Vaccine safety; Dissonance in "equitable access"

Newsletter Edition #3

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Hi,

Welcome back! As we get into the rhythm of this weekly communication, I continue to streamline this newsletter, helpfully supported by suggestions from readers.

While the focus of this initiative is very much global health in Geneva, we are also informed by events elsewhere, especially at the time of this pandemic. Apart from our own analyses, the goal is to also bring you critical expert voices to help go beyond the headlines. So here is a timely interview for you.

In line with the extraordinary (somewhat lop-sided) interests in vaccines, this week we discuss vaccine safety in the context of the recent adverse event with the Oxford-AstraZeneca vaccine candidate. Vaccine safety scientist, Dr Rebecca Chandler shares her expertise and helps us understand how to interpret this event.

(The genesis of this interview was a workshop by Serena Tinari of Re-Check on evidence-based medicine , at Dataharvest, the European Investigative Journalism Conference. Apparently, asking questions of regulators is very important, especially during a pandemic. Thank you for that!)

What we also found interesting this week, is a dissonance of sorts in our conversations around equitable access to health products. Read on…

Finally, a note of thanks to all those readers who have showed their support through generous donations to Geneva Health Files.

See you next week!

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Best,

Priti

If you want to write to me, get in touch here: patnaik.reporting@gmail.com


1. Story of the week

READING THE ASTRAZENECA-OXFORD TRIAL. WHAT’S AT STAKE?

Given the scientific, economic, political, commercial and moral compulsions around vaccines for the pandemic, the adverse event in a clinical trial of a leading vaccine candidate has been a humbling moment for citizens, governments, companies and hopefully, politicians.

The goal of this expert interview is to help us read the recent pause in a leading clinical trial (AZD1222) following a suspected adverse event and the subsequent news of the resumption of the trial in the UK. A lot has been published already on this trial, already in phase III, but a few aspects worth underscoring.

First, that Pascal Soriot, CEO of AstraZeneca reportedly told investors that the trial was also halted previously in July “after a participant experienced neurological symptoms”. Experts have raised questions on the lack of transparency not only among trial participants, but also within the scientific community.

Also note, the recent “historic pledge” by industry leaders to uphold the integrity of the scientific process as they work on potential global regulatory filings and approvals for the first vaccines for the pandemic. This New York Times story, cites researchers’ concerns that this pledge did not offer “a promise to share more critical details about their research with the public and the scientific community.”

Second, when this edition went to print, the U.S. FDA was still investigating the safety of the vaccine candidate and had halted the trials in the U.S. It is important to note that UK’s Medicines and Healthcare products Regulatory Agency (MHRA), had already confirmed that it was safe to resume the trials in the UK. (It has been subsequently reported that Brazil, South Africa and India had regulatory approvals to resume trials.)

For geeks tracking regulatory intelligence, this is significant. Regulatory divergences offer clues on how different countries view risks for their populations. It also helps us understand the stakes better.

As Dr Chandler explains in her interview, “..I would hate to see safety signals ignored, because we have already invested  lots of money and effort into getting a vaccine to market.”

And of course, the stakes are high.

According to MarketWatch, American depositary shares of AstraZeneca have gained 8% this year compared with gains around 5% for the S&P 500 index. The market capitalization of the company stands at more than $145 billion.

AstraZeneca (AZN) Presents At Morgan Stanley 18th Annual Global Healthcare Conference - Slideshow: Source Seeking Alpha

A recent story by Fortune showed that AstraZeneca stock and options owned by CEO Soriot increased by nearly $15 million in value since early April, citing calculations by Kaiser Health News based on company disclosures.

Also read this comprehensive WSJ story (“If Oxford’s Covid-19 Vaccine Succeeds, Layers of Private Investors Could Profit”) that parsed through the web of direct and indirect investors around the Oxford-AstraZeneca vaccine candidate. Parties in the web include Vaccitech, Alphabet Inc (formerly called Google Ventures), Sequoia Capital China, and UK government’s Future Fund among others. (The story also says that “an investment arm of Huawei Technologies Co., have small stakes in a firm that ranks as Vaccitech’s biggest investor”)

So what was WHO’s response to uncertainties around clinical trials?

Responding to a query on the pause in the AstraZeneca trial, WHO top officials said last week that it was perhaps “a lesson for everyone to recognize the fact that there are ups and downs in research. We have to be prepared for those.”

Enough from me, here’s what Dr Rebecca Chandler has to say.

Q&A with Dr Rebecca Chandler, Senior Pharmacovigilance Expert, Uppsala Monitoring Centre

Photo credit - Gerard Ross

1. Briefly, what are some of the red flags as far as the AstraZeneca trial is concerned? 

The first read flag was the news on last Wednesday that the trial had been halted for a safety concern which an anonymous source said was transverse myelitis (TM).  An inflammation of the spinal cord, this particular diagnosis is one of those which catches the attention of people like me who work in vaccine safety.  It has been reported after a number of viral vaccines, such as influenza vaccine.  It is considered what we call an “Adverse Event of Special Interest” which means that safety surveillance systems will prioritise looking for cases of TM during both clinical trials and in post marketing use after licensure.

The second red flag was that later in the day last Wednesday the press reported that this was the second time that this trial had been halted.  A second case, last summer, apparently was also diagnosed with TM but was subsequently given a diagnosis of multiple sclerosis which was deemed unrelated to the vaccine.  TM can be the presenting sign of multiple sclerosis, so this in and of itself was not concerning, that the diagnosis had evolved from one to another.  What is concerning is that TM is a very rare disorder, occurring at an annual incidence of around 4 per 1 million and up to 20 per million if you include those cases of TM than go on to develop multiples sclerosis or other neurological disorder.  So, two cases of TM in a study population of 12,330 study subjects compared to a disease for such a rare disease is striking.

