A year ago, Peter Selley, featured below got interested in the trials for an RSV vaccine.  I paid no heed but Peter had smelt a story.  Soon after I smelt a related story about efforts to enrol pregnant women in clinical trials.

Sixty years after we introduced Randomized Controlled Trials (RCTs) into the regulations governing the licensing of drugs, aimed at forestalling catastrophes like the birth defects caused by thalidomide, we were now for the first time running trials in pregnant women.  A story, an arc of history, has come full circle.  What could we, might we, learn from this.

There are two versions of this talk.  One by me alone which is here in English – it was due to be given in Bruxelles but was cancelled at the last minute because of venue issues.  It has been translated into French by Ariane Denoyel – Femmes Enceintes et Essais Cliniques.  The slides below feature in the Solo Video Version Here and in French version.

The other version involves both Peter and I and his set of slides which form the beating heart of this talk have some overlaps with and some differences from mine.  Peter and David Duet is Here.

Slide 1:            Peter Selley, whom you see above, is primarily responsible for the research on the RSV vaccines in this talk.  I provide the framework which you might call the ethical or the marketing issues – its increasingly difficult to distinguish ethics from marketing.

Slide 2:            My entry to these issues came when asked to write a chapter for a book being edited by bio-ethicists I know and respect. I assumed the book would feature the hazards of pregnancy research.

Not so.  The book was in favour of more research on pregnant women and the chapter by Dee Mangin and I saying letting pharmaceutical companies near this area was a bad idea and that RCTs do not offer the gold standard evidence that people claim, was the exception.

The view the book was leaning toward seemed naïve to me. But strange things have happened lately. I’ve worked with lawyers who fought pharmaceutical companies on SSRI and other drugs and know all the tricks but who in the case of the Covid vaccines pretty universally figured companies like Pfizer will have played things straight. I found it hard to believe these hard bitten hombres thought this this way.  I was more inclined to think Leopards don’t change their spots.

Slide 3:     Here is – for me – the key slide in this talk.  Its the Oval Officer and John F Kennedy has just signed the 1962 Food and Drugs Act and is handing the pen over to Frances Kelsey who stood in the way of the licensing of Thalidomide in the USA.  She is the only woman in the room.

The 1962 Act was all about Drugs in Pregnancy.  It replaced a 1938 Act which centred on Safety and the judgement of a woman like Kelsey with an Act that stressed Efficacy and replaced human judgement with an Algorithm.  Regulation generally is about Safety – whether Food, Traffic, or Stock Markets.  Its strange that the one place where Efficacy triumphs over Safety is in the case of Medicines – which are unavoidably risky.

Slide 4:            The 1962 Act may explain this intriguing graph which shows that at a time when women don’t take alcohol or even eat cottage cheese while pregnant, there has been a steady increase in the number of meds they take – white university educated women leading the way.

Slide 5:            The US government is now pushing to get pregnant women in trials as part of an empowerment agenda. The chapters here all advocate the involvement of pregnant women in research, especially RCTs.  Women, they say, are not vulnerable subjects.  When pregnant, more than at any other time, they need to have good evidence and it is not good enough to find that doctors can offer none.  These are all reasonable positions and they point toward Randomized Controlled Trials (RCTs) which it is believed offer Gold Standard evidence.

Slide 6:            The changing climate is reflected in the imagery here.

Slide 7:            When it comes to RSV research, Bill Gates has been a major donor both to studies in pregnancy and to efforts to change the climate about vaccines in pregnancy.

Slide 8:            RSV vaccines have a history. In the 1960s, the first vaccine had a grim outcome – more children on the vaccine died and we recognized the phenomenon of Vaccine Associated Enhancement of Respiratory Disease (VAERD) which has haunted vaccines ever since.

Slide 9:     This article from 25 years ago make the case that any of us entering clinical trials hoping to benefit family, friends countrymen are in fact putting everyone we know in a state of legal jeopardy.  How so?  Well companies have decided that unless an RCT shows something to be happening to a statistically significant extent – then its not happening.  So you get injured in a company trial and you vanish and companies use the absence of any injuries in their trials as evidence against anyone else who is then injured in trials on their drugs or vaccines.

