EMERGENCY USE AUTHORISATION OF VACCINES: A GLANCE AT FIRST FIVE NATIONS TO GRANT IT - The Daily Guardian
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EMERGENCY USE AUTHORISATION OF VACCINES: A GLANCE AT FIRST FIVE NATIONS TO GRANT IT

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Regulatory agencies around the world are under intense pressure to grant approvals for the new Covid-19 vaccine(s). Several developed countries have indicated that if there is a compelling case for the use of a vaccine before it qualifies for full licence, they would be prepared to authorise emergency use approval on grounds of public health. The condition is that the balance of risk and benefit must justify temporary supply of the vaccine. A favourable benefit-risk determination can be made for vaccines that offer more than a modest benefit or for those with sufficient data to assess its safety profile.

An emergency use authorisation (EUA) route is being adopted by many countries to facilitate the availability of Covid-19 medicines and vaccines to priority population groups. Though each country is free to adopt criterion for such an authorisation, there are some guiding principles.

Let’s look at the processes adopted by the five countries which are amongst the first to give EUA to Covid-19 vaccines—the ‘Lighthouse countries’.

The US FDA, in its October 2020 guidance entitled Emergency Use Authorization for Vaccines to Prevent Covid-19, explains that, for a Covid-19 vaccine among others, issuance of an EUA would require that the vaccine’s benefits outweigh its risks, based on data from at least one well designed Phase 3 clinical trial that demonstrates the vaccine’s safety and efficacy in a clear and compelling manner.

Further, at the time of the submission of the application, the Phase 3 study should have already enrolled at least 3,000 vaccine recipients and shown sufficient information to support a low-risk for vaccine-induced respiratory disease. To ensure that a widely deployed Covid-19 vaccine is effective, the primary efficacy endpoint point estimate for a placebo-controlled efficacy trial should be at least 50%.

The European Medicines Agency and the UK’s Medicines and Healthcare products Regulatory Agency have adopted a similar approach. According to the Emergency Use Authorization granted to Covid-19 vaccines by Pfizer-BioNTech and Moderna, the US FDA has followed this process and requirements. Similar is the case with the UK’s MRHA while reviewing applications for the Pfizer-BioNTech and AstraZeneca/Oxford vaccines.

China started work on Covid-19 vaccines in January 2020. A vaccine based on the adenovirus delivery system was approved for limited use in June 2020 on the conclusion of Phase II trials. By the end of November, between 40,000 and 50,000 army men were vaccinated with this vaccine. Two inactivated vaccines had been approved for limited use in China to vaccinate high risk groups (including healthcare workers) since July 2020, following encouraging the results of Phase I and II clinical trials. Chinese regulators appear to be satisfied with the data of animal studies and the safety and immunogenicity data from Phase I and II trials. According to reports, hundreds of thousands of people in China have received these vaccines, which include healthcare workers, pandemic prevention personnel, border inspection personnel, etc.

Russia had launched clinical trials on its adenovirus-based Covid-19 vaccine in June 2020. On the 11th of August, Russia announced that its regulators have approved a limited roll out of its Covid-19 vaccine, named Sputnik V. At the time, when the Russian vaccine had been approved by its national authorities, it had data for Phase I/II but none had been published.

In India, the Central Drug Standard Control Organisation (CDSCO) is the apex regulatory authority to approve public use medicines, diagnostics tests, devices, vaccines, etc. The New Drugs and Clinical Trials Rules, 2019, framed under the Drugs and Cosmetics Act, 1940, lists the multiple provisions to be followed for review and approval of new drugs, clinical trials and vaccines. In these rules, there is also a provision to accelerate the approval of a new drug intended for use against diseases of special relevance to India or for filling an unmet medical need in India, especially for a disaster or special defence use. In such a situation, marketing approval could be granted based on Phase II clinical data if remarkable efficacy had been observed with a defined dose in the Phase II clinical trial of the new drug. The regulator can then also grant market approval for the new drug or vaccine based on Phase II data to meet what the rules define as ‘unmet medical needs of serious and life- threatening diseases in the country’.

