians to COVID-19-associated investigational medicines and medical devices. This is one of the quickest mechanisms existing to deal with large-scale public health emergencies, without following the usual regulatory process.[26] In this pandemic, HC reduced administrative burden of clinical trials and promoted efficient investigation of drugs and medical devices to treat, prevent, mitigate, or diagnose COVID-19. HC's IO reduces the administrative requirements for trials that involve new uses of drugs and medical devices that are already being marketed. These adjustments would be of particular benefit for such complex clinical trials as multi-site, multi-arm and remote trials, and those that involve repurposing drugs and devices. Required clinical trial reviews by HC and a Research Ethics Board have also been prioritized for COVID-19-related drugs and devices. The scope of the two guidance documents, one for drug clinical trials and one for medical devices, include trials related to COVID-19 for pharmaceutical and biologic drugs, including blood and blood components; medical devices and combination products. The IO and guidance apply to clinical trials in Phase 1-3.[2728]

The IO stresses that, the trial-related adverse event reporting should continue as it was present during normal time. Furthermore, HC retains oversight flexibility, and may intervene in trials “when required to safeguard the best interests of clinical trial participants.” This flexibility includes “being able to partially suspend or revoke a trial. This will allow the suspension of one arm, or treatment group, of a randomized trial, if needed. The rest of the trial would be allowed to proceed so that other participants can continue to receive a prospective therapy,” said HC.[29] Total 361 medical devices and 34 testing devices are authorized for sale or import in Canada. List of authorized clinical trials-54 (Hydroxychloroquine, Nitric oxide, Isoflurane, Sevoflurane, Recombinant Novel Coronavirus Vaccine [Adenovirus Type 5] [Ad5-nCoV) etc.].[30]

Clinical trial regulations

Clinical trials are studies authorized by HC that investigate the safety and efficacy of a drug or vaccine that exists but is to be used for another purpose or is not yet available in Canada. Sponsors in Canada should apply to conduct a clinical trial. For drug and vaccine clinical trials not related to COVID-19, existing regulations and processes still apply. To conduct a clinical trial for COVID-19 purposes: HC is offering priority to the review of all clinical trial applications pertaining to COVID-19 and at present granted authorization to a number of trials. Sponsors of COVID-19-related drug and vaccine clinical trials can choose between two different processes: existing process outlined in the food and drug regulations or process outlined in new IO for clinical trials with regards to medical devices and medications pertaining to COVID-19.[31] Under the IO, HC is reducing the administrative burden for sponsors applying to conduct a COVID-19 clinical trial, while maintaining safety of patients and validity of trial results. It is also introducing flexibility by expanding the types of health care professionals who can conduct a clinical trial. Further information can be found in the IO notice. The Pfizer-BioNTech is a mRNA vaccine that has been permitted for the prevention of severe acute SARS-CoV-2 infection among individuals belonging to 16 years of age and older.[32]

The Brazilian Health Surveillance Agency (Agencia Nacional de Vigilancia Sanitaria)

This agency was formed in 1999 and the chief goal was to guard and promote public health surveillance pertaining to products and services in Brazil.

The Brazilian Health Regulatory Agency (Agencia Nacional de Vigilancia Sanitaria)

Agencia Nacional de Vigilancia Sanitaria (ANVISA) integrates the Committee for Emergency Operations against the Coronavirus. The committee is responsible for preparing Brazil's public health system for the treatment and prevention of cases in the country.

ANVISA has defined extraordinary rules for the evaluation of requests for registration of medicines and biological products for preventing and treating COVID-19. The rules also establish extraordinary procedures for postregistration changes, when the company changes the original registration of the medicine or biological product. In addition, there is an extraordinary change in the registration of products for the laboratory (in vitro) diagnosis of the virus. The purpose of the measure is to expand prevention and treatment options, as well as to avoid product shortages. It also aims to increase the alternatives for detecting the disease and to speed up the order analysis process.

Regulatory Approval for COVID-19 in Japan

Remdesivir is the first officially authorized drug in Japan for the treating COVID-19. The drug received nod by the regulatory authority of Japan, Ministry of Health, Labour and Welfare on May 7, 2020, to treat patients with severe COVID-19. It was granted go-ahead under the exceptional approval pathway in Japan following the drug's EUA by the USFDA.[33] The drug is given as intravenous infusion in hospitalized patients with severe COVID-19 illness.

