On human challenge trials

Why we should have started in April.

Each day 10,000 or so people worldwide die as a result of COVID-19. A single day’s delay, whether through FDA bureaucracy or bad luck with clinical trials, has massive consequences. And that’s without even considering the economic costs of social distancing.

This April, the organisation 1DaySooner signed up thousands of volunteers willing to be deliberately infected with COVID-19 in order to accelerate the development of a vaccine. 

We are fortunate to have multiple safe and effective vaccines ahead of the 12-18 month schedule many experts forecast. Yet I can’t help but think the failure to start human challenge trials in the first wave of the outbreak was a massive error. 

When 1DaySooner’s campaign was launched, there were multiple objections. Some objected on ethical grounds. For instance, Prof Charles Weijer, a medical ethicist argued that a key condition of any medical trial is that “volunteers will under no circumstances be exposed to the risks of irreversible, incurable or possibly fatal infections”.  Yet, under other circumstances we allow individuals to consent to greater risks in order to save lives. For example, Kidney donation carries a 1 in 3,000 risk of death.

Weijer hints that informed consent is not possible due to a lack of understanding of the risks of coronavirus. Yet we allow soldiers to consent to take greater risks under uncertainty. During the Iraq War, Marines died at a rate of over 8 per 1,000. Many others were severely wounded. It seems unlikely the Military provided soldiers with in-depth probabilities of death or injury.

As a society, we also allow workers to trade off an increased risk of death for higher pay. Loggers, deep sea trawler-men, and oil rig workers all accept risk of death and injury for higher pay.

It seems unlikely that for healthy young adults (say 18-34 years old), the risk of death from contracting coronavirus is greater than the above risks.

Indeed, if it were as risky as the above activities, it seems unlikely that anyone would have seriously talked about a herd immunity strategy back in March.

We should also think in terms of net risk. Some groups, e.g. key workers, are more likely to contract the virus than others. Almost everyone I know who works in the NHS seems to have contracted coronavirus at some point. If you have a 50% chance of contracting the virus through working in a supermarket then your net risk increase from participating in a challenge trial will be lower than if you spent the year working from home.

And by failing to act we, by omission, expose many more non-volunteers to the risks of a potentially fatal infection.

If we limit challenge trials to the healthy young population who are at highest risk of contracting the virus, then the ethical objections simply don’t hold up to scrutiny.

But there are practical objections. On his excellent blog, In The Pipeline, Derek Lowe raises a few.

The most important of which is the generalisability of results from the young and healthy to clinically vulnerable populations.

“… the data you would obtain from such a challenge is skewed heavily away from some of the people that you are going to want to treat first. Both efficacy and safety can (and do) vary by age, existing medical conditions and other variables that you’re going to have to make sure to not address in the challenge trial.”

Another issue to consider is manufacturing. Part of the reason we have beaten the initial 12 to 18 month timeframe forecast, was because we started scaling manufacturing capacity ahead of time and pre-ordering vaccines ahead of time. The work of groups like Accelerating Health Technologies on this front shouldn’t be underplayed.

So if challenge trials produce results that may not be generalisable to the vulnerable population and are still subject to manufacturing constraints, would they have still been worth doing?

I think so, for a few reasons.

1. Proof of concept

Until recently, it was far from accepted that we would have a working vaccine. In September within the Government there was “a widely held view that the country might have to learn to live with the virus”. In mid-October (!), a Whitehall source told the i: “Matt Hancock is the only person here who thinks there is actually going to be a vaccine … it’s a running joke with other departments.”

If there was proof of concept from a Human Challenge Trial and we knew in May that the odds of approval from a Phase III trial in November were high, then it would have had massive implications for policy.

The argument that we should try to live with the virus would have held less weight. Prematurely ending interventions such as the Job Retention Scheme would have been harder to justify if there was a clear ‘Victory over Covid Day’ on the horizon.

2. Faster deployment

Manufacturing constraints may have meant that even if we discovered a vaccine was safe and effective for the young and healthy population, we would have still been months off from starting to vaccinate the general public. But it’s inconceivable that more information ahead of time would not have helped speed up the process. If we knew in May that Pfizer and Moderna’s vaccines were more than 90% effective, governments could have placed larger orders, invested in cold-chain storage, and vaccine-makers would have responded by expanding production.

Even if the rollout starts on roughly the same date, it could be completed much sooner if we had more time to prepare. 

But if manufacturing constraints were not binding, then we could start vaccinating high-risk young people first. This could reduce R as key workers, such as those working in care homes or hospitals, would be less likely to become infected and pass it on.

3. Better understanding of how the vaccine works

A key benefit of challenge trials is that the subjects are closely monitored and researchers are able to gain a better understanding of how the vaccine works. For instance, does it prevent infection altogether or just reduce symptoms? It can also give us an idea of how the vaccine might prevent further transmission. This information will help us choose between the 200 or so candidate vaccines. It will also give us a much better idea of how quickly life can return to normal.

The UK is set to begin challenge trials next month. The first will test a nasal vaccine. If it works, it could save countless lives across the world.

We missed the opportunity to do human challenge trials when they could have had the biggest benefit, but they can still make a difference by helping us test the second wave of vaccines - something that will become significantly harder after the first wave of vaccines have been rolled out. To those who have volunteered to take part, I salute you!