Like the benchmark set by the WHO and others, the Central Drugs Standard Control Organisation (CDSCO) indicated in its draft ‘regulatory guidelines for vaccine development, with special consideration for Covid-19 vaccine’ that “to ensure that a widely deployed Covid-19 vaccine is effective, the primary efficacy endpoint point estimate for a placebo-controlled efficacy trial should be at least 50%”.

In the first week of January 2021, based on the recommendations of the Subject Expert Committee of Central Drugs Standard Control Organisation (CDSCO), the DCGI accorded Restricted Emergency Approval to the Covid-19 virus vaccine by Serum Institute of India (AstraZeneca/Oxford vaccine, named Covishield) and Bharat Biotech (inactivated vaccine, called Covaxin).

The SII vaccine had submitted interim safety and immunogenicity data generated from trials in India and the data was found comparable with the data from the overseas clinical studies.

The SEC took cognisance of Bharat Biotech’s vaccine’s Phase I and Phase II clinical trials. It also noted that the Phase III efficacy trial was initiated in India among 25,800 volunteers and till date about 22,500 participants have been vaccinated across the country and the vaccine has been found to be safe, as per the data provided. The data on safety and immunogenicity of the vaccine was reviewed and the SEC recommended granting permission for restricted use in emergency situations in public interest as an abundant precaution, in clinical trial mode, to have more options for vaccinations, especially in case of infection by mutant strains. The clinical trial being carried within the country by the firm will continue. Based on these recommendations, the Drugs Controller General of India has accorded emergency use authorisation, with conditions, to the two vaccines.

The WHO has developed a concept of Stringent Regulatory Authority (SRA) to guide medicine procurement decisions and is now recognised by the international regulatory and procurement community. Based on a laid down criteria, the WHO considers regulatory authorities of 35 countries (as of November 2020) stringent, which means that these regulatory bodies are uncompromising. This is relevant to countries which do not have a regulatory authority or have a weak one because they can adopt an approval given by one of the stringent regulatory authorities for a medicine (including vaccines) on the faith that it would have been well scrutinised. The Russian, Chinese or the Indian regulatory authorities do not figure on the list.

The writer is an infectious disease epidemiologist.

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Medically Speaking

BHARAT BIOTECH’S COVAXIN IS SAFE, SAYS THE LANCET

Shalini Bhardwaj

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British medical journal The Lancet has published a study on the effects of India’s indigenous vaccine, Bharat Biotech’s Covaxin and said that the vaccine doses are well tolerated with no vaccine-related serious adverse events found.

The Drug Controller General of India had granted restricted emergency use authorisation to Bharat Biotech’s Covaxin under the clinical trials mode where consent was required from beneficiaries before vaccination. Bharat Biotech successfully administered the dose of its COVID-19 vaccine, Covaxin, to 13,000 people.

BBV152 (also known as Covaxin) is a whole-virion inactivated SARS-CoV-2 vaccine. The double–blind, multicentre, randomized, controlled trials were conducted in 11 hospitals across India.

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IMA TO START SAVE HEALTHCARE INDIA MOVEMENT

Shalini Bhardwaj

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The Indian Medical Association (IMA) has announced a pan-India relay hunger strike of doctors, which will start from February 1, in protest against a notification issued by the Central Council of Indian Medicine (CCIM) that will allow postgraduate practitioners of Ayurveda to perform general surgical procedures, including 58 types of surgical procedures. This sort of medicine has been given the name “mixopathy”.

“We object to the mixing of streams as it is unsafe and unscientific. People should have a right to choose the stream for getting treated by any system of medicine from qualified doctors of that system,” says the statement by the IMA.

The IMA has given directions to all its members across the country to launch the “Save Healthcare India Movement”, the statement informed. Doctors will take turns to sit on a 24-hour hunger strike from February 1. The IMA will release posters and banners for awareness across the country.

“All IMA members shall update their Members of Parliament and MLAs regarding the true picture of the notification and integration policy. IMA will also give its representations to all state governments. Under this Save People Movement, all NGOs will be updated on the core issues. Representatives of the IMA shall visit the various places across the country for public awareness,” the statement added.

