Comparison of Regulatory Process of COVID-19 Vaccines Between Emerging Markets, EU

Coronavirus disease, COVID-19, has affected all of our lives primarily since the end of 2019. We have faced experiences and a period that we had never come across before. In particular, we have to wear masks, and we should have social distance and sterility in order to avoid it, because this infectious disease spreads through droplets of saliva or discharge from the nose when an infected person coughs or sneezes, according to the definition of WHO.

Some of us still may not know about the virus itself. So, what are coronaviruses? Well, they are a large family of viruses that cause illness ranging from the common cold to more serious diseases such as Severe Acute Respiratory Syndrome (SARS-CoV). The 2019 version of coronavirus, COVID-19, was not seen in humans before and it has caused viral pneumonia, which was first seen in China and came out from Wuhan’s South China Seafood City market in December 2019, and has spread all over the world since then.2

Many pharmaceutical companies and scientists have been working on the solution. A lot of work and research have been done on vaccines, as well as on the pharmaceutical products for the treatment that could be the solution for the disease. Please see the table below for the vaccines that have been approved3:

Name Vaccine Type

BNT162b2 mRNA-based vaccine

mRNA-1273 mRNA-based vaccine

Oxford accine Viral vector

Sputnik V Non-replicating viral vector

EpiVacCorona Peptide vaccine

CoronaVac Inactivated vaccine

Unknown (not announced) Inactivated vaccine

BBIBP-CorV Inactivated vaccine Developers

Pfizer, BioNTech; Fosun Pharma

Moderna, BARDA, NIAID

The Oxford University, AstraZeneca

Gamaleya Research Institute, Acellena Contract Drug Research and Development Federal Budgetary Research Institution State Research Center of Virology and Biotechnology

Sinovac

Wuhan Institute of Biological Products; China National Pharmaceutical Group (Sinopharm) Beijing Institute of Biological Products; China National Pharmaceutical Group (Sinopharm) Country of Origin

Multinational

US

UK

Russia

Russia

China

China

China Approval

UK, Bahrain, Canada, Mexico, US, Singapore, Oman, Saudi Arabia, Kuwait, EU

US, Canada

UK, EU

Russia

Russia

China

China

China, United Arab Emirates, Bahrain

The European Medicines Agency (EMA) plays a great role in regulatory guidance, as well as on the scientific evaluation, approval and monitoring of COVID-19 vaccines in the EU, as shown below for the flow of the stages:

Figure 2. Flow of COVID-19 vaccine evaluation in EU Globally, vaccine development for COVID-19 is being fast-tracked. Getting scientific advice from regulators helps to speed up the development process. EMA offers informal consultancy with its team “COVID19 Task Force (ETF)”, and they give fast scientific advice during this period.1

Even though safe methods are used for development of the vaccine, new methods have also been tried and used for the vaccines for COVID-19 for increasing the stability, quality, process period, and production efficiency. However, existing methods for vaccine production have also been used for increasing capacity and to have production at a large scale. EMA, and most of the health authorities in EU as well

Figure 3. COVID-19 vaccines timeline in EMA

as in emerging markets are doing their best to speed up the evaluation period for COVID-19 vaccines to have the MA approval. So, as the principle is protecting the people and avoiding the risks, the legislation in EMA and guidelines of national health authorities in EU provide guidance accordingly. In order to get approval, all the test results are submitted to the health authorities in the EU.

As biotechnology products are registered via a centralised procedure in EU, COVID-19 vaccines will also be evaluated with the same procedure. Although the standard timeline for the evaluation of a pharmaceutical product is up to 210 active days, EMA treats MA applications for COVID-19 products in an accelerated way, which allows the timeline for evaluation to be less than 150 working days with a “rolling review” procedure. So , the data can be evaluated when they become available during the development stage by EMA, to accelerate the MA application process.

As the evaluation is completed, EMA may recommend a “conditional marketing authorisation”, which is a kind of approval for medicines in emergency situations, and this is recognised by the WHO and EU Health Authorities.1

The first COVID-19 vaccine (two-dose vaccine), Sputnik V, registered in Russia with 92% efficacy, which has a patent protection in Russia on its method as well as its substance and which came out earlier than most of the other vaccines in 2020, got the attention of many countries around the world including UAE, Saudi Arabia, Indonesia, Philippines, Brazil, Mexico, Serbia and India. Now it has been applied in 40 countries for MA approval.5,7

The results of Phase I–II clinical trials of the vaccine were published in one of the world's most respected medical journals, The Lancet, in September 2020, and Phase III data was published afterwards. Sputnik V can be administered to the population of a particular country after approval from a national regulator.

