Safety and efficacy are the two words used to describe the requirements for any new therapy, including vaccines. This article details the specific metrics behind these generic descriptors that a Covid-19 vaccine will have to satisfy.
The other questions tackled are: When will a vaccine be available? Is the vaccine being fast-tracked, and, therefore, unsafe? Can we trust the vaccine when it is approved? As much as we all would like the comfort of certainty, all of these questions have answers with caveats. Some reasons for the ambiguity are articulated below.
When will a vaccine be available?
This depends on two factors.
One is the approval timeline for a new vaccine per the regulatory framework of a country. The other is the wide commercial availability – and that depends on the manufacturing capacity and distribution ability in a country.
New vaccine approval: Metrics, trials, and timelines
The World Health Organization (WHO) and the US Food and Drug Administration (USFDA) have issued guidance for approval of a Covid-19 vaccine.
There are three main criteria.
One, it has to show efficacy in clinical trials conducted in healthy humans (not affected by Covid-19). Two, the vaccine’s protective ability should last for an appreciable duration. Three, it should cause minimal safety events such that the overall risk-benefit balance is determined to be favourable.
Out of the three, the first two have clear metrics.
Vaccine efficacy is calculated using the percentage of people that contract Covid-19 between two groups. One group is vaccinated and the other is typically given a placebo (e.g., a saline injection). Both groups are tracked periodically to determine the number of individuals infected with COVID-19. For example, if 10 out of 100 people (10%) in the vaccinated group were infected and 25 out of 100 (25%) in the placebo group were infected, the vaccine efficacy would be 60%, or, 0.6 (1-0.1/0.25).
Another approach to efficacy is to intentionally expose vaccinated individuals to the virus. This is called controlled human infection model (CHIM), and is generally considered unethical. The USFDA guidance presently considers it an inappropriate pathway, but, interestingly, leaves open a future possibility of adopting it if current strategies fail.
The WHO and USFDA both recommend a minimum 50% average efficacy. The USFDA additionally recommends that the range around this average efficacy (in terms of a statistical confidence interval) start at 30%. As a comparison, one flu vaccine (Fluzone trivalent) has 68% average efficacy with range from 48%-80% in adults aged 18-55. The Shingles vaccine (Shingrix) showed an average efficacy of 97.2% (93.7%-99.0%) in adults over 50.
The second criterion is the vaccine’s protective ability; the WHO recommends at least 6 months for this timeframe. This guidance also acknowledges that data might not be available initially to fulfill this criterion, and that it can be furnished later.
The third criterion – safety – has minimal numeric metrics. The USFDA recommends a 3,000 patient safety database. Routine side effects (such as aches and fever) are tracked for up to 30 days. Major side effects are tracked for the length of the study – a duration of up to two years. The final decision is by a committee that determines the overall risk-benefit balance based on the efficacy numbers and the side effect profile.
The above requirements are typically proven through a large clinical trial (with thousands of individuals) called the Phase 3 or pivotal trial. As the name suggests, the Phase 3 trial is conducted only after successful Phase 1 and Phase 2 trials. These early trials are smaller (range from 10 to few hundred individuals), and provide initial safety data and some efficacy data. Important complementary data – such as antibody levels – that could be correlated with efficacy is also monitored in these trials.
Therefore, the time to approval is the sum of the time required to complete a successful Phase 3 trial and the time required to complete requirements before Phase 3. As shown below, there are opportunities to reduce the time taken in both these areas – especially to prove efficacy in Phase 3.
Dr Tushar Gore’s focus area is pharmaceuticals. He studied at IIT-Bombay and the University of Minnesota, and has worked at McKinsey and Novo Nordisk. He is the former MD/CEO of Resonance Laboratories, a niche pharmaceuticals manufacturer.
Is the development of the vaccine being hurried through for approval by the year-end?
Recently, Pfizer indicated that it would file for approval in October (assuming positive results), implying a Phase 3 trial of 4-5 months’ duration. Efficacy is proven when the metric as described above is met. Thus, the trial is likely to proceed faster, if it is conducted in an environment with a significant outbreak.
To understand the above point, consider the Shingles vaccine trial as an example. It was conducted over 3-4 years and detected 210 patients infected with Shingles in the placebo (unvaccinated) group of about 7,000 people. Thus, the annual rate, or incidence, of Shingles is about 9 infections per 1,000 persons.
Compare this to the annual incidence of Covid-19 in the United States: It is at least 65 per 1,000 persons, based on new cases in July 2020. Actual counts, by some estimates informed by antibody prevalence surveys, could be 10 times the case counts.
Assuming the annual incidence of Covid-19 to be 100 per 1,000 persons, using ratio calculations, a trial similar to the Shingles trial would need 4 months to evaluate efficacy (i.e., detect 210 infections in 7,000 people).
Ironically then, countries with a good control on the outbreak are at a disadvantage to conduct vaccine trials. An example is China: companies are signing up partners in other countries, as Phase 3 progress in China is slow. Currently the bulk of the Phase 3 trials are taking place in the US, UK, Argentina, Brazil, and South Africa.
A modification of Phase 2 can add to this natural gain in trial timeline.
