‘ENABLER’ is a peculiar choice of word to describe a regulator, but in light of the Medicines and Healthcare products Regulatory Agency’s (MHRA) role in the global launch of mRNA vaccines, it’s one that few would quibble with. Its Chief Executive Dr June Raine certainly doesn’t.
Appearing in December 2020 before the Commons Health and Social Care Committee in the self-congratulatory aftermath of MHRA’s issuance of a temporary use authorisation (TUA) for the Pfizer/BioNTech vaccine, she said: ‘This country has brilliant scientists. Their ability to move to areas of public health importance has been totally impressive,’ and that ‘The agency, which is an independent regulator, but formerly seen perhaps as a watchdog, should now become an enabler by active engagement earlier on with those brilliant scientists.’
In fact no British scientists had been involved in the development of the German/American Covid vaccine. Enabled by the MHRA, however, a new class of drug – mRNA ‘therapeutics’ – which delivers genetic information into the human body, arrived in the guise of a standard vaccine, and was lobbed on to the market via a regulatory wormhole.
It was a bold and hubristic opening act for an agency that had, so far as actually evaluating pharmaceutical drugs goes, been in hiatus for the quarter century since the European Medicines Agency (EMA) was created to harmonise the work of national medicine regulatory agencies. Hedley Rees, an expert in pharmaceutical manufacturing and operations, says that the MHRA lost the skills to evaluate drugs in 1995, when it all moved to the EMA in Canary Wharf: ‘The MHRA just pretended it had done the evaluation on the Covid-19 vaccines, and waved them all through’ (personal communication).
When the committee asked Dr Raine how MHRA accomplished the feat, she asserted, ‘As the Covid-19 pandemic is a public health emergency, we undertook to complete our scientific evaluation and approval in the shortest possible time, while complying with established and robust safety, quality and effectiveness standards.’
Parallel teams of clinicians and scientists worked on various aspects of the data, she said. ‘In the case of a rolling review – in this case – we reviewed data in packages or tranches as soon as they became available from the ongoing studies, on a staggered basis. By reviewing data as soon as it became available, we could reach an opinion sooner on whether the medicine or the vaccine could be approved.’
The European Medical Agency and the (US) Federal Drugs Administration were reviewing data submitted by Pfizer/ BioNTech at the same time. Raine argued that ‘they too have been able to look in a rolling way’ while claiming that it was ‘the flexibility and agility of the clinicians and scientists at the MHRA, coupled with their familiarity with vaccine development and approval and the access to independent expert advice, [that] was key to our ability to progress in the shortest time.’
However the purpose of the EMA rolling review differed from the MHRA’s. Its aim was to speed up the approval process by identifying gaps and deficiencies early, enabling the company to remedy them so that an approvable dossier could be submitted for final evaluation. On November 16, 2020, EMA product team peer review of the reports found much work needed still needed to be done, stating that: ‘Only partial information on the quality and non-clinical data has been submitted. Other modules of the dossier (eg clinical) have not been submitted.’
Proof of concept in animal models is normally required before human clinical trials begin. BioNtech had promised investors in April 2020 that, as part its Covid vaccine programme ‘Project Lightspeed’, it would produce ‘strong evidence of vaccine efficacy in animal models’. However the previous month Moderna’s Chief Medical Officer Dr Tal Zaks had openly admitted to an alternative reality, saying in March 2020: ‘I don’t think proving this in an animal model is on the critical path to getting this to a clinical trial.’
Unlike Moderna, BioNTech did run a non-human primate viral challenge test alongside its human clinical trials which underwhelmed the EMA with the methodology and results: ’Although the model is considered adequate to demonstrate immunogenicity and viral clearance, it is considered insufficient to demonstrate efficacy against the disease.’
The report pointed out that the young monkeys used in the study were not getting sick when challenged with the virus whether vaccinated or not. Efficacy, the EMA declared, would have to be proved in the human clinical trials.
On November 9, 2020, Pfizer issued a press release claiming their interim analysis showed a 90 per cent efficacy rate. Nine days later, on November 18, they announced that ‘after conducting the final efficacy analysis in their ongoing Phase 3 study’ their vaccine which they reported had been tested on 43,000 volunteers, had 95 per cent efficacy against Covid-19.
In the same week, on November 15, Moderna released its interim claiming analysis claiming an 94.5 per cent efficacy rate. Presumably by the time of the dosing of the Phase 3 volunteers (which began on July 27, 2020), Moderna had resolved the fundamental problem later admitted by Dr Zaks. It was that ‘during the first Phase 1 and 2 trials, nobody could actually measure in the blood whether this vaccine was working because people had to set up the assays as fast as we had to develop the vaccine.’
In fact BioNTech had dosed only 400 people with its mRNA products in cancer drug trials and had not previously tested any candidates against an infectious disease in humans, leaving open the question as to whether they were encountering the same problem Moderna was with assays.
On November 26, 2020, Dr Peter Doshi, the deputy editor of the British Medical Journal, issued a public caution over the companies’ efficacy claims, calling for scrutiny of the full data. Dr Doshi is an associate professor of pharmacy who is an expert in the drug approval process. Five weeks later he raised the alarm level further when he questioned ‘the trustworthiness and meaningfulness of the reported efficacy results’. A specific concern that he expressed was the manipulation of the Pfizer/BioNTech efficacy data through the removal of five times as many subjects from the vaccine arm of the study as from the placebo arm, thus raising the efficacy of the vaccine from 29 per cent to the headline 95 per cent rate.
