On March 22, 2021, by a media release, AstraZeneca announced that its ‘US Phase III trial of AZD1222 demonstrated statistically significant vaccine efficacy of 79% in preventing symptomatic COVID-19 and 100% efficacy at preventing severe disease and hospitalization.’

Quite unexpectedly, on March 23, 2021, the above claim on AstraZeneca’s Covid-19 vaccine, triggered a rare post-midnight statement by the National Institute of Allergy and Infectious Diseases (NIAID) of the United states. It rekindled a lurking fear of many, yet again, on the issue of questionable data integrity within the drug industry, in general.

This News Release articulated: “Late Monday, the Data and Safety Monitoring Board (DSMB) notified NIAID, BARDA, and AstraZeneca that it was concerned by information released by AstraZeneca on initial data from its COVID-19 vaccine clinical trial.”

The concern was on the possible inclusion of outdated information from that trial, ‘which may have provided an incomplete view of the efficacy data.’ It urged AstraZeneca to work with the DSMB to review the efficacy data and ensure the most accurate, up-to-date efficacy data be made public as soon as possible.

Later on that very day, AstraZeneca released another statement saying: “The numbers published yesterday were based on a pre-specified interim analysis with a data cutoff of 17 February. We have reviewed the preliminary assessment of the primary analysis and the results were consistent with the interim analysis. We are now completing the validation of the statistical analysis.”

The company further emphasized, “We will immediately engage with the independent data safety monitoring board (DSMB) to share our primary analysis with the most up to date efficacy data.” And also added that AstraZeneca intends to issue the results of the primary analysis within 48 hours.

However, the impact of the NIAID’s announcement on the unfurling of AstraZeneca’s Covid-19 vaccine in the U.S, is yet to be ascertained. It’s also still unknown what this news could mean for the vaccine’s alleged efficacy. Be that as it may, it all happened at a time when millions of people, in many countries of the world, including India, have already taken, at least, the first dose of this vaccine.

In this article, I shall deliberate on broader aspects of this critical issue and its relevance in the present case. However, before doing so, let’s try to figure out, why data integrity still remains a major concern of many experts in this area.

Why data integrity is still a major issue:

There are many studies that raised serious concern in this area, over a period of time. For example – ‘Dozens of recent clinical trials may contain wrong or falsified data’ – was claimed by the research paper that was discussed in ‘The Guardian’ on June 05, 2017.

This study reviewed data from 5,087 clinical trials, published during the past 15 years, in two prestigious medical journals – JAMA and the New England Journal of Medicine, and six anesthesia journals. In total, 90 published trials had underlying statistical patterns that were unlikely to appear by chance (or be termed as ‘unforced error’) in a credible dataset, the paper concluded.

Even my own article of September 30, 2019 deliberated on various facets of ‘data integrity’ involving novel therapy, across the world. There, I quoted one of the top medical experts related to the above paper, saying: “It’s very scary that we may be treating patients based on false evidence.” He further added: “It may be the case that certain treatments may need to be withdrawn from use.”

The ghost of a recent example still haunts:

Not so long ago, much reported fallout from Novartis’ alleged data manipulation fiasco with its billion-dollar gene therapy Zolgensma, shook all concerned. So much so, that the Company CEO had to pledge during an investor conference that: ‘the company will be more proactive in reporting data integrity issues to the FDA.’

He also added, Novartis has responded to the FDA’s Form 483 and is making documents available as requested, while reiterating that the data manipulation uncovered at the San Diego site “does not impact the safety, efficacy or quality of Zolgensma.”

The key point to ponder, therefore, especially in AstraZeneca’s Covid-19 vaccine case – is the same ghost haunting us, yet again?

Is it happening again? 

One may, possibly, find some cue of the answer to this question while looking at what followed after ‘validation of the statistical analysis’ by AstraZeneca, as it was promised by the company. Interestingly, the following day, after apparently a thorough analysis, the data released by AstraZeneca, re-iterated effectiveness of its COVID-19 vaccine, which apparently, is broadly similar to the results released earlier.

The Company highlighted therein, ‘US Phase III primary analysis confirms safety and efficacy,’ with the following points:

• 76% (earlier shown as 79%) vaccine efficacy against symptomatic COVID-19
• 100% efficacy against severe or critical disease and hospitalization
• 85% efficacy against symptomatic COVID-19 in participants aged 65 years and over.

It may continue to remain unclear to many – whether or not there was some suspected issue of data integrity – till the answers, at least, to the following questions are made public:

• Why did the data and safety monitoring board for the trial write a harsh letter to AstraZeneca on its claim, and copied the leadership of NIAID and the Biomedical Advanced Research and Development Authority?

• As the proof of the pudding is in its eating, why there will even be a slight downward revision in the rate of efficacy of AstraZeneca Covid-19 vaccine?

Conclusion:

I wrote in this blog, way back on August 03, 2015 that data manipulation issues are dangerously leapfrogging into clinical trial domain, even in India. As a result, many domestic drug players had to pay a heavy price – in terms of drug import bans by USFDA and other regulators. Several questions on the quality of efficacy and safety of Indian generic drugs were also raised in many developed countries. A number of best-selling books were also written on this issue.

Some may recall, just ahead Covid pandemic struck, trial data of a highly complex and very expensive gene therapy was also questioned by the US-FDA, for the same reason. However, on March 31, 2020, on completion of its review of the information, records of the inspection, the evidence collected, and the firm’s corrective actions, US-FDA stated: “Objectionable conditions were found and documented but the objectionable conditions observed during the inspection do not meet the threshold for regulatory action.”

Almost in a similar line, after the NIAID decided to make its data related concern public on AstraZeneca Covid-19 vaccine, its head, Anthony Fauci, reportedly, characterized this issue as “an unforced error.” This is indeed a cryptic comment. The root cause of this entire saga with details is still awaited.

Interestingly, the term “unforced error’ is widely used in Tennis, and means, ‘a mistake in play that is attributed to one’s own failure rather than to the skill or effort of one’s opponent.’ From this perspective, after AstraZeneca’s statement of clarification on its Covid-19 vaccine data, the concern on its phase three trial data would possibly be put to rest. At least for now, let’s not see the ghost of data integrity for this vaccine, where there doesn’t seem to be any.

By: Tapan J. Ray  

Disclaimer: The views/opinions expressed in this article are entirely my own, written in my individual and personal capacity. I do not represent any other person or organization for this opinion.