The man you see here is Ian Hudson – the Chief Safety Officer of GSK – essentially stating under oath that our drug paroxetine causes no problems at all.   This is at a trial triggered by Don Schell being put on Paxil and 48 hours later shooting his wifec, his daughter and 9 month old grand-daughter and then himself.  Hudson is saying there is no evidene our drug could have done this – the jury disagree and in fact GSK’s trials show their drug could do it. But Hudson later became the Head of Britain’s drugs regulator and this is the view ensconced at the top of all regulators – FDA – EMA and WHO.

Ian now works for the Gates Foundation and so his views continue to have some weight in the places that count.

Slide 10:      This much more recent article covers Covid Vaccine consent forms, which seduce us into trials telling us that if injured call the investigator – giving the phone number, and that Pfizer and other companies have insurance policies – giving the number.  But the companies have no intention of honouring this.  People injured in the trial like Augusto Roux and Bri Dressen disappear.

The man in the middle is Mark Barnes, receiving an award as litigator of the year. Barnes is perhaps the single most interesting person in these developments.  In 2009 Pfizer were fined over $2 Billion for failures to properly inform doctors of drug hazards. Soon afterwards Barnes who works for Ropes and Gray set up MRCT – which was AllTrials before AllTrials – set up after GSK were fined $ 3 Billion.  MRCT and AllTrials completely support the Hudson view and MRCT have likely helped WHO issue instructions to clinical trialists in vaccine trials – to never link an adverse event to a vaccine in a trial.  See Harmatology.

Slide 11:      Clinical trials are dangerous for patients and terrible for doctors and the public given that we do not get to see the data – Not Even FDA sees the data.  But if you are an investor in the company, a little over a decade ago, the US Supreme Court decided you have rights to see the data and make up your own mind as to what those data mean.  You will see this is a pertinent issues in the RSV vaccine trials.

Slide 12:          Finally here is part of the consent form for Pfizer’s RSV vaccine trial.  You but not your baby are getting the vaccine and so there is no risk to your baby?  Is this reasonable?  And remember when getting recruited to a trial, a woman is likely to be lying on her back with some doctor having their hands on her abdomen.

You notice the word Advarra here.  What we call Ethics Committees in Europe, were IRBs in the US but have now become businesses and consolidated down to 2 or 3 big companies – one of which is Advarra, in which Mark Barnes has a key role.  These businesses often write much of a trial protocol, they then approve.  They are among the most profitable businesses now to invest in – more so than the companies that run trials that can go wrong.

You are now going to hear a lot more details of other RSV trials.  If you were a pregnant woman considering entering Pfizers’s phase 3 trial, should you have been told about what you are about to hear?

Slide 13:      Which brings us to Pfizer’s RSV vaccine trial – Matisse – which is just led to licensing of this vaccine for RSV.

Slide 14:          First we need to visit GSK. In a trials that was drafted in 2016, they applied for NHS Ethics Committee approval for their RSV PED-003 vaccine. The committee were unimpressed with the idea of taking blood from infants to measure antibodies – measuring infections was reasonable but antibodies are irrelevant and a lot blood tests on infants did not seem a good idea. GSK were given an unfavourable opinion and the trial never took place in the UK.  It took place elsewhere but there are no results to show for it.

Slide 15:           At the same time GSK were running their Grace study – an RSV PreF vaccine for pregnancy. This terminated early.  Nobody except their investors were any the wiser as to what went wrong.  No journal articles etc. The company later told regulators there was a premature birth issue.

Slide 16:          It was a year before anyone else found out what was up.  In a presentation, GSK gave figures for premature births but also neonatal deaths, which were doubled.  They had no idea what was going wrong and no evidence their vaccine was the cause.

Slide 17:          This slide at a recent talk gives some of the take home points – prematurity was commoner in women in LMIC countries. Having another vaccine, GSK said, lowered the prematurity rate but increased the difference between vaccinated and placebo – the vaccinated of course now had two vaccines and this happened while women were being encouraged to be vaccinated for Covid.

Slide 18:     What do you make of this?  This trial of a Covid vaccine in pregnant women was abandoned.  You can believe the story that almost all pregnant women were already vaccinated if you want.   Pfizer committed to keeping a pregnancy registry but this has never materialized.

Slide 19:          Against this background, NEJM publish Pfizer’s RSV vaccine Phase 2 trial. Usually an article like this looks like the final publication but now they are interim publications – and we may never have a final publication.  This Weathervane publication claims the vaccine works well and is safe.  The first author is Eric Simoes.

Slide 19:          The paper states that there were 15 premature births across all groups in this trial – it does not tell us that 14 of these 15 were in the vaccinated group.

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