Besides these efforts, the IMA will also write to the Prime Minister and convey its feelings, the association said.

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PYORRHOEA: HERE’S WHAT YOU NEED TO KNOW

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Pyorrhoea (Periodontitis) is set of inflammatory disease affecting the periodontium, i.e., the tissues that surround and support the teeth. It is usually a slow process, caused by bacteria that colonise on the teeth and in the sulcus (the space between the teeth and gums). These bacteria create acids, enzymes and toxins that decay and erode the structures that support the teeth (gums and bone surrounding the teeth). Periodontitis involves progressive loss of the alveolar bone around the teeth, and if left untreated, can lead to the loosening and subsequent loss of teeth.

Poor oral hygiene is the single most common causative factor. Other risk factors include diabetes, smoking, diet high in sugar and refined carbohydrates, etc.

EFFECTS OF PYORRHOEA OUTSIDE THE MOUTH

Pyorrhoea results in a greater degree of bacteraemia (bacteria in blood) especially while brushing and chewing foods. There is sufficient evidence to support the fact that these harmful bacteria and the resultant inflammation can result in a relatively increased risk for:

• Myocardial infarction (heart attack) as the bacteria in the blood causes platelets to aggregate resulting in clot formation in blood vessels (atherosclerosis).

• Infection in heart valves

• Cerebrovascular stroke (brain attack) due to atherosclerosis

• Prosthetic joint infections

• Premature delivery/labour pains in pregnant females

• Low birth weight babies (<2500 gm).

• Pulmonary diseases

• In those over 60 years of age, impairments in delayed memory, depression and poor circulation and other brain disorders

A strong association has been established between diabetes and periodontitis. Blood sugar levels are much more difficult to maintain in diabetic patients with pyorrhoea as compared to diabetic patients without pyorrhoea.

Therefore, it is a must for all diabetic patients to undergo oral screening to rule out the gum infections (pyorrhoea).

HOW YOU CAN DIAGNOSE PERIODONTITIS/PYORRHOEA

Patients should realise gum inflammation and bone destruction are largely painless; and in many individuals the disease has progressed significantly before they seek treatment.

If you have any of the following symptoms you should visit a periodontist (specialists in the treatment of periodontitis and their field is known as “Periodontology” or “Periodontics”.)

• Redness or bleeding/pus discharge from gums while brushing teeth, using dental floss or biting into hard food (e.g. apples)

• Gum swelling that occurs frequently even after professional cleaning/scaling.

• Progressively large gap between the teeth and their outward movement

• Halitosis or bad breath, and a persistent metallic taste in the mouth

• Gum recession, resulting in apparent lengthening of teeth. (This may also be caused by heavy-handed brushing or with a stiff tooth brush.)

• Loose teeth, in the later stages.

WHAT IS THE TREATMENT OF PYORRHOEA?

Treatment primarily comprises of control of periodontal inflammation in the form of non-surgical therapy (professional cleaning/scaling of teeth and oral hygiene instructions) and if needed, surgical therapy. It is a common myth that teeth become loose after scaling procedure. Deep pockets (space between gums and teeth) of 6-7 mm or more requires specialised cleaning, antibiotics or even surgery with bone grafting because at this depth there is a high risk of systemic infection and tooth loss, and risk of other diseases. It should be understood that it is not always possible to form the lost bone in all cases, however further progression of bone loss can be arrested with proper treatment and patient compliance.

HOW YOU CAN PREVENT THE PYORRHOEA

• Maintain good oral hygiene with proper and effective brushing technique as well as flossing or interdental brushes prescribed by your Periodontist.

• Avoid sugar and refined carbohydrates.

• Regular visit your periodontist

Dr Vikender Yadav is Assistant Professor, Periodontics, Centre for Dental Education and Research, AIIMS, New Delhi.

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COVID-19: GOING BEYOND ANTIBODIES

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Covid-19 has affected over 95 million people worldwide and more than two million people are dead. The immune system plays a critical role in determining the clinical course and outcome of Covid-19 (caused by SARS-CoV-2) infection.