Typically, Phase 2 is a bridge between Phase 1 and Phase 3. Instead of jumping from a Phase 1 trial that has tens of individuals to a Phase 3 trial, a Phase 2 bridge minimises health risks and costs. As an added step, however, it consumes additional time. In modified Covid-19 vaccine trials, Phase 2 is considered as an expanded safety trial, and the efficacy data collection is moved to Phase 3. Nomenclature such as Phase 1/2 and Phase 2/3 is used.
As per The New York Times vaccine tracker, as on September 8, nine vaccine candidates have progressed to Phase 2/3 or Phase 3. Out of these, six companies have published their Phase 1 and 2 data in peer reviewed journals. These are AstraZeneca-Oxford, Moderna, Pfizer-BioNTech, CanSino, Sinopharm, and Gamaleya. The first three have Phase 3 trials ongoing in multiple countries for more than four weeks now. Each plans to recruit about 30,000 individuals; almost half of these individuals will be in the vaccinated group.
In India, Bharat Biotech and Zydus Cadila have launched Phase 1 and Phase 2 trials. Each company plans to enroll around 1,100 individuals across the two phases. A Phase 2/3 trial with target enrollment of 1,600 is under way for Serum Institute’s vaccine. (Serum Institute is a contract manufacturer for the AstraZeneca-Oxford vaccine.) Although the study is titled as a Phase 2/3 study, the data collection protocol does not include measuring the number of individuals that get the Covid-19 infection – a number necessary to determine efficacy.
The positive news is that published data, especially from the first three companies in the list of six above, indicates minimal safety events and a strong immune response as measured on three metrics: antibody levels, T-cell numbers, and neutralizing capability of these antibodies against either the Covid-19 virus or similar virus.
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Antibodies and T-cells are two branches of the immune system. Separately, the studies also showed that the levels of antibodies detected in trial participants were comparable to levels measured in individuals affected by Covid-19 (not part of the study).
For a vaccine approved by December (assuming data submission in October), 4-6 months of data will be available on the Phase 1/2 participants (50-500 vaccinated individuals). About 3 months of data will be available on the Phase 2/3 participants (about 15,000 vaccinated individuals).
A successful global trial from any of the three leading candidates will prove efficacy as per the discussed criteria. The other two criteria – durability of vaccine protection and long-term safety – that need data for a defined time period, might not be fully satisfied at the time a vaccine is proven efficacious.
There is no solution to this problem – data that have to be collected for a specific amount of time cannot be fast-tracked. An approval decision, therefore, will have to weigh the risk of such partial information against the benefit of an efficacious vaccine.
When can everyone have the vaccine?
The clinical trial timeline is only one part of the puzzle of immunising the entire globe. Manufacturing and supply chain considerations are critical. A clinical trial by one company might need 30,000-50,000 doses in a couple of months, whereas the market needs more than 7 billion doses (assuming 1-2 doses for 70% of the world population) as soon as possible!
There are two potential barriers in developing adequate vaccine supply within months of approval.
One is just the sheer scale of manufacturing. Currently, annual consumption of all vaccines combined is about 3.5 billion doses. Developing capacity capable of manufacturing 7 billion doses in months is a significant challenge.
Other parts of the supply chain could also present bottlenecks: cold storage facilities, components such as glass vials, vial stoppers, and even testing materials. Per the New York Times’ Covid-19 vaccine tracker, 3 out of the 9 companies in late stage trials have declared an annual capacity totaling to about 3.5 billion doses.
The second is a regulatory issue.
One principle is that the manufactured and sold product has to be “identical” in key aspects to the product used during clinical trials. Otherwise the clinical trial data is invalid for the commercially sold product. During scale-up, certain manufacturing procedures, materials, and testing methods can change. In such instances, the manufacturer has to prove that the product from the new procedures is the ‘same’. Additional studies might be required to fulfill this criterion if these changes are significant.
Can you trust the new vaccine (when it comes)?
As discussed earlier, a faster. efficacious vaccine will mean less safety data. This does not necessarily mean that the vaccine is unsafe.
Safety has many aspects to it, and reviewers will draw on additional sources for safety data (animal trials, other vaccines with similar platforms, data from other Covid-19 trials in progress) to establish as comprehensive a picture as the data allow. Possibly, the conclusions could be different for different demographics.
In most instances, approval will be conditional on a post-approval safety vigilance programme. Furthermore, each country has its own approval mechanism. Thus, multiple regulatory committees, including the WHO that supports the United Nations (UN) in its purchase of vaccines for developing countries, will scrutinize the data. Such multiple reviews will provide an individual with many viewpoints to consider for making a personalised decision.
The clinical data is only one component of the trust in the consumed product. The second component is the conviction that the manufactured product matches the product used in the clinical trials. Authorities inspect the manufacturing facilities to check conformance to required standards.
This review, however, is a spot check, and regulators rely on the manufacturer to continue the good practice demonstrated during any inspection. For a new product especially, consumers could choose to favour manufacturers with a track record, including accreditation from international agencies, of manufacturing similar products.
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A safe and effective Covid-19 vaccine within months will be a “never-before”-type event. Although authorities will try their best to review the risk-benefit balance, a consumer can benefit by keeping herself informed and educated about the vaccine (the ‘Prescribing Information’ document for any approved product is an excellent detailed source) – and by making a decision based on her personal risk-benefit equation in discussion with the physician.
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