COVID-19-clinical trials with Remdesivir

Adaptive COVID-19 Treatment Trial

A randomized, double-blind, placebo-controlled trial that included adults hospitalized with COVID-19 who were on intravenous Remdesivir and having signs of lower respiratory tract involvement. It was conducted by the U.S. NIAID at 47 U.S. and 21 international sites. Preliminary results of this trial included data from 1059 patients (538 allocated to Remdesivir while 521 to placebo) reported a shortening of the median recovery time with Remdesivir (11 days, 95% confidence interval [CI]: 9–12 days) when compared to placebo (15, 13–19 days; rate ratio for recovery: 1.32; 95% CI: 1.12–1.55; P < 0.001). However, significant improvement in survival rates was not reported with drug (7.1% in Remdesivir and 11.9% in placebo group; hazard ratio for death: 0.70; 95% CI, 0.47–1.04). The preliminary report concluded the supportive role of 10 day course of Remdesivir in COVID-19 patients requiring supplemental oxygen therapy. Results of this trial formed a major basis for regulatory approval of Remdesivir by the USFDA and Japan.[34]

As per the concluding report of the ACTT-1 trial, the time to recovery was shortened with Remdesivir when compared to placebo.[35]

Gilead “SIMPLE” Trials

GS-US-540-5773 trial

This trial assessed the safety and efficacy of Remdesivir in a 5-day versus 10-day course, in patients suffering from severe COVID-19. The trial included 397 randomized patients (200 patients were treated for 5 days and 197 for 10 days). There was no significant difference between 5 days and 10 days of treatment duration with Remdesivir with respect to clinical status on day 14. It was concluded that in the absence of placebo as control group, the magnitude of benefit could not be ascertained.[36]

Second “SIMPLE” trial

This was an open-label study which assessed Remdesivir plus standard of care, versus standard of care alone with 5-day and 10-day treatment duration. It was reported that on day 11 patients on Remdesivir group for 5 days had 65% further likelihood of achieving improvement clinically as compared to the standard of care group (odds ratio [OR] 1.65 [95% CI 1.09–2.48]; P = 0.017). The clinical status also improved in 10-day treatment group of Remdesivir versus standard of care group although statistical significance could not be attained (OR 1.31 [95% CI 0.88–1.95]; P = 0.18). New safety signals were not detected with Remdesivir in either of the two treatment groups.[37]

World Health Organization-SOLIDARITY Trial

The results of this trial concluded that Remdesivir has slight or no beneficial effect in COVID-19 patients (hospitalized), as demonstrated by overall mortality, ventilation requirement, and length of hospital stay.[38]

Dexamethasone

Dexamethasone is the second drug to be approved for COVID-19 treatment in Japan following Remdesivir. The drug was granted fast track approval on July 22, 2020 by Japan Health ministry to treat severe cases of COVID-19 in Japan.[39]

RECOVERY Trial

The RECOVERY trial of the United Kingdom, backed by the National Institute for Health Research Clinical Research Network, and conducted at 176 National Health Service organizations. 2104 patients were assigned to dexamethasone group while 4321 to usual care. The trial concluded that there was a decline in 28-day mortality among patients on invasive mechanical ventilation or oxygen alone on dexamethasone use but the benefit was not observed in patients who did not receive any respiratory support.[6]

Favipiravir

Favipiravir was approved for use in Japan for flu outbreaks. However, it has not been approved for use in COVID-19 by Japan health ministry so far.

It acts by inhibiting RNA-dependent RNA polymerase thereby blocking viral replication inside host cell.

The efficacy of Favipiravir in COVID-19 was tested in a multicentric trial by Japan's Fujita Health University. The study included two arms: in the first arm Favipiravir was administered to patients in early stage of illness and in the second arm, drug was given later than those in the first arm. More than 94% of the patients in the group receiving early treatment with Favipiravir had a significant and rapid reduction in viral loads (dropping them below 50%) and alleviation of fevers within 2.1 days on average. However, the results were not statistically significant. The findings of the study, albeit, highlight the drug's potential to avoid disease progression to more severe or critical clinical stages in COVID-19 patients, along with its beneficial use in patients having mild or moderate COVID-19 infection.[40]

Phase 3 trial of Favipiravir

This was an open-label, randomized, parallel-arm, multicenter, Phase 3 trial comprising of 150 COVID-19 patients confirmed with RT-PCR and having no or mild-to-moderate symptoms underwent randomization to oral Favipiravir and standard supportive care versus supportive care alone. There was a significant improvement in time to clinical cure in Favipiravir arm. 36% of patients in Favipiravir and 8% in control patients reported adverse events. Most common adverse events reported with greater incidence in Favipiravir arm compared to control arm were increased blood uric acid, abnormal liver function tests and viral pneumonia; all were graded as mild or moderate in severity. One patient in control group died due to worsening of disease. No new safety signals were reported. The study concluded that Favipiravir was beneficial in mild-to-moderate COVID-19.[41]

Other Drugs Being Tested in Japan for COVID-19

Nafamostat mesylate, an agent used in acute pancreatitis is believed to possess antiviral properties due to its potential to attack the proteins on the surface of coronavirus, thus hindering viral multiplication. Currently, clinical trials are underway in Tokyo University using combination of Nafamostat mesylate and Favipiravir.[42]

COVID Vaccines

Regarding vaccines for coronavirus, none of the vaccines has so far been approved by Japan Health Ministry.

