The Unintended Costs of Rushing a Vaccine

I am a volunteer in a phase III clinical trial for a COVID-19 vaccine. As a scientist and a citizen, I believe this to be a fundamental duty. My clinical colleagues are risking their lives each day fighting the pandemic and volunteering seemed like the least I could do.

As I was enrolling in July, I answered a battery of questions about my health and risk factors, among other criteria. In return, I had a one simple question that seemingly could not be answered until this week, “What happens to the trial if the FDA approves a vaccine before full trial results are obtained?”

This discomforting silence in no way reflected ignorance on the part of trial coordinators. Rather, it reflected a lack of guidance from the pharmaceutical company sponsoring the trial, which in turn reflected the absence of an answer from the Food and Drug Administration (FDA). Indeed, the study director and staff informed me they have been asking the same question for weeks, and have yet to receive an answer.

But the more I considered this question, the more I have struggled with the enormity of its implications.

For those not familiar with clinical trials, this might seem like a minor issue. But as someone who studies the history of vaccine and drug development, I’ve grown increasingly concerned.

Let’s walk through some basics. Phase I and II trials provide initial information about dosage and efficacy, but participants number in just the dozens or hundreds. Vaccine and drug approvals are generally based upon phase III trials, which involve thousands of participants and thus are sufficiently “powered” — a statistical term meaning that the trial is large enough to provide conclusive evidence about whether those receiving a vaccine or drug actually benefit from its desired effects.

In making this determination, statisticians utilize complex formulas to decide how many subjects must be enrolled in trial’s treatment and control arms. Otherwise, it can be hard to gather statistically-meaningful data that distinguishes desired benefits from the effects of a placebo.

For a vaccine trial, current design standards suggest that average enrollment should be something like 30,000 people, divided evenly and randomly between vaccine and placebo groups. This number incorporates a certain “fudge factor,” since some patients inevitably will drop out or become “non-compliant,” effectively negating their contributions. It’s like the number of people who actually attend a wedding vs. the number who said they’d come.

Multiple COVID-19 vaccines are being developed in the clinic, with at least seven phase III clinical trials are currently underway for COVID19 vaccines and more being introduced seemingly every week. 

 So, back to the question: What will happen now that the FDA has approved vaccines before the long-term safety and efficacy data have been collected for potential follow-on? My worry is that such a move could undermine countless hours of work, billions of dollars in research and most importantly the health of the nation — and indeed the world.

Most people, including myself, want access to a vaccine as soon as possible, even though some of us are participating in a clinical trial for another. And indeed, it is entirely appropriate and ethical that those enrolled in comparable trials be granted access to any newly-approved vaccine.

Therein lies the rub. Once the FDA approves one vaccine, the statistical rigor “powering” other trials will likely be undone. Those who had received placebos could be “contaminated” by taking the newly-approved vaccine. Those who had received an experimental vaccine will now have had two vaccines. Many, and perhaps all, ongoing trials will be scuppered.

Yet excluding participants in other trials from receiving an FDA-approved vaccine would be inappropriate and frankly unenforceable. This is particularly true for those who are in the placebo group (but do not know it), as it could leave them vulnerable to infection.

If by sheer luck the first vaccines (i.e., Pfizer/BioNTech & Mderna) ultimately prove to be the best one, then no harm will have occurred. Yet it would be na?ve to presume the first will be the best. Moreover, competing trials that aren’t simply scrapped will have to be re-configured to compare the new vaccine with the experimental vaccine (or in an even more complicated trials, to compare those with one vaccine versus those with two).

 Such confusion means that it may be years before we know the outcomes or whether there might be a “better” or “best” COVID-19 vaccine. Given the added costs and competition, some sponsors may reasonably elect not to continue advancing their programs, figuring the market has been addressed. In a nightmare scenario, this could mean that better vaccines are long-delayed and perhaps never even introduced.

None of this is particularly mysterious. Such risks are completely avoidable, and well understood by scientists and pharmaceutical companies. In normal times, the FDA’s thoughtfulness and experience would render such outcomes practically unthinkable. But 2020 has been anything but normal. The consequences could be profound.

So, that same question keeps ringing in my ears.