Sputnik V post-registration clinical trials included over 44,000 people in Russia, the United Arab Emirates (UAE), India, Venezuela and Belarus. More countries expressed interest in carrying out clinical trials of Sputnik V.

Before the clinical trials, all of the preclinical trial stages with experiments on different types of animals were performed. Clinical trials of the vaccine started accordingly, and Phase I and II were completed by August 2020. No unexpected or unwanted side-effects were seen. The vaccine generated cellular immune response. After getting the Sputnik V vaccine, the members of the clinical trials did not get COVID-19 and its efficacy was confirmed with the test results shared with the health authorities.

AstraZeneca, which is a British company and Gamaleya Research Institute, which is a Russian medical-research institute that developed the Sputnik V vaccine in Russia, signed an agreement in December 2020. And AstraZeneca will start clinical trials to test a combination of its experimental COVID-19 vaccine with the Sputnik V shot

Figure 5. Rolling review cycle of COVID-19 vaccines

to see if this can increase the efficacy of the British company’s vaccine. The Sputnik V coronovirus vaccine was applied in EMA in February 2021. 8

BioNTech’s vaccine, developed in Germany and having a partnership with Pfizer, which is BNT162b2, is an mRNA based vaccine, and they claim that it is an alternative to conventional vaccines because of their advantageous characteristics, which are subject to translation with clinical data, including: • Immunogenicity • Flexible manufacturing process • Safety

They say “mRNA vaccines represent an alternative to more conventional vaccines because of their potential to produce a robust and targeted antigenic immune response, combined with their tolerable administration profile and rapid, scalable manufacturing”.6

And how do the mRNA vaccines work? mRNA vaccines teach the cells to make a protein that will trigger an immune response without using the live virus that causes COVID-19. The human body then makes the antibodies which support in fighting the infection. When a person is given the vaccine, their cells produce the spike protein. The cell breaks down the instructions and gets off them following the making of the protein piece. The cell then displays the protein piece on its surface. The immune system recognises that the protein is not present there any more and begins building an immune response and making antibodies.6,12

In the EU and Switzerland, BNT162b2 got conditional marketing authorisation to increase immunisation for people 16 years of age and older. In the USA it has been authorised under emergency use authorisation, as Pfizer-BioNTech COVID-19 vaccine. In the UK, it has been authorised under “Temporary Authorisation for Emergency Supply”. They have applied for MA approval in Japan and Australia as well, and have received approvals in many other countries. Also, additional submissions are in progress.

So, there are many vaccines being developed and the ideas and comments of the authorities may change from one to another. When we evaluate the aspect of EMA and FDA, we see that they differ in many ways. For example, the FDA asks for all the raw data from the laboratory, for non-clinical and clinical trials, whereas the EMA accepts the analyses data of the pharmaceutical. But in emerging markets, for instance in Africa, countries are looking for common regulatory aspect by sharing their experiences. In fact, even for the dosing there are different opinions, like the FDA’s, regarding the period of protection after a single dose of vaccine. They think the periods are not sufficient between the doses and the present clinical data is not sufficient. And they say the target is to minimise the risks for the public health. Regulatory experts in MHRA also claim that more than 21 days are given between the two doses to see the results more properly. For PfizerBioNTech vaccine they are doing it, and they are evaluating Moderna in the UK.12

As the vaccines were administered before the conclusion of all three phases of clinical trials in China, Russia and the United Arab Emirates, it brought the acceleration of approvals harmonisation in vaccine regulation. At least 51 pathways were found for different types of accelerated vaccine approval in a group of 24 countries. Greater harmonisation would bring many advantages. It would be beneficial for pharmaceutical companies for common and accepted definitions, as well as guidelines for different types of approval, in order to see the status of their vaccine. This would really be time-saving for regulators and for the companies.4

The regulatory experts want to share their experiences along with the data they have, discussing together in order to decide on the right and best solution. So, a harmonised file complying with international regulatory standards and requirements would be suitable for a fast and precise way.

The ICMRA (International Coalition of Medicines Regulatory Authorities), which has members from China, Europe and the United States, have reached an agreement on the testing of COVID-19 vaccines, for the animal model part as well as the ideal clinical trial end points. The coalition’s COVID-19 team is now trying to harmonise the vaccine monitoring as they are prepared.