Innate immunity and adaptive immunity are the two major components of the immune system. The innate immune system is the first line of defence that plays an important role in the initial phase of virus infection by producing a number of proteins including interferons, and proinflammatory cytokines. Interferons prevent virus multiplication, whereas proinflammatory cytokines cause beneficial inflammation. However, excessive production of proinflammatory cytokines may result in serious Covid-19 disease and death. On the other hand, the adaptive immune system, the second line of defence, keeps the memory for the virus for a long duration and plays a critical role in defence against coronavirus. Because of this feature of memory, cells of the adaptive immune system respond rapidly and in a more robust manner when re-exposed to the same virus or the booster dose of the vaccine.

The adaptive immune system consists of two major cell types: T cells and B cells, T cells come in several flavours. The killer T cells (CD8) kill virus-infected cells. B cells make antibodies that help neutralise the effect of Covid-19. Individual T cells (Type 1 helper) are required for efficient functions of killer CD8 T cells, and T follicular helper cells for B cells to make antibodies. We have to remember that B cells make both viral neutralising and non-neutralising antibodies. Therefore, the mere presence of coronavirus antibodies may not correlate with clinical outcome of Covid-19. Long-term follow-up studies are needed to answer the question of how long would be Memory T cells and Memory B cells, therefore, how long antibodies would last after coronavirus infection?

Recent studies have shown that coronavirus specific memory B cells and T cells are present in patients who recovered from Covid-19 for at least eight months after the infection. Are antibodies and antibody-secreting B cells alone sufficient to fight Covid-19 infection? The answer is no. Some of the Covid-19 patients with mild symptoms do not have any antibodies. In contrast, severe and critically sick patients with the disease have high levels of antibodies. Furthermore, published international study as well our own study of patients born with a genetic defect of the immune system, in which patient either do not have T cells or B cells or these are dysfunctional do not make antibodies against coronavirus, show that many of these patients had mild disease, and all those admitted to the hospitals have recovered from Covid-19. If antibodies were the sole and critical component of the immune system, we would have observed these patients be critically ill with a high death rate. This would suggest that T cells play an important role in defence against coronavirus.

Current vaccine trials have predominantly tested neutralising antibodies. However, limited data show that vaccines also induce T cell responses. It is critical to study longitudinally for the next two to three years the presence of functionally active coronavirus-specific killer T cells, neutralising antibodies, and memory T and B cells following vaccination. It would be of interest to compare the differences in the induction of effective T and B cells responses including generation of long-term memory T and B cells among different vaccines.

We should remember two factors about mutations and RNA viruses. Mutations are a frequent occurrence with RNA viruses, and mutations do not necessarily induce more serious disease than the original virus. Since the start of the pandemic, Covid-19 must have undergone hundreds of mutations. However, recent mutations (UK strain and possibly, African, Brazilian and others; I would not be surprised if there would be an Indian strain) appear to be more contagious. However, so far there is no evidence to suggest that these mutations are causing more serious Covid-19. Current vaccines should be effective against these mutations.

Would these mutants be more resistant to the immune defences? That is possible; however, these mutant strains have not only to evade B cells (neutralising antibodies) but T cells as well. We should be optimistic about current and future vaccines that they would induce strong and durable T and B cell responses to be effective against various mutants of Covid-19.

The writer is a professor of medicine and microbiology at the University of California.

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Coronavirus vaccine safe, must be taken now, say top doctors

As the government tries to tackle vaccine hesitancy among people, medical experts and doctors reassure that the indigenous Covid vaccines are safe to take and people should focus on evidence instead of misinformation.

Shalini Bhardwaj

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Vaccine hesitancy has become one of the biggest concerns for the government even after getting two ‘Made in India’ vaccines against Covid-19, Covishield and Covaxin. Union Health Minister Dr Harsh Vardhan called it a paradox, saying, “The paradox is that countries across the globe are asking us for access to the vaccines while a section of our own is fomenting misinformation and doubts for narrow political ends.”

According to some experts, the reason behind lesser people coming for vaccinations has to do with trusting the vaccines. Some healthcare workers are also confused regarding their entitlement to the vaccines and the functioning of the CoWIN app.