Why didn’t the MHRA experts reviewing the company’s submissions make this same finding, or if they did, why did they ignore it? It is evident from Dr Raine’s words of reassurance to the public on the day the temporary use authorisation (TUA) was announced that the efficacy claim was given the greatest weight: ‘Safety is our watchword, and we are globally recognised for requiring the highest standards of safety, quality and effectiveness for any vaccine. Our scientific and clinical experts look at the safety, quality and effectiveness data for a vaccine.’
She insisted: ‘We robustly and thoroughly review it with scientific rigour. We pore over many pages of information and tables of data looking at a whole range of things from laboratory studies to the clinical trials and more. We particularly look at how the vaccine protects people from Covid-19 and the level of protection it provides (emphasis added). We look at the data on product stability and storage, we look at information on each step of the manufacture and on the controls used and on the controls used to make sure that each batch of the vaccine is consistently of good quality. And there are many other tests. No stone shall be left unturned.’
Matt Hancock’s Department of Health and Social Care asked MHRA for a temporary use authorisation for the Pfizer/BioNTech injectable on November 17, 2020. Even to a lay person reading the November 16 EMA assessment of the incomplete dossier, it’s evident that Hancock’s request was premature. The EMA report completely undermines Dr Raine’s claim that ‘no corners whatsoever were cut’.
Two years later Dr Raine, in a speech boasting of her mRNA enabling role, revealed the critical influence in this of Sir Andrew Pollard, Chief Investigator on the University of Oxford Covid-19 Vaccine (ChAdOx-1 n-CoV-19) trials and heavily involved in the development of a SARS-CoV-2 vaccine at Oxford, and how she and the head of the vaccine task force, Kate Bingham, decided to ‘tear up the rule book’.
In addition to authorising an entirely new class of medicine (mRNA), the product contained two excipients (constituents such as carriers, fillers or preservatives other than the active substance) that had notbeen authorised for use by the EMA and a third, which had been approved only for intravenous use, not for intramuscular use, which is how the Covid vaccines were administered. Excipients must be safety tested individually as they can constitute up to 90 per cent of a drug product.
Furthermore, each vial contained 0.45ml of the active drug substance which was to be diluted with 1.8ml of sodium chloride to make five doses of vaccine. The 2ml vials the drug was supplied in were too small to accommodate the 2.25ml of liquid that this step was meant to produce. This meant that vaccinators could not follow the manufacturers’ directions for use.
Good Manufacturing Practice regulations are meant to ensure that a product of reliable and consistent quality is produced. To upscale to commercial production levels Pfizer changed to a new manufacturing method referred to in the regulatory documents as Process 2. Not only was the percentage of intact mRNA produced using Process 2 manufacturing method variable, but the amount that survived intact when it was made into the drug product varied again even for mRNA originating from the same batch.
The encapsulation of mRNA in lipid nanoparticle (LNP) is a critical manufacturing step. The EMA states that the efficacy of the drug product depends on the size of the LNP. In the clinical batches used in the trials the LNP size ranged from 59-74 nanometers (nm). But instead of narrowing it to 68-71 nm for the emergency supply as appears to have been originally proposed, Pfizer was asking the EMA to widen the acceptable range from 40-180 nm. The variability in the percentage of intact RNA and of the size of the LPN carrying it into the cells may explain why some lots are deadlier than others.
The public might reasonably expect regulators like MHRA to assess the actual product they are enabling manufacturers to supply for use on the public, but the EMA assessment reveals that the testing of Process 2 batches on Phase 3 volunteers was irrelevant. It states: ‘The first doses from the Process 2 batch were dispensed on 19 October 2020, and the first subjects received dose 2 on 09 November 2020. As the cut-off date for the Interim Analysis (IA) was prior to 09 November 2020, the IA doesn’t include data from subjects dosed with Process 2 material, and the Company does not expect to have Process 2 included in the Final Analysis dataset either.’
Josh Guetzkow was one of the researchers who discovered that the Process 2 product was tested on only 269 trial participants ‘at most’. He told me: ‘What is most shocking to me is that the rate of adverse events for the Process 2 product is two and a half times higher than it was for the clinical batches.’
Batch EJ0553, which the MHRA authorised in December 2020, was sent to four sites in the US including the one where Maddie De Garay, a teenage girl left permanently disabled by the vaccine, was dosed on December 30, 2020. However Guetzkow says he and Dr Retsef Levi have been unable to determine what Batch EJ0553 was being used for in the trial as only 17 new main trial volunteers were dosed after November 19 (personal communication). Guetzkow says it may have been used for the children’s trial or possibly the booster trial that began almost immediately.
The American Food and Drug Administration’s (FDA) emergency use authorisation on December 11, 2020. Three days later Pfizer began smashing the control arm of the clinical trial by unblinding participants and offering the vaccine to those who had received the placebo. ‘By March 2021, 90 per cent of the placebo group had had at least one dose of vaccine. We think they were given the clinical batches, not Process 2,’ said Guetzkow. Even so, in Pfizer’s six-month report to the FDA the company reported significantly higher rates of adverse events in the former placebo group ‘as expected’ after they were given the actual vaccine.
Dr Raine told the Health and Social Care Committee that the MHRA had learnt ‘very important lessons about the imperative of engagement with developers in a proactive way from the earliest stages’ before saying: ‘When we think about the future, and the important role of vaccines in our switch to a preventative health care system, those vital therapeutic tools should be part of our national infrastructure. At the agency we look forward to the VMIC coming on stream – the Vaccine Manufacturing and Innovation Centre that our own inspectors and experts in the field have been working to help establish.’
Given Dr Raine’s vision of the MHRA as an enabler, we should all be worried about what’s coming next.