Previously, the WHO requested that both FDA and EMA should evaluate the suitability of COVID-19 vaccines for countries in need in emerging markets, for issuing emergency authorisations. They are expecting an agreement and, if either of them agrees, then the WHO can issue its own EUL (emergency use listing), which would be a collaboration.

The WHO is really acting supportively on collaborations, exchanging experiences and fast-track approvals of clinical trials, as well as emergency MA approvals and clarifying the roadmap for each vaccine. This means collaboration with the country regulatory experts will be required to apply local authorisation for emergency use.

The WHO’s emergency use listing (EUL) opens the door for countries in emerging markets to accelerate their own regulatory approval processes to import and administer the vaccine. It also makes it possible for UNICEF and organisations like the PanAmerican Health Organization to supply the vaccine for distribution to countries that need it.10

The WHO is really encouraging companies to develop more vaccines complying with

safety and efficacy standards in order to reach all countries.

The aim of the emergency use listing (EUL) procedure is to make the vaccines and pharmaceutical products, medical devices which comply with certain requirements and criteria of efficacy, safety, quality standards as reachable and available as possible. It is not an easy way to apply, since the process needs accuracy and speed at the same time. Late Phase II and Phase III clinical data and safety, efficacy, quality data and a risk management plan are evaluated in EUL for the COVID-19 vaccine. The data is reviewed by the WHO experts and teams of regulators from national health authorities and further steps are taken accordingly.10,11

All the countries may follow a different flow and local policy along with the global regulation and procedure. But even though the application type is emergency or conditional, all the data on quality, safety, immunogenicity and efficacy should comply with the standards and criteria, both country-specific and from a global perspective. The developers and manufacturers should be committed to fulfilling the requirements in advance, as well. The regulators in the EMA, national health authorities in the EU, the FDA, the WHO, and other national health authorities should gather and the regulatory experts from different regions should have detailed discussions on the evaluation and decisionmaking in order to reach the best solution and the most accurate results. REFERENCES

1. www.ema.europa.eu/en/human-regulatory/ overview/public-health-threats/coronavirusdisease-covid-19/treatments-vaccines/ covid-19-vaccines-development-evaluationapproval-monitoring 2. www.europeanlung.org/en/covid-19/what-iscovid-19/ 3. www.raps.org/news-and-articles/newsarticles/2020/3/covid-19-vaccine-tracker 4. www.nature.com/articles/d41586-020-03458-z 5. Sputnik: Ref: FAQ | Official website vaccine against COVID-19 Sputnik V. (sputnikvaccine.com) 6. Overview COVID-19 | BioNTech (biontech.de/ covid-19) 7. RDIF applies for Sputnik V vaccine approval in 40 countries (news.ru) (news.ru/en/world/ rdif-applies-for-sputnik-v-vaccine-approvalin-40-countries/) 8. Russia to submit Sputnik V vaccine for EU approval | Deccan Herald (www.deccanherald. com/international/russia-to-submit-sputnikv-vaccine-for-eu-approval-939000.html) 9. www.biospace.com/article/fda-don-t-messwith-the-covid-19-vaccine-doses/?s=130 10. www.paho.org/en/news/31-8-2020 nationalregulatory-authorities-participatediscussion-covid-19-vaccines-who 11. www.who.int/news/item/31-12-2020-whoissues-its-first-emergency-use-validationfor-a-covid-19-vaccine-and-emphasizesneed-for-equitable-global-access 12. www.canada.ca/en/health-canada/services/ drugs-health-products/covid19-industry/ drugs-vaccines-treatments/vaccines/pfizerbiontech.html

Pelin Boran

Pelin Boran has a Bachelor’s degree in Chemical Engineering and an MSc. in Pharmaceutical Chemistry. 16 years of experience in the pharmaceutical industry in the areas of QC, R&D, Regulatory Affairs for Global Projects and Business Development. Have my own company, “Pelin Boran Regulatory Affairs Solutions & Consultancy” for 6 years. We share our global expertise to support our clients around the world and find the best solutions for them; on Regulatory Affairs, Pharmacovigilance, GMP inspections and Business Development Activities in EU, UK, USA, Canada, Latin America,Israel, CIS Region, Balkan Region, Turkey, Asia Pacific Region, MENA Region, GCC Region with my team mates. Our head office is in Istanbul, Turkey and we give our services end to end in all these regions and countries with my local team mates and partners.

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