The revelation that AstraZeneca paused its clinical trials for a Covid-19 vaccine has focused attention on the company and the clinical trial process.

The hold occurred after a participant in the trial developed symptoms consistent with a rare but serious spinal inflammatory disorder called transverse myelitis.

To better understand the ethics of vaccine trials in the time of coronavirus, I talked with Ruth Faden, a Johns Hopkins bioethicist with a special interest in vaccine development. Here’s a lightly edited version of our conversation.

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Is the process for clinical trials of vaccines different from the process for drug or device trials?

Mostly no. The principles, design, and basic structure of a vaccine trial are more or less the same as for a trial for a new medication. The research ethics considerations are also similar.

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The big difference between the two is that the participants in a preventive vaccine trial are, by and large, healthy people — or at least they are people who don’t have the illness for which the agent being tested might be effective. That significantly heightens the risk-benefit calculus for the participants.

Of course, some people in a Covid-19 vaccine trial could personally benefit if they live in communities with a lot of Covid-19. But even then, they might never get it. That’s very different than a trial in which individuals have a condition, say melanoma or malignant hypertension, and they are taking part in a trial of a therapy that could improve or even cure their condition.

Does that affect when a company might stop a trial?

In every clinical trial, the data and safety monitoring board takes routine and prescheduled looks at the accumulated data. They are checking mainly for two things: signals of harm and evidence of effectiveness.

These boards will recommend stopping a trial if they see a signal of concern or harm. They may do the same thing if they see solid evidence that people in the active arm of the trial are doing far better than those in the control arm.

In both cases, the action is taken on behalf of those participating in the trial. But it is also taken to advance the interests of people who would get this intervention if it was to be made publicly available.

The current situation with AstraZeneca involves a signal of concern. The company’s first obligation is to the participants in the trial. It cannot ethically proceed with the trial if there is reason for concern, even based on the experience of one participant.

So halting the trial to investigate what happened with one participant is OK?

AstraZeneca did exactly what it should have done. That’s an important point to underscore.

There’s something peculiar about my framing the situation that way. The context in which a vaccine against Covid-19 is being developed is so politically charged that it’s deeply heartening to see a pharmaceutical company do what it should do.

In the “before time,” if a company developing a new vaccine saw a signal like this, it would have stopped the trial, people who were involved in its development would have made note of it in the relevant professional press, and life would have gone on. Nobody would have heaped praise on the company for stopping.

Yet I’m joining the community of people who are saying, “Yay AstraZeneca! Thank you for doing what you were supposed to do.”

So what happens from this branch point?

An episode like this can be both reassuring to the general public and unnerving. Reassuring because the company did the right thing. Unnerving because the Oxford University-AstraZeneca vaccine is among the few that are closest to the authorization finish line.

When a participant develops an illness or condition during a clinical trial, it could be linked to the agent being tested. But it also might not. Symptoms and diseases occur for many reasons. In this case, the participant’s symptoms could have emerged had she not been in the trial. It happens. And it’s part of what all of us need to appreciate and not get completely panicked.

AstraZeneca needs to take the time to get experts who are arm’s length from the company to investigate what happened and then say it’s OK to proceed — or not.

If it turns out that this case of transverse myelitis in a trial participant is attributable to the vaccine, that could be a serious setback for the goal of getting a Covid-19 vaccine to the world as quickly as possible. That said, it’s far better for the world that we know this occurred and that AstraZeneca is doing the right thing than if the company had kept quiet and allowed its trials to proceed.

AstraZeneca seems to have offered more information to its investors than to the public. Is that a problem?

I think that’s ethically problematic.

There are circumstances in which it may be appropriate for a for-profit corporation to share information with investors that it doesn’t share with the public, although that distinction is itself fraught; for publicly traded companies, investors include members of the general public. Still, if I was an investor in a for-profit corporation, especially a significant investor, I might expect to receive information that isn’t made generally available to the public. That’s in the nature of a for-profit corporation.

But it really depends on the kind of information, and the context. Here we are talking about a very high-profile, critically important product for the public’s health in the midst of a pandemic. The stakes are as high as they get. Anything that even hints at less than full, public transparency is, at best, unhelpful.

