Coronavirus pandemic prompts increased transparency of drug companies

The unprecedented nature of the SARS-CoV-2 coronavirus pandemic has begun to influence the transparency of drug company trials of potential COVID-19 vaccines.

On September 17th The New York Times reported that Moderna and Pfizer were releasing the protocols that describe the trial process to test a potential COVID-19 vaccine. On September 19th they reported that AstraZeneca had done the same. This heralds a significant change on the part of drug companies. Although in practice complex vaccine trial protocols would need to be interpreted by say, science journalists, in order to be understood by the wider public particularly given the multicultural nature of today’s communities in developed nations. [See references below for protocols]

As trials have progressed to Phase III in which data on the safety and efficacy of vaccines are collated, the interest of the public has grown significantly. Intense media attention surrounded the recent pause of the Phase III trial of the vaccine being developed by AstraZeneca in partnership with scientists from Oxford University. Not surprisingly public interest has turned to pressure for more transparency as to how trials are conducted.

From July 24th to August 7th Ipsos surveyed respondents from 27 countries [PDF] on attitudes toward a COVID-19 vaccine. 74% of respondents said they would have a vaccine if it was available. The most common reason for rejecting the vaccine was concern over side effects (56%). This was followed by doubt of its effectiveness (29%). The importance of transparency surrounding Phase III trials is confirmed by the weight of these two reasons for rejecting the vaccine.

These vaccines are being developed rapidly under the gaze of a public that expects at some time to be given such a vaccine. It’s understandable that anxiety surrounding both efficacy and safety of COVID-19 vaccines existed long before the specifics of Phase III trials became public. That those specifics have become better understood due to an issue with safety does raise matters of trust within the public.

Of course the increased attention over safety and efficacy would never have arisen during development of the many so-called “alternatives” to regulated vaccines. Alternative products are not subject to reliable scrutiny and as such the acute and chronic effects are in fact undocumented or unknown. The safety and efficacy of such listed (as opposed to regulated) therapeutic products is almost always merely assumed.

Establishing trust between the public and the government and health authorities is important. Increased transparency of vaccine trials will help promote trust. Sustaining trust is significantly reliant on clear information and explanation of complicated issues that raise public concern. This is particularly true in the present environment where changing evidence may come across as inconsistency and if left unacknowledged may lead to suspicion. The proper interpretation and presentation of available information is essential.

Normally data gathered during a trial are published after the trial. However the dynamic nature of COVID-19 vaccine development and the global impact of this pandemic have already changed what may be considered normal. Added to this is information that is leaking out. The Oxford trial has recommenced on the advice of an independent safety committee. AstraZeneca announced that they “had not confirmed a diagnosis” of transverse myelitis in the study volunteer.

What has also recently become apparent is that the study was paused in July after a male volunteer who had received one dose of the vaccine developed transverse myelitis. See page 10 of this participant information sheet. There was a review by independent experts. The trial resumed after it was determined that the individual had a previously undiagnosed case of multiple sclerosis unrelated to the vaccine. Still, there was a persistent concern that AstraZeneca had not revealed in detail what had happened to the woman whose significant neurological symptoms led to the most recent trial pause.

On the September 14th edition of The Health Report Dr. Norman Swan interviewed Professor Bruce Neal, Executive Director of the George Institute Australia. The occasion was to discuss the launch of a project called Join Us. A challenging issue about Phase III trials is that drug or vaccine development may stall or fail due to lack of suitable participants. This isn’t due to drop out or resistance. Rather the cost and administrative difficulty of finding suitable participants is significant. Join Us aims to secure pre-consent to trials of a certain nature.

Whilst that’s interesting information about trials, Swan also asked Professor Neal about his thoughts on the reluctance of AstraZeneca to reveal details about the woman responsible for the second pause of the Phase III trial. Neal considered reasons to release more information. It would give a heads up to other researchers around the globe allowing them to “provide input and information into it”. However he also noted that releasing such information midway through a trial may have negative consequences.

There may be confidentiality issues as such a “severe unusual event” might lead to patient identity being leaked. Perhaps most interestingly was the observation that the trial may well end with a conclusion that the event was not an issue related to the vaccine. By then the damage is done. The public have already internalised the notion of a negative side effect. The media effort to reverse that belief is not likely to be successful.

Professor Neal stated;

And so the media surrounding the announcement of something like that is going to retain much more prominence probably than the media that tries to reel that back in and say, look, actually it wasn’t an issue. And that could have ramifications down the track when you try to get people to take the vaccine.

It’s important to note that the FDA has not allowed the AstraZeneca trial to resume in the US. The National Institutes of Health stated that it remains to be seen if the illnesses are coincidental and that, “pausing to allow for further evaluation is consistent with standard practice”.