Pfizer Vaccine

Pfizer has recently applied for COVID-19 vaccine approval in Japan. As reported in a news conference earlier, according to Japan Chief Cabinet Secretary Katsunobu Kato, approval will be granted to COVID-19 vaccine on filing after confirmation of efficacy and safety.[43] However, the Japan government has made a deal with Pfizer for supply of 120 million vaccine doses manufactured by Pfizer and its partner BioNTech (Germany).[44]

Moderna Vaccine

Clinical trials on Moderna's COVID-19 vaccine are planned to start as early as in early January in Japan. Takeda and Japan's health ministry signed an agreement with Moderna in October 2020 on a deal to supply 50 million doses of the vaccine to Japan beginning in the first half of 2021.

Astrazeneca-Oxford Vaccine

Phase 1 and 2 clinical trials of Astra-Zeneca COVID-19 vaccine (AZD1222 or ChAdOx1 nCoV-19) are being conducted in Japan.[45] Based on the interim results of trials in UK and Brazil, the vaccine is reported to be 90% effective. There were not any hospitalizations or severe COVID-19 in the individuals who received the vaccine. The vaccine has shown to be effective and cheaper.[46]

Regulatory Approval for COVID-19 in United Kingdom

Medicines and Healthcare Products Regulatory Agency has permitted temporary authorization to Pfizer. This forms the first Emergency Use Authorisation subsequent to a global Phase 3 trial of a vaccine to combat against COVID-19. This is based on a RR, the findings of Phase 3 trial, demonstrated an efficacy rate of 95% (P < 0.001) in participants with no past SARS CoV2 infection that was the one of the primary objectives. The other primary objective was participants with and without prior SARS CoV2 infection. The response was determined 7 days following the second dose.[47]

The COVID-19 mRNA vaccine BNT162b2 encodes for the spike (S) protein of SARS-CoV-2 virus. This can be administered to individuals aged 16 years and older. In order to complete the vaccination series every individual has two take two doses. The safety and efficacy of vaccine in youngsters <16 years of age have not been proven till date. There is also a limited experience in pregnant women, breast feeding and on fertility.[48]

AstraZeneca

Results of the interim analysis of the four RCTs conducted at the UK, South Africa, and Brazil have pooled outcomes regarding the safety and efficacy of the Oxford– AstraZeneca vaccine against COVID-19. It is a chimpanzee adenovirus vectored vaccine ChAdOx1 nCoV-19 (AZD1222) that can be administered in individuals aged 18 years and older.[49] Out of the four ongoing trials, interim efficacy results of the two trials from the UK and Brazil have been reported. Prespecified primary analysis against the primary endpoint after the second dose was 70·4% in the vaccine group versus 101 (1.7%) in the control group. Efficacy was evaluated at 21 days past the first dose, the results were suggestive of short-term protection with a dose.[50]

Regulatory Approval for COVID-19 in Australia

Australia stopped the vaccine production against COVID-19 after the trials revealed that it may perhaps interfere the diagnosis of HIV. The University of Queensland and biotech firm CSL were involved the development of vaccine. A Phase 1 trial that involved 216 participants, the vaccine provoked a “robust” immune response against the SARS-CoV-2 virus with no serious adverse events.[51] According to the trial data, the vaccine produced antibodies that interfered with HIV diagnosis, leading to false-positive HIV tests. The CSL also revealed that follow-up tests of the trial participants did not show any presence of HIV and also there exists no possibility that the vaccine would cause infection.[52]

Regulatory Approval for COVID-19 in China

On December 30, 2020, China approved its first COVID-19 vaccine for its public use. The vaccine is developed by Sinopharm and has been granted market authorization by China's National Medical Products Administration. According to an interim analysis of the Phase-3 clinical trials, the vaccine has shown 79.34% efficacy against COVID-19.[53]

Regulatory Approval for COVID-19 in Russia

Russia was the first country to approve vaccine against COVID-19. On August 11, 2020, the Gamaleya National Center of Epidemiology and Microbiology (Moscow, Russia) developed The Sputnik V vaccine.[54]

Conclusion

The battle against COVID-19 pandemic is the need of the hour. As COVID-19 pandemic is a global emergency and there is no definitive therapy, different drugs and vaccines have been under trial and have to authorize for emergency use. Therefore, various regulatory authorities have been working in collaboration with each other to fight this pandemic. Hopefully, with all these efforts worldwide, we will be able to overcome this pandemic.