AstraZeneca may run additional trial

AstraZeneca said on Thursday it was likely to conduct an additional global trial to assess the efficacy of the Covid-19 vaccine it was developing along with University of Oxford after some studies raised questions over its level of protection and a lack of transparency around the late-stage clinical trials.

The new trial would be run instead of adding an arm to an ongoing US trial and would evaluate a lower dosage that performed better than a full amount in AstraZeneca’s studies, according to a Bloomberg report. “Now that we’ve found what looks like a better efficacy we have to validate this, so we need to do an additional study,” the pharma group’s chief executive officer Pascal Soriot told Bloomberg. It will probably be another “international study, but this one could be faster because we know the efficacy is high so we need smaller number of patients”.

Health experts are concerned about the data that showed the vaccine candidate was up to 90% effective, citing a lack of transparency around the late-stage clinical trials that could make or break the chances for billions of people to get early access to a cheap coronavirus inoculation.

The questions surround the use of the half-strength initial dose, which the developers said had higher efficacy but also revealed as having been administered as a mistake, and the possible lack of uniformity in the way the trial was split and its findings reported from locations in two countries: the United Kingdom and Brazil.

“AstraZeneca/Oxford get a poor grade for transparency and rigor when it comes to the vaccine trial results they have reported... AZN is evaluating their vaccine in multiple trials across the world, yet these are not embedded under a unified protocol. In fact, the trials seem to be quite different by country, in terms of populations, subgroups, etc...,” wrote Natalie Dean, assistant professor of biostatistics at University of Florida, in a series of tweets on Wednesday.

Oxford and AstraZeneca announced that their trial findings were based on 131 infections among 20,260 people split across trial sites in the UK and Brazil. Among these, those that were given a half-strength initial shot appeared to be more protected than those who were given two full-strength shots, a difference that the university’s scientists as well as the pharma firm’s executives said were unexpected.

The announcement of the vaccine’s efficacy raised hopes for countries like India, since AstraZeneca has committed a billion doses to the Covax Facility which aims to distribute vaccines to low- and middle-income countries. Among producers of the vaccine is Pune’s Serum Institute of India, which has committed to supplying half of the doses it makes to India, making it the first vaccine likely to be available in the country.

According to a top expert, in India, where the vaccine is undergoing a separate late-stage trial, the approval process can be based on the lower-efficacy, two full-strength dose approach, which too exceeds the 50% efficacy bar set by regulators. “Since the Indian trial is with two full doses, we can bridge to two full doses of the vaccine in the UK and Brazil and should not bridge to a dosing that we have not evaluated in India. Perhaps after the application to DCGI is done, they could propose additional studies in India, based on which they could apply for a labelling change,” said Dr Gagandeep Kang, former executive director, Translational Health Science and Technology Institute, a Department of Science and Technology (DST) organisation.

Kang said that the questions now being raised do not mean the trial results should be rubbished. “The results are good. Better than we hoped for when WHO, FDA and DCGI laid out the 50% efficacy point estimate criterion. All vaccine trials are different, and these are not head-to-head comparisons between vaccines that claim 90, 95 or 60 or 70% efficacy,” she added.

However, the controversy could have an impact on the approval process itself, which could itself depend on what regulators in the UK decide. “…Reporting out a secondary analysis that was not pre-specified is not desirable. If they seek to get the half-dose approved, they should wait until they have a compelling result,” Dean wrote, seemingly referring to the trial protocol AstraZeneca released for the experiments in the US. Protocol for the UK and Brazil trials have not been disclosed but are expected to be the same.

According to a report in the New York Times, AstraZeneca executive Menelas Pangalos said the error was made by a contractor and regulators were notified of it and signed off on continuing to test the vaccine at different doses.

But experts added that there are now multiple questions that need to be addressed. “Isn’t the different efficacy a subgroup analysis, and couldn’t the differences be statistical variability,” said Paul Bleicher, a former Harvard Medical School resident who now works as a strategic adviser, in a series of tweets on Wednesday.