On Saturday, AstraZeneca and Oxford University announced they were given permission by the British Medicines and Healthcare Products Regulatory Agency to restart the Phase 3 clinical trial of their investigational Covid-19 vaccine in the U.K. The trial is still on hold in the U.S. and other countries.
The company stopped the trial last week to review safety data after a trial participant developed a serious adverse event; transverse myelitis, an inflammatory syndrome that affects the spinal cord. This condition can be caused by a viral infection. But, it is as yet unknown whether the experimental vaccine was responsible.
In spite of the pause, Pascal Soriot, AstraZeneca’s CEO, says the company could still file for approval of its Covid-19 vaccine with the Food and Drug Administration (FDA) by year’s end.
Indeed, a number of politicians, policymakers, public health officials, and pharmaceutical executives have been forecasting a Covid-19 vaccine debut by the end of this year.
In some respects, Operation Warp Speed has lived up to its hype. The public-private partnership has condensed what would normally be years of work into a much shorter time period, as multiple promising vaccines are in late stages of development. Pfizer CEO Albert Bourla has even said that he expects to know by the end of October whether the investigational vaccine being developed by Pfizer and its partner, BioNTech, works.
However, as the AstraZeneca trial hiccup indicates, things can go wrong in Phase 3. Nothing is certain in vaccine development. Moreover, besides development hurdles, manufacturing, distribution, and uptake challenges lie ahead should a vaccine(s) be licensed.
In Phase 3, investigational vaccines are administered to thousands of people, randomized into a vaccine and placebo group. The Moderna and Pfizer vaccine candidates are expected to complete enrollment of 30,000 and 44,000 trial participants, respectively, by the end of this month. Both of these candidates must be dosed twice. So, after the first dose, there’s a booster 4 weeks later. At that point, investigators will need to wait several few weeks before seeing the expected immune response. They also hope that among the placebo group a sufficient number become infected and are symptomatic in order to properly compare the groups and determine if one or both candidate vaccines protect against Covid-19.
A rather common reason for failure is that something unexpected – such as a severe side effect or a safety issue – emerges during Phase 3. Other grounds for failure include not meeting endpoints for efficacy.
Murphy’s Law tells us that even under the best of circumstances, drugs and vaccines in Phase 3 may strike out.
In 2017, the FDA published a series of case studies of experimental drugs and vaccines that failed in Phase 3 after having successfully traversed Phase 2. The 22 examples of drugs and vaccines showed divergent efficacy and safety results in Phases 2 and 3.
In addition to the vaccines included in the FDA publication, one of the more remarkable failures occurred with the Respiratory Syncytial Virus vaccine. It looked very promising in Phases 1 and 2, and yet flunked in Phase 3.
While interim findings of the Phase 3 trials of Covid-19 vaccines could be released by the end of October, it’s unlikely given the phasing of doses as well as the wait period required following the second dose to observe the immune response. Subsequently, it will take time for regulatory agencies to review the findings and make a decision to approve a vaccine(s) for emergency use, or, pending full results that indicate success, for marketing.
The AstraZeneca experience and any other future unforeseen adverse event could impact recruitment of volunteer trial participants. But, perhaps more importantly, it could also impede sufficient uptake of a vaccine once approved for marketing. Some people may be reluctant to take a vaccine that they may perceive as having cut corners during the regulatory process. While perception and reality probably differ, in that the FDA commissioner and others have offered assurances that the approval process is guided by science and not politics or shareholders, what may still frighten people is the extraordinarily abbreviated timeline.
In what was perhaps a preemptive action to reassure the public, chief executives from nine vaccine developers issued a pledge 10 days ago that they would only seek approval from the FDA or other regulatory agencies if the safety and effectiveness data warranted it.
While people worldwide are hoping a vaccine will be ready by the end of this year, as this would facilitate a gradual return to normalcy, many scientific experts, some public health officials, and even several pharmaceutical executives, have repeatedly warned that it may take longer.
Notably, some pushback to the notion of achieving an approved vaccine in 2020 has come from Merck’s CEO Kenneth Frazier. Several months ago, he went against the grain and expressed doubts about whether having a vaccine by the end of the year would be possible. This may be because Merck’s own investigational product is in an earlier stage of development than its competitors. But, surely Merck has enough vaccine experience – many decades worth – to be able to anticipate the obstacles ahead.
It’s also noteworthy to mention that some European public health officials have been more cautious than their American counterparts in their assessment of the status of clinical trials and the timeframe for approval. For example, three days ago, Director of the Dutch National Institute for Public Health and the Environment, Jaap van Dissel, said he believes a vaccine won’t be widely available until early summer of 2021.
Since January, the race has been on to develop a safe and effective vaccine. While progress has been breathtakingly fast, approval, manufacturing, distribution, and uptake of Covid-19 vaccines will face challenges which can’t necessarily be overcome in a matter of a few months. It’s therefore prudent to temper raised expectations and adopt a cautiously optimistic wait-and-see approach.