In summary, what was alarming to me last week was that we had TM, an adverse of special interest, apparently occurring at a rate in the clinical trial at a rate far exceeding what one might expect by “chance”.

2. The U.K. Medicines Health Regulatory Authority has said that details on the volunteer's illness cannot be shared due to confidential reasons. How should one read this?

A third red flag for me deals with the issue of transparency.  According to news sources, such as NYTimes, Nature and STAT, the diagnoses of TM and multiple sclerosis were communicated by the Astra Zeneca CEO at a meeting of investors, the minutes of which have not been shared.  I spent the weekend watching for an update of the official Participant Information sheet which is available online. A new version was published on 11 September with the following wording:

“In the current trial we have undertaken safety reviews when volunteers in the trials of ChAdOx1 nCoV-19 developed unexplained neurological symptoms including changed sensation or limb weakness, and have paused the study while a safety review took place. After independent review, these illnesses were either considered unlikely to be associated with the vaccine or there was insufficient evidence to say for certain that the illnesses were or were not related to the vaccine. In each of these cases, after considering the information, the independent reviewers recommended that vaccinations should continue.”

It appears that there are two levels of lack of transparency here:  a lack of information to trial participants as well as a lack of information to the scientific community.  At the moment, I am most alarmed by the lack of transparency to study participants.

3. Are you concerned that the trials have already resumed? 

I am not sure that I would say that I am concerned that the trials have already resumed.  I am concerned that the trial continues without full transparency to volunteers regarding the health of other participants.  I would hope that, during the halt, the safety surveillance system for the trial, including all global locations, will have been optimised to detect any more of these types of events. 

Further, I would hope that AZ/Oxford will continue to follow any patients with such events/diagnoses in an effort to understand if the vaccine has caused harm;  too often, these cases are tossed aside as “coincidence”, and there is no effort to try to elucidate a potential mechanism between the vaccine and the event. 

4. What are your opinions on the unprecedented pace of vaccine development in the current pandemic, much celebrated by both WHO and the industry. 

Overall, I can understand the approach to diversify the number of vaccine candidates and to work in a manner in which typically later actions /preparations are started earlier (overlapping of trials, construction of manufacturing facilities). 

I would hope, however, that this approach will be resistant to any pressures of “too big to fail” – I would hate to see safety signals ignored, because we have already invested  lots of money and effort into getting a vaccine to market.

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2. What we found interesting this week:

I. THE DISSONANCE IN EQUITABLE ACCESS

The Bill & Melinda Gates Foundation released the COVID-19: A global perpspective 2020 Goalkeepers report.

One of the questions raised in the report is how many lives could equitable access save? A very useful question as WHO, Gavi and other stakeholders work on this complex problem of future vaccines distribution.

The report cites modeling estimates by Northeastern University’s Laboratory for the Modeling of Biological and Socio-technical Systems (MOBS LAB). The lab “ran counterfactual scenarios examining what would have happened if a vaccine had been available starting in mid-March. This allows the model to work with observed data related to events that have already taken place, instead of guesses about data related to events that might take place a year from now,” the report explains.

In the two scenarios simulated: first - approximately 50 high-income countries received the first 2 billion doses (out of 3 billion) of an 80 percent effective vaccine; in the other - all countries received the 3 billion doses proportional to their populations, the report explains.

The outcome of the simulations showed that vaccines distributed to high-income countries first results in averting 33% of deaths, vaccines distributed to all countries proportional to population averts 61% of deaths.

One could not help, but recall the intervention of Bill Gates with respect to Oxford University vaccine candidate which was first meant to be a non-exclusive license in order to promote equitable access.

See this Fortune story, also cited above, from earlier in the year:

“We went to Oxford and said, Hey, you’re doing brilliant work,” Bill Gates told reporters (on June 3, a transcript shows.) “But … you really need to team up.” The comments were first reported by Bloomberg.

Soon after in April, AstraZeneca and Oxford University announced agreement for COVID-19 vaccine.

In June it was reported: “AstraZeneca starts manufacturing potential Oxford University vaccine and strikes deal with Bill Gates-backed health organizations”.

Also, in June, AstraZeneca became the first vaccine manufacturer to sign up to the Gavi Covax Advance Market Commitment. Under the terms of the Memorandum of Understanding, the company will guarantee 300 million doses of the AstraZeneca- Oxford vaccine candidate.

Vaccine prices will determine how many doses governments can buy for their populations. While these are still being discussed and negotiated, one can safely assume that non-exclusive licenses for vaccines production will achieve greater equitable access.

II. THE ADOPTION OF THE OMNIBUS RESOLUTION AT U.N.G.A.

This week the United Nations General Assembly adopted an omnibus resolution [Comprehensive and coordinated response to the coronavirus disease (COVID-19) pandemic]. While Israel and United States voted against, Ukraine and Hungary abstained, 169 voted in favor.

Geneva Health Files had previously analysed some of the negotiations around this resolution. Suggestions from the EU on references to ACT Accelerator were added to the text, but there was no reference to Costa Rica’s proposal that became the COVID-19 Technology Access Pool.

While the role of immunization has been recognized as a global public good in the context of the pandemic, there is no mention of vaccines as global public goods.

Finally, the resolution does not specifically refer to the flexibilities in the TRIPS Agreement. It refers to the TRIPS Agreement and the 2001 World Trade Organization Doha Declaration on the TRIPS Agreement and Public Health.

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