“In Delhi, there are two vaccines, Covishield, which is prepared by the SII, and Covaxin, which is prepared by Bharat Biotech. Now, Bharat Biotech has put up on their website information related to the entitlement of beneficiaries which doesn’t match the information given by the Government of India,” pointed out Dr Girish Tyagi of Delhi Medical Council.

“There are concerns about safety and authenticity. People are thus scared. There is also controversy regarding the guidelines,” he added.

The Indian Medical Association (IMA), which is working jointly with the Government of India at various levels, believes that vaccines in India are the safest for protecting against Covid-19.

“When a new drug comes, it’s a natural process. There are doubts created about the procedure and about various other things. The system isn’t working, so doctors are waiting for a call or SMS to get their vaccinations done. Yes, there are issues related to Covishield and Covaxin but modern medicine is evidence-based and it’s evolving. Today what is true may not be the truth after a few days or years. So, it’s advisable to take a second opinion. It is quite natural that not all questions are being answered, but with the evidence available, we are sure it is safe,” said Dr J.A. Jayalal, president of the IMA.

“This hesitancy will be settled soon. Since we have taken vaccines and have no symptoms, I am looking at this positively,” he said.

“India eradicated polio and smallpox with vaccination. We have seen people die in front of our eyes due to tuberculosis, but now the effect and complication of TB have been reduced. I think we need to give this vaccine at a large scale to the maximum number of people. We are not facing any serious complications,” says Dr Jayalal.

Regarding vaccine hesitancy, Dr Samiran Panda, Head, Epidemiology and Communicable Diseases division, ICMR said, “This is an issue which is important as the disease is new to humankind. Earlier it used to take so much time but the vaccine for this was developed in just 11 months of time. But when the vaccine is here, why are we waiting? This hesitation is normal but overcoming it is superlative. We need to repeatedly underline that with these vaccines, no corners have been cut for their safety. We need to make people understand. Wrong information spreads very fast so for those who are yet to make up their minds, it’s our responsibility to make them understand.”

While the government is trying to make people aware of vaccination, the Indian Medical Association has also started campaigns through various mediums.

“The Indian Medical Association is doing social campaigns, bringing out scientific evidence to make people aware. We are making arrangements in each state and telling people and going in teams. The registration problem is also getting resolved. We are also monitoring those who have already taken vaccines,” said Dr Jayalal.

Meanwhile, Dr Girish Tyagi said, “We are asking doctors to make people aware about the vaccine.”

Dr Panda emphasised, “I would say that the time to get the vaccine is now. The vaccine prevents infection and stops the chain of infection. So, the vaccine prevents you from Covid-19 and also benefits society at large.”

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HEALTH MINISTRY RELEASES GUIDELINES AND ADVISORY FOR CORONA VACCINATION

Shalini Bhardwaj

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Corona

The Ministry of Health & Family Welfare (MoHFW) has released a set of guidelines and advisory around Covid-19 vaccination.

Essentials: The Covid-19 vaccination is only for people who are 18 years and above. The vaccines will be administered in two shots separated by a time frame of 14 days. Interchangeability of Covid-19 Vaccines is not permitted, the second dose should also be of the same Covid-19 vaccine that was administered as the first dose. People with a history of anaphylactic or allergic reaction to a previous dose of Covid-19 vaccine and those who experience immediate or delayed-onset anaphylaxis or allergic reaction to the vaccine or injectable therapies, pharmaceutical products, food items etc, should not be a part of the vaccination drive. Pregnant and lactating women have not been a part of any vaccine trial so far and thus, Covid-19 vaccine will not be given to them.

Conditions: A temporary prohibition from the vaccination is advised at least for 4-8 weeks after recovery in these conditions: persons who have active symptoms of SARS-CoV-2 infection, SARS-COV-2 patients who have been given anti-SARS-CoV-2 monoclonal antibodies or convalescent plasma, and patients who are acutely unwell and hospitalised.

Precautions: The vaccine will be administered carefully to patients who have a history of any blood clotting, coagulation disorder or platelet problem.

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