Pfizer (PFE 0.55%) and BioNTech (BNTX 0.58%) are on the cusp of producing phase 3 data that could show their coronavirus vaccine, BNT162, protects participants from developing COVID-19 better than placebo. But investors should be aware that there are some caveats that could result in a negative clinical trial even if the vaccine actually helps patients.
1. Early infection
The clinical trial starts classifying patients as a positive for COVID-19 if the test occurs seven days after the second and final dose of the vaccine. Pfizer and BioNTech set the measurement based on the formation of antibodies in participants enrolled in earlier-stage studies, but if it takes longer to fully protect participants, some of the participants who received the vaccine could become infected between Day 7 and when the participant is truely protected, which would reduce the perceived effectiveness of the vaccine.
2. Virus in the nose
The vaccine is designed to create antibodies that can bind and inhibit the coronavirus once it enters the blood stream. But the tests for COVID-19 look for virus in patients' noses.
Participants in the study could be protected from the coronavirus, but still test positive for COVID-19 because the immune system doesn't wipe out the virus in the nose and upper respiratory tract where the test sample is taken.
It's possible that a participant might end up being exposed to the virus, not end up developing COVID-19, but still be counted as a positive case based on detection of the virus in the patient's nose.
Image source: Getty Images.
3. False positive testing
COVID-19 tests aren't 100% accurate. A study of 90 patients who were tested with a COVID-19 test developed by Danaher's (DHR 0.32%) Cepheid unit, which is being used in Pfizer and BioNTech's study, produced two false positive results.
Pfizer and BioNTech's study also requires patients to have at least one symptom within four days before or after the positive test to be counted as a positive COVID-19 case, but many of the symptoms, including fever, cough, soar throat, diarrhea, and others, are associated with other more benign diseases.
With 21,000 volunteers in the study having received the vaccine, it's easy to imagine that there might be a few participants who get a false positive test and also have one of those rather benign symptoms.
Hard to handicap
While all three issues are theoretically possible, it's hard to determine how much they'll end up effecting the patients who received the vaccine in the clinical trial. Unfortunately, even a small effect could sway the results, considering that the early study results hinge on very small numbers.
The first interim analysis, for example, comes after just 32 people in the study have developed COVID-19. If six or fewer cases come from the group who received the vaccine, the study will be deemed a success, but a single false positive positive person in the group could push the analysis beyond the success criteria.
Of course, it's equally likely that the three issues will result in a false positive in the placebo group, but a false negative in each group could still end up skewing the results against a statistically significant result. Consider the possibility that a true result would result in six participants who were given the vaccine getting COVID-19 while 26 participants who received placebo developed COVID-19. Add in just one additional false-positive to each group before the true readout, and now the ratio could be 7:25 after 32 cases, resulting in a negative interim result.
There are multiple interim analyses of the study, so one miss isn't necessarily the end of the world, but a cumulative addition of false-positive patients could potentially negate the final measurement, which will be taken after 164 positive COVID-19 cases.