Understandably some health professionals in the US remain concerned. Whilst investors were told of the second problem it has become clear that the company did not immediately alert the F.D.A. and advise them of the independent safety board’s recommendation to pause the trial. Virologist Dr. Peter Jay Hotez based at Houston’s Baylor college of Medicine has not been impressed. He claimed communication has been “horrible and unacceptable” citing the failure of UK regulators to provide rationale for resumption of the trial.

The New York Times also reported;

Dr. Paul Offit, a professor at the University of Pennsylvania and a member of the F.D.A.’s advisory committee on vaccines, said that it’s unclear how the company — or the U.K. government — determined that the second case was not related to the vaccine.

Offit has also noted that the rarity of transverse myelitis in the general public has not been reflected in the UK trial population. The extra caution we are seeing in the US is reason for the public to have increased confidence in the influence regulators have over the safety of vaccine trials. Consequently there is reason for the public to be less anxious about the safety of COVID-19 vaccines that are eventually marketed. Given that independent safety experts in the UK have advised it is safe for the Oxford trial to resume it will be very interesting to see what further evaluation by US authorities concludes.

There has been research into immunisation and the likelihood of subsequent development of transverse myelitis (TM) and acute disseminated encephalomyelitis (ADEM). Key points from the 2016 paper Acute Demyelinating Events Following Vaccines: A Case-Centered Analysis are as follows;

Results: Following nearly 64 million vaccine doses, only 7 cases of TM and 8 cases of ADEM were vaccinated during the primary exposure window 5-28 days prior to onset. For TM, there was no statistically significant increased risk of immunization. For ADEM, there was no statistically significant increased risk following any vaccine except for Tdap (adolescent and adult tetanus, reduced diphtheria, acellular pertussis) vaccine. […]

Conclusions: We found no association between TM and prior immunization. There was a possible association of ADEM with Tdap vaccine, but the excess risk is not likely to be more than 1.16 cases of ADEM per million vaccines administered.

Acknowledging vaccine safety concerns as a cause of vaccine hesitancy, in July this year Nicola Principi and Susanna Esposito published a narrative review, Do Vaccines Have a Role as a Cause Of Autoimmune Neurological Syndromes?

The authors wrote in part in their abstract;

Only well-conducted epidemiological studies with adequate evaluation of results can clarify whether a true association between vaccines and adverse event development truly exists. Autoimmune neurological syndromes that follow vaccine use are among these. […]

Literature analysis showed that most of the associations between vaccines and nervous system autoimmune syndromes that have been reported as severe adverse events following immunization are no longer evidenced when well-conducted epidemiological studies are carried out. Although the rarity of autoimmune diseases makes it difficult to strictly exclude that, albeit exceptionally, some vaccines may induce an autoimmune neurological disease, no definitive demonstration of a potential role of vaccines in causing autoimmune neurological syndromes is presently available. Consequently, the fear of neurological autoimmune disease cannot limit the use of the most important preventive measure presently available against infectious diseases.

The Institute for Vaccine Safety at Johns Hopkins University logically argues that a number of vaccines “may prevent transverse myelitis”. The institute published Do Vaccines Cause Transverse Myelitis? Last updated September 18th 2020 the article opens with the conclusion;

Natural viral infections with influenza, hepatitis A, measles, mumps and rubella and varicella have all been associated with myelitis, albeit rarely. Thus, these viral vaccines may prevent transverse myelitis by protecting against natural infection. Vaccines currently routinely recommended to the general population in the U.S. have not been shown to cause transverse myelitis.

Ultimately this research in conjunction with the cautious US approach at present does not support a contention of general recklessness in the production of this vaccine or of other potential COVID-19 vaccines.

This dynamic provides yet another blow to anti-vaccination conspiracies. Namely the contention that there is collusion between drug companies and health regulators to suppress the supposedly inherent dangers of vaccines that anti-vaxxers wrongly insist lead to an abundance of vaccine injuries. More so Dr. Paul Offit has been derided, verbally attacked and threatened by the global anti-vaccine lobby for many years as a callous profiteer of vaccines. Yet he has constantly raised a voice of caution to ensure safe COVID-19 vaccine development.

It is certain that placing the AstraZeneca trial on hold following advice from the F.D.A. is not a unique event. Rather the fact that measures employed to control the current pandemic are being played out before the public in real time has provided insight into events that are usually ignored. In the previous post I listed some other aspects of anti-vaccine conspiracy that simply cannot be sustained following media reports of the AstraZeneca/Oxford Phase III trial pause. Even cursory attention to the details of this trial has exposed the dishonesty of anti-vaxxer claims.

