What's a clinical trial? How did they work in the development of the COVID-19 vaccines?

Mark J. King

Here’s more on the safety and effectiveness of the forthcoming COVID-19 vaccines and our conversation with Mark J. King, Novant Health’s vice president of research and innovation. King was formerly a senior scientist at Pfizer, where he worked on clinical trials. Read the first segment of this series here.

What role do clinical trials play in vaccine approval?

They’re essential.

And so are the volunteers who allow the vaccine to be tested on them. Those volunteers include a control group that receives a placebo. “Randomized, placebo-controlled trials are the bedrock of modern clinical decision-making and remain the most efficient way to obtain reliable results,” according to a Dec. 2 report in the New England Journal of Medicine written by a group of experts from the World Health Organization.

“Informed consent is a crucial part of clinical trials,” King said. “When you go to a doctor for a procedure, you typically sign a one-pager that says you agree to, for example, have your knee replaced, and the doctor will do everything he or she can to keep you safe but that there are always risks. In clinical trials, it’s not unusual to see informed consent forms that are upward of 30 or 40 pages long.”

Scientists learn about a vaccine’s potential side effects – both mild and severe – because volunteers experience them. Trials, conducted by pharmaceutical companies, happen in phases. But before testing in humans can even begin, the Food and Drug Administration evaluates preclinical data to determine if it’s safe to proceed.

“It’s in vitro – or ‘in glass’ – first, and then they'll go in vivo, which means ‘within the living,’” King said. “In vitro testing starts with cell lines in a petri dish. In vivo testing typically starts in animals. The model starts with a mouse or rat, then moves through a number of species before testing can begin safely in humans. They extrapolate from there how they believe the vaccine candidate is going to work in humans, and that informs the dose they're going to use in phase 1 of human trials.”

Phase 1

Phase 1 determines the safety of the vaccine in development. It’s in this phase that doctors aim to discover if a vaccine is safe and tolerable in a small number of healthy individuals – usually 20 to 100. “These are truly healthy patients who have to meet certain inclusion criteria and not have any of the exclusion criteria that are written into the protocol,” King said. “For example, you must be 18 to 65; that's typically an inclusion criterion for most clinical trials. Any clinical trial done in the U.S., by law, has to be listed on clinicaltrials.gov.” The study outcomes are also posted online here, making the process completely transparent.

Some volunteers are given a dose of the drug, while some are given a placebo, and observed closely. The healthy people who participate in a phase 1 study do it knowing they might experience the side effects listed in the informed consent form.

At the end of phase 1, doctors aren’t actually sure if the vaccine works, since all phase 1 is designed to do is show it’s safe.

“Phase 1 looks at safety of the treatment, as compared to the placebo,” King said. “They are looking for all the things you see in the fine print of a typical drug ad or the ‘fast talking’ you hear in a drug commercial: ‘May cause headache, diarrhea, constipation, dry eye, injection site reaction, difficulty breathing.”

Phase 2

The Food and Drug Administration allows a vaccine candidate to move to phase 2 if and when results from phase 1 are satisfactory. About 70% of drugs are approved to move to this phase. Phase 2 studies include more people – hundreds – and involve various dosages. This time, the volunteers may be from different demographic groups that are placed into the randomized, controlled studies. Both safety and efficacy are evaluated in this phase.

Phase 3

In phase 3, scientists determine whether a vaccine works in a large, diverse, randomized population. Tens of thousands of volunteers participate in this phase. For a vaccine to be deemed effective, the number of participants who got the vaccine and who tested positive for, or got sick with, COVID-19 must be significantly lower than the number who got the placebo and got COVID-19.

In phase 3, half the volunteers typically get the vaccine and the other half get a placebo shot. (With the COVID-19 vaccine, both groups – active and placebo – got doses spread out over a couple of weeks.) Both groups then go about their daily lives. King said the consent forms the volunteer participants signed likely instructed them to mask, social distance, wash hands frequently – but the study sponsors likely expect there will be some “renegades.”

In the ensuing months, scientists track how many people develop side effects that could be the result of the vaccine. Some side effects, like a low fever, might be acceptable. “The FDA and trial sponsors will actually collect adverse effect – or AE – data for years,” King said.

The COVID-19 trials are even larger than usual; there are 30,000 participants. “And even when the pharmaceutical company believes their study is a success, all those data must be submitted to the country’s regulatory agency – in the United States, that’s the FDA – for a complete review of safety and efficacy before the vaccine is approved or made available through an Emergency Use Authorization,” King noted.

How do we know the COVID vaccine is effective?

Through the rigorous clinical trial protocols. The COVID-19 vaccine hasn’t just proven to be occasionally effective, it is highly effective.

“We get flu vaccines that are typically 40% effective,” King said. “The early data we’ve seen on the COVID-19 vaccine shows it to be something like 94% or 95% effective with very few adverse effects. When it comes to vaccines, the regulatory process in the U.S. is one of the most robust in the world. I have faith in it, in part because it's not controlled by politicians, but by science.”

How do we know the clinical trial results are accurate?

Transparency is essential in establishing public trust, and the pharmaceutical industry is committed to that with the COVID vaccine. Taxpayer dollars have been used with some – but not all – of these trials, so pharmaceutical companies are accountable to citizens rather than shareholders.

“The companies behind four of the leading vaccine candidates — Moderna, AstraZeneca, Pfizer and Johnson & Johnson — have publicly released their full phase 3 trial plans, including the predetermined number of infections they are looking for,” The Washington Post reported.

Pfizer didn't join Operation Warp Speed to develop or manufacture its vaccine; the company wanted complete autonomy. “Pfizer’s COVID-19 vaccine development and manufacturing costs have been entirely self-funded, with billions of dollars already invested at risk,” King said. “The company will continue bearing all the costs of development and manufacturing … to help find a solution to this pandemic as fast as possible. The company did get one of the largest supply contracts.

“I believe the clinical trial process is beyond rigorous,” King said. “I intend to get the vaccine.”

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