There have been endless conversations about whether people will be willing to take a Covid-19 vaccine in the numbers that, from a public health point of view, would be needed to contain the pandemic.

Vaccines are a key weapon in the arsenal to get us out of this pandemic as quickly as possible. There are two huge challenges here. One is developing safe and effective vaccines. The other is being able to instill enough confidence in enough people so they will want to be vaccinated in order for vaccines to have the needed public-health impact.

A good vaccine that nobody wants won’t help us.

Do you think this is a teachable moment for companies testing experimental vaccines?

This whole pandemic has been one teachable moment after the other. Sadly, we don’t seem to be learning from many of them.

We haven’t talked about the public pledge by nine pharmaceutical and biotech companies in the Covid-19 vaccine space that they will not seek government authorization until they have sufficient safety and effectiveness data. It shouldn’t be necessary for vaccine developers to have to say this. But in this extraordinary time, they did, and many people were excited that they did. It’s deeply unfortunate to have such a low bar.

As someone who works daily with people in the vaccine R&D space and in vaccine policy, I know firsthand that many, many people of integrity and good faith are working hard to deliver safe and effective Covid-19 vaccines to the world.

The teachable moment here is that if people just follow with integrity the tried-and-true steps that have been followed in vaccine development for years, we will be fine. The caveat, of course, is that these steps are now under a microscope. Everything that happens in this space will draw an amazing amount of public attention.

Pollyannaish though it might sound, my advice is, “Follow the rules.” And recognize that any misstep has the potential to have negative consequences far beyond what they ordinarily would be.

What’s the price of a misstep?

We won’t get a do-over. If there is a big misstep in the Covid R&D vaccine space, it will be difficult to recover from the public health and societal fallout.

A big misstep would erode public confidence and have huge public consequences. We aren’t talking about a drug that will be given to tens of thousands of people or a vaccine that’s going to be given to a couple of million people. We’re talking about an intervention that could be given to millions upon millions of people around the world. Missteps will reverberate at an extraordinary scale.

If something goes radically wrong at the beginning of a vaccine deployment program, it will be difficult to recover from, even if the next vaccine that comes along fixes the problem. Or consider this scenario: Vaccines are rolled out, many people get them, and then a significant problem emerges. Where are we then? That is why the focus on vaccine safety looms so large.

To take this all back to AstraZeneca and its response to a signal of a serious illness in its trial of a Covid-19 vaccine: AstraZeneca did what it should have done and paused the trial to allow for a thorough investigation of the event. We shouldn’t have to be grateful for simple, ethical acts like that. But welcome to the time of coronavirus in America.

  • Right now safety and efficacy need to be separated a bit. The impact of Covid 19 is profound and happening quickly. 60 % effective is better than zero. Acupuncture (repeated) vaccination in the nursing home is ok. The oral vaccine at Migal labs should get more attention as it appears to be the 3rd world answer.

  • Really? People are questioning whether of not AZ should have stopped? I’m skeptical. Of course they should have stopped and I haven’t heard anybody say otherwise.

  • Dr. Faden fails to address the “what happens now question?” Will the risk of transverse myelitis be disclosed to future subjects? It should be. Who will compensate this person? Who will pay his/her medical costs?

    And backwards. Was the risk of TM disclosed to subjects?

    • The participant who fell ill is based in the UK so to a large extent the issue of medical costs doesn’t really arise. With regard to your other point, I seriously doubt that they will disclosing anything until after the independent investigation takes place and all the facts are known.

  • The STAT article dated September 9, 2020 reported that “The board tasked with overseeing the data and safety components of the AstraZeneca clinical trials confirmed that the participant was injected with the company’s Covid-19 vaccine and not a placebo …” Curiously, none of the major news services seem to have confirmed or even noticed this remark that is extremely problematic from an ethical perspective. In a double-blinded clinical trial, this information should be disclosed only to the DSMB for the trial and not to AstraZeneca employees (who should be excluded from the DSMB). Armed with this information about the treatment arm, would I volunteer for the trial? If I had received one dose, would I accept a second? Transverse myelitis is very uncommon; but it is a known, rare complication of virus infections and of vaccines. Disclosing the treatment to anyone would be problematic; disclosing it to investors before trial participants and the public is deeply disturbing.

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