Well before the trial pause led to media attention, public anxiety and now transparency of drug companies, the importance of trust in accepting a COVID-19 vaccine had been raised in Australia. Prime Minister Scott Morrison made a significant mistake with respect to public confidence in vaccine development and uptake. In August he announced that Australia had signed a deal to produce the vaccine being developed at Oxford University if Phase III trials were successful.

His mistake was to add that it would be “as mandatory as you can possibly make it”. Morrison realised the mistake and in under a day had produced the anticipated walk back. Nonetheless the many anti-science and anti-reason groups that are feverishly misrepresenting the motives of governments and health authorities during this pandemic were delighted. Within hours of Morrison’s announcement the AVN published a video mocking the notion of “safe and effective” vaccines whilst contending they “had always known this was coming”.

There were of course no “walk backs” from the AVN when Morrison corrected his position. Pushing fear of mandatory vaccination has always translated to profit for this group and Scott Morrison had done them a favour. Say no to mandatory vaccination read the back of a T-Shirt weeks later in Perth during Australia-wide “solidarity” rallies. Messages on social media continue in the same vein. Still, the reality is that messages and memes on mandatory vaccination would be common had Scott Morrison made no such statement.

Any harm done to the uptake of a COVID-19 vaccine in Australia is likely negligible. A survey conducted in April found that just under 86% of Australians aged over 18 would get a COVID-19 vaccine. 4.9% would not whilst 9.4% were indifferent. These figures are promising but were collated before the widely publicised pause in the AstraZeneca trial and increased public reflection on the safety of a COVID-19 vaccine. Survey responses were to the statement, If a COVID-19 vaccine becomes available, I will get it.

Ipsos published their global attitudes results on September 1st, indicating an 88% uptake of a COVID-19 vaccine in Australia. 59% strongly agree and 28% somewhat agree with the statement, If a vaccine for COVID-19 were available, I would get it. Only China and Brazil were more likely to accept a vaccine. These figures were also collated before the pause in the AstraZeneca trial. Follow this link to read Key Findings for Australia.

Another area that’s causing anxiety is the posturing of Donald Trump toward authorising a COVID-19 vaccine before the upcoming election. Consider the measure of Trump for a moment. He will tempt the voters with the promise of a vaccine in weeks. However it is more realistic to expect a safe and effective COVID-19 vaccine in months. These promises demand a disregard for vaccine safety. Yet in March 2014 Trump was tweeting in support of the mythical vaccine/autism link, a bogus view that bemoans a lack of vaccine safety. After the last election, research fraud and vaccine/autism profiteer Andrew Wakefield attended an inaugural ball from which he posted a social media video calling for an overhaul of the CDC.

Others have long ago considered the measure of Trump in regard to the election and a COVID-19 vaccine promise. In early June University of Pennsylvania professors Dr. Paul Offit and Dr. Ezekiel Emanuel wrote an opinion piece in The New York Times entitled Could Trump turn a vaccine into a campaign stunt?

It included;

In a desperate search for a boost, he could release a coronavirus vaccine that has not been shown to be safe and effective as an October surprise. […]

Given how this president has behaved, this incredibly dangerous scenario is not far-fetched. In a desperate search for a political boost, he could release a coronavirus vaccine before it had been thoroughly tested and shown to be safe and effective. […]

Thousands of Americans have already died as Donald Trump has perpetually postponed effective public health interventions and made poor therapeutic recommendations. We must be on alert to prevent him from corrupting the rigorous assessment of safety and effectiveness of Covid-19 vaccines in order to pull an October vaccine surprise to try to win re-election.

At the beginning of the second week of September the CEOs of nine drug companies, arguably competing in the development of a COVID-19 vaccine, signed a pledge to stand with science and not launch such a vaccine until it met “high ethical standards and sound scientific principles”. The pledge statement as it appears on Pfizers website is in references below. It came at a time when public health specialists and scientists expressed concern that the Trump administration was pressuring regulators to authorise a vaccine before the November 3rd election.

The New York Times reported;

The joint statement by competitors was seen as an effort to restore public trust as President Trump has pushed for a vaccine before the presidential election.

An out-take from the pledge from Pfizer’s website is as follows;

Following guidance from expert regulatory authorities such as FDA regarding the development of COVID-19 vaccines, consistent with existing standards and practices, and in the interest of public health, we pledge to:

Always make the safety and well-being of vaccinated individuals our top priority.

Continue to adhere to high scientific and ethical standards regarding the conduct of clinical trials and the rigor of manufacturing processes.

