Issue #60: The ultimate clinical trial

Written by Nobel Laureate Professor Peter Doherty

Over the past weeks, we’ve been considering the various types of trials, both in animals and in humans, that are required before a drug or vaccine can be approved for human use (#53-#59). That discussion ended with a brief account of the penultimate trial, in this case the double-blind, randomised Phase III vaccine trial that involve tens of thousands of volunteers who vary in age, ethnicity, gender and, as such trials can only be done in sites where the virus is circulating at a high level, location (#59). All that data has to be cumulated, analysed and presented by the company conducting the trial – with central input from the trial’s fully independent DSMB (data safety monitoring board) – to key regulatory agencies like the US FDA, the European EMA and Australia’s TGA.

Top regulators like the FDA will have been involved at every stage of, at least, the human Phase I to Phase III trials, and will have been allowing those trials go forward. At the end, the FDA’s highly professional scientists and medical doctors scrutinise the Phase III data in great detail before approving any drug or vaccine for wider use. Even an Emergency Use Approval (EUA) will likely take at least a month of intense effort. Thereafter, the regulators will also be monitoring for the possible untoward side effects as the number of people involved goes from tens of thousands to tens of millions, and beyond. With any new product we are, in effect, participating in this ‘Phase IV trial’. There, monitoring by the regulators is greatly enhanced by the statistics collected by hospitals and public health agencies.

For the next few weeks, I’ll touch lightly on some questions that have been widely asked since vaccines began to roll out in Australia and, particularly, since the ‘highly infectious Indian’ B1.617.1 variant (the k mutant under the new WHO nomenclature) ‘escaped’ from hotel quarantine and, once again, triggered a ‘circuit-breaker’ lockdown across the state of Victoria. Later in the year, I’ll come back to many of these topics in greater detail. With regard to the current lockdown, my only comment is that the Victorian public health authorities are doing exactly the right thing and, I think, just about everyone understands that.

Our role, as we house the central virus diagnostic reference laboratory (VIDRL) – led by Mike Catton, who, with Julian Druce and their team, got the SARS-CoV-2 PCR test up and running back in January, 2020, confirmed the first Australian case later that month, isolated the infectious virus and distributed it to all legitimate laboratories across the planet that requested it – is to do large numbers of PCRs while monitoring the integrity of that effort across the state. In addition, the MDU (Microbiological Diagnostic Unit Public Health Laboratory) led by Ben Howden (they normally deal with bacteria and fungi) has been sequencing the SARS-CoV-2 ‘product’ recovered by PCR and is doing the genomic analysis that is of such great importance to the contact tracers in the public health arm. And, if we do have substantial numbers of clinical cases (we hope not!) our VIDS (Victorian Infectious Diseases Service) infectious disease physicians, research nurses and so forth who work also in the hospital wards, will be heavily involved.

In Australia we have, as everyone is well aware, current access to only the locally made (by CSL/Sequirus) adenovirus vectored ChAdOx1 AstraZeneca (AZ) vaccine, and a more limited, imported supply of the PfizerBioNTech (PB) mRNA vaccine (#43, #49). Initially, from the human trials, it looked like the mRNA vaccine was somewhat more effective. But, when Public Health Scotland, then PH England (the UK also uses these two vaccines) reported back on what was happening in the community, it seemed both work equally well at preventing both severe and relatively mild disease. Of course, vaccines may be of little value to those who are severely immunocompromised, due to advanced age or some other ‘co-morbidity’.

Currently, the available data from the UK that’s relevant to the k variant suggests that one dose of either vaccine protects about 35% against any clinical disease while, with completion of the two-dose homologous (with the same product) prime and boost regime, it seems that PB is about 80% effective compared with 60% for AZ. Even so, because of the long interval (12 weeks versus three weeks), this may be a bit biased against AZ. And, while there’s as yet no published data, those reporting these results suggest that one or two doses of either vaccine will provide much greater protection against severe disease. We can only hope!

The nasty surprise with the AZ vaccine, and with the adenovirus-vectored J&J vaccine used in the USA, was that these products cause potentially lethal blood clots in a small number of, particularly, healthy young women. First detected in Norway and rigorously analysed in Germany, this Thrombosis with thrombocytopenia syndrome (TTS) is, according to our TGA, occurring in about 1:100,000 of those under 50, or 1:200,000 for older subjects. This can happen from four-30 days after the first AZ dose. Fortunately, while this is still a very severe complication, treatment has greatly improved. Any recent vaccinee with one or more severe symptoms (headaches, blurred vision, nausea, vomiting) should seek help immediately.  To be continued…