Pause: A Covid-19 Drug Trial Hits A Snag

The Covid-19 vaccine trial organized and monitored by the Astra-Zeneca drug company was “paused.” A volunteer at a site in Great Britain who received the experimental vaccine developed a neurologic complication. What little has been said about this adverse event suggests that this previously healthy woman developed inflammation of the spinal cord. Perhaps it was a coincidence.  Perhaps it is the beginning of the end for this vaccine trial, but there are numerous other vaccine trials ongoing, and our friends in Russia and China may have already developed a vaccine. We have no way of knowing.

What the major governments of the world all seem to agree on is the need to keep their populations poorly or uninformed about this plague that has already killed more than 200,000 Americans and left thousands more permanently disabled.

The Significance of the Pause

This “pause” was worrisome even though this trial has resumed and other trials may be declared successful. The Food and Drug Administration (FDA) procedures for getting a vaccine approved are fairly lenient, especially if the targeted disease is as lethal or disabling as Covid-19.  Dr. Anthony Fauci, the director of the National Institute of Allergy and Infectious Diseases (NIAID, not FDA) rightly pointed out that a vaccine is considered adequate to justify widespread distribution even if it has only 70% efficacy.  This means that if it fails to protect 30 out of every 100 people exposed to the virus, it is still good enough to distribute. 

In the 1990s the German government faced a whooping cough (pertussis) epidemic in West Berlin when the Berlin wall came down. Apparently most East Berliners had not received vaccination against this disease, and pertussis infections spread from East Berlin to West Berlin. West Berliners exposed to this infection had a 30% chance of developing the disease even if they had been vaccinated. Dr. Fauci’s remark underlined the low bar set for any approach that will slow or stop the Covid-19 pandemic.

Management of the major drug companies came together after the most recent “pause” to reassure the public that no vaccine would be released prematurely. All testing would be comprehensive, and political pressure to come up with something, indeed anything, that could be touted as a breakthrough would be ignored. 

Many news outlets reported this as good news, but I must admit this sounded to me like Jim Jones telling his followers to drink the Kool-Aid. (Yes, I know it was not actually Kool-Aid. He mixed the poison with a less expensive flavoring.) Much of the general public is already wary of vaccines that have proven to be safe and effective for decades. That they will celebrate the inevitable announcement that “We did it” is unclear.

Whoever comes up with a vaccine for Covid-19 first will get an order from the U.S. government for several hundred million doses. The carrot at the end of this vaccine stick is worth tens of billions of dollars. The pressure to have something the government can buy is huge.

Vaccine Development is a Three-Phase Process

The “pause” occurred in phase 3 of the vaccine development. Phase 1 focuses on safety.  Healthy people are given the vaccine or a dummy (placebo) injection and side effects in both groups are closely monitored. Spontaneous complaints, i.e., headache nausea, blurred vision, etc., and observed events, i.e., rash, blood changes, vomiting, etc., are tallied for both groups without the trial conductors knowing who got the vaccine and who got the placebo. An independent safety committee is usually established to look at who got what if a volunteer has a serious problem during phase 1 or if a common complaint develops.  These problems are called adverse events, and if the event is serious enough and linked to the vaccine, the trial is stopped. 

In phase 2, both the safety and efficacy of a drug or vaccine is tested in a relatively small group of volunteers. Obviously, a major objective with phase 2 in a vaccine study is to again look for adverse events, since no one would purposely expose these volunteers to the virus against which the vaccine has been developed.  What are called “surrogate markers” are monitored.  In the Covid-19 vaccine trial, surrogate markers being followed include antibody production in response to the vaccine. A robust production of antibodies to Covid-19 in response to the vaccine is the desired result.

In phase 3, a large population of volunteers is given the vaccine or a placebo and adverse events and surrogate markers are monitored. If the surrogate markers look good and the adverse events are not worrisome, the vaccine gets a conditional approval. It is conditional because there is still a requirement that there are no surprises when millions of people get the vaccine. A problem sufficient to “pause” development usually appears in phase 1 or phase 2. That a possible adverse event appeared during phase 3 is especially worrisome. 

To reach phase 3, corporations need to invest tens of millions of dollars. With the Covid-19 vaccine trials, phase 2 results were widely publicized and investors considered each announcement with unbridled optimism. There was a pause in July when a volunteer developed a neurologic complication that was subsequently attributed to undiagnosed multiple sclerosis, and the phase 3 trial resumed.  In September the trial was paused again for a neurologic problem in another volunteer, but this too was deemed irrelevant, and the study that had already enrolled 18,000 volunteers was resumed.

The uninitiated will naturally suggest that this latest adverse event was probably just a fluke, a red herring, a coincidence or a mistake. Regardless of what is subsequently offered to explain the second “pause,” the event that occurred could not be explained away, rationalized, papered over or buried by statistical manipulation. Something terrible may have happened. Perhaps it was nothing to panic about. In any event, we would be well-advised to adopt measures we know help to protect us and not rush to adopt a vaccine that needs to be proven safe and effective.

Dr. Lechtenberg is an Easton resident who graduated from Tufts University and Tufts Medical School in Massachusetts and subsequently trained at The Mount Sinai Hospital and Columbia-Presbyterian Medical Center in Manhattan.  He worked as a neurologist at several New York Hospitals, including Kings County and The Long Island College Hospital, while maintaining a private practice, teaching at SUNY Downstate Medical School, and publishing 15 books on a variety of medical topics. He worked in drug development in the United States, as well as in England, Germany, and France.

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