Only submit for approval or emergency use authorization after demonstrating safety and efficacy through a Phase 3 clinical study that is designed and conducted to meet requirements of expert regulatory authorities such as FDA.

Work to ensure a sufficient supply and range of vaccine options, including those suitable for global access.

We believe this pledge will help ensure public confidence in the rigorous scientific and regulatory process by which COVID-19 vaccines are evaluated and may ultimately be approved.

Yes to the cynical eye this may seem to present the pharmaceutical CEOs as really great guys. However I recommend reading the entire Biopharma Leaders Unite pledge. More to the point with increased transparency the public and the media have an invested interest to see a suitable outcome here. This pledge is certainly a step up from Fauci saying he has “confidence and some faith” that the COVID-19 vaccine approval won’t be political.

Earlier in the year it was reported that a significant number of Americans are likely to refuse a COVID-19 vaccine. A robust anti-vaccination lobby and rising numbers of the vaccine hesitant mean that the number of Americans who accept the vaccine may be insufficient to sustain herd immunity, which may require between 50 – 70% of the population to be immune. The more recent Ipsos survey found 67% of US citizens would have the vaccine.

Exactly how many must be vaccinated to achieve herd immunity is still uncertain. The WHO suggest 95%. Mathematical modelling reflecting age and social activity level produces a herd immunity “illustration” as low as 43%. Other reports suggest a vaccine uptake of over 70% is needed. The Mayo clinic point out that reaching this level of immunity through infection and not vaccination would overwhelm the health system and cause millions of deaths.

Thus there is ample reason to hope greater transparency of vaccine trials leads to justified improved confidence in the safety and efficacy of COVID-19 vaccines and increased uptake. Of course given the speed of current COVID-19 vaccine trials let us also hope that the vaccines that make it to market are extremely safe and splendidly effective. The fewer challenges that accompany immunisation on a global scale the better.

Another area that is getting more scrutiny if not exactly transparency is that of vaccine nationalism. This term refers to agreements between governments and vaccine manufacturers that ensure developed nations have secure access to vaccines for their entire population before they are available for other nations. With COVID-19 this may result in a delay in vaccinating health workers in developing nations, individuals at high risk of severe disease or death and those living in a region of a sudden dangerous cluster.

COVID-19 is a global pandemic. Yet we are faced with a situation where wealthy nations will be able to vaccinate their populations whilst countries that rely on aid organisations will be unable to vaccinate health workers and at-risk populations without organised help. A recent Science Friction podcast looks at the ways in which this problem can be combated. Australia’s Friends of Science in Medicine actively support equitable access to “COVID-19 vaccines and related health technologies”.

No doubt the anti-vaccine lobby will use information in the trial protocols in the same way they use vaccine package inserts. Thanks to exceptional cognitive dissonance they will list reasons as to why information from vaccine manufacturers can’t be trusted whilst using that same information to defend these reasons. The good news is that as we’ve seen, increased transparency and media attention has exposed tenets of anti-vaccine conspiracy and beliefs as vacuous and fallacious. On these points it’s a case of watch this space.

In conclusion it can be seen that the increase in transparency of COVID-19 vaccine development should indeed serve to increase public trust and confidence in the quality of eligible vaccines. I cannot finish without stressing again that the safety and efficacy elements of Phase III trials do not apply to the raft of concoctions marketed as alternatives to medicine. All consumers should seek reputable sources of information and beware of the many hoax “cures” of COVID-19. Discuss any novel plans to manage or prevent COVID-19 with a registered medical practitioner.

Finally whilst the importance of transparency with respect to vaccine trials has become clear, it was also confirmed by the Ipsos global survey on attitudes to a COVID-19 vaccine. The most common reasons for intending to refuse a vaccine are safety followed by efficacy. The establishment of which is the very aim of Phase III trials.

REFERENCES

Phase 3 clinical trial of investigational vaccine for COVID-19 begins

Moderna Clinical Trial Protocol – SARS-CoV-2 vaccine

Pfizer Clinical Trial Protocol – SARS-CoV-2 RNA vaccine

AstraZeneca Clinical Trial Protocol – COVID-19 vaccine

Oxford Vaccine Trials – Participant Information Sheet: COV002 (July 2020)

Oxford Vaccine Trials – Participant Information Sheet: COV002 (Sept. 2020)

Willingness to vaccinate against COVID-19 in Australia

9 in 10 Australians say they would get vaccinated for COVID-19 – Ipsos

Global attitudes on a COVID-19 vaccine – Ipsos [PDF]

A future vaccination campaign against COVID-19 at risk of vaccine hesitancy and politicisation

Biopharma Leaders Unite To Stand With Science – Pfizer