I was struck by Professor Carl Heneghan’s comments to a House of Commons All Party Parliamentary Group reported last week. Like me, he is scathing about Medicines and Healthcare products Regulatory Agency’s (MHRA) safety management. In relation to MHRA’s strategies and proposals to improve medicine safety he said that “fine words butter no parsnips”. How true. I want to go a step further and explain why I think medicine safety will actually get worse, not better, unless MHRA learns from other safety critical sectors.
Unlike other safety-critical sectors, medicine safety is managed in relative terms, not absolute. Take aviation for example. Aircraft are designed to meet absolute safety targets such as the number of fatal incidents per million flying hours. In contrast, MHRA do not set safety targets for licensed medicines like ‘no more than x deaths or y serious adverse events’. Instead, MHRA licenses a medicine if the clinical trials data indicate that ‘the benefits outweigh the risks’. That’s a charter for collateral damage to start with.
It gets worse. In 2014, Patrick Vallance (then working for GlaxoSmithKline) told Health Ministers that “In the future, medicines will come to market quicker with less data, with more research being conducted in the post-license phase.” Imagine Airbus or Boeing telling the Transport Secretary that they intend to ignore absolute design safety targets, do less testing on new aircraft and then find the missed safety problems once they’re in service. Or nuclear power plants. Or oil/gas rigs. It would be ridiculous, but bizarrely, it’s okay for medicines.
On to the post-license phase. Other safety-critical sectors define absolute tolerable levels of in-service safety incidents and investigate them all. Not MHRA. They don’t define a tolerable level of harm, and they don’t investigate even just the fatal/serious Yellow Card reports and those involving children or pregnancy. It’s excuse is pathetic – it doesn’t have the resources (see slide 23 here). Instead, MHRA does statistical analysis of Yellow Card reports to compare the likelihood of different types of adverse events between different medicines. That’s a relative assessment of safety. And bear in mind that the vast majority of adverse events go unreported. So it’s a poor relative assessment at that. Nor does MHRA assess causation of Yellow Cards – to what extent was the reported fatal/serious adverse event caused by the medicine: definitely, probably, possibly, unlikely or not related. There are, of course, other aspects to MHRA’s pharmacovigilance but June Raine has confirmed that statistical analysis of Yellow Card reports remains “the most significant method” of its safety management (see slide 19 here).
To make matters even worse, MHRA knows that its statistical analysis misses safety signals:
a) In 2013, MHRA listed 27 medicines withdrawn on safety grounds since 1995. The average time on the market was 11 years. That’s how long it took MHRA to wake up to missed safety signals. Earlier this year, I asked MHRA to update the list to 2023 but they said it would cost too much to find the data.
b) In 2020, the Cumberlege Inquiry reported on two drugs and one medical device where MHRA missed safety signals for years. Sadly, the report’s recommendations tinkered around the edges. Indeed, the main one was the establishment of a Patient Safety Commissioner to “listen to patients” – a safety net, but it’s too late at that point anyway. There was nothing to improve the fundamentals of safety management because, as Appendix Five of the report confirms, the Inquiry had no input from those involved in managing safety in other safety critical sectors. That’s a failure soon to be repeated by the Covid Inquiry – Baroness Hallett is planning to appoint an independent vaccine safety expert but not any wider safety management experts. The Perseus Group offered to help but has so far been declined. The only glimmer of hope is that the Patient Safety Commissioner confirmed to me recently that she is “engaging beyond the healthcare sector to learn from other high-safety industries”.
c) For the Covid ‘vaccines’, MHRA admitted that it missed safety signals until mid-2022 when it changed its methods of statistical analysis. Ironically, one of those changes was to assess Covid vaccine safety against other drugs not other vaccines. But that works both ways – the safety of other drugs is now being compared against the Covid vaccines! Hands up if you think that’s a good idea.
d) MHRA’s statistical analysis uses signal detection thresholds. Setting low thresholds generates lots of potential safety signals which they don’t have the resources to investigate. Setting higher thresholds leaves more potential safety signals undetected.
The corollary to all of this is that those missed safety signals from all drugs down the years remain in the Yellow Card database and are incrementally baked into the baseline of MHRA’s relative statistical analysis of comparative drug safety. Day after day, the baseline of acceptability goes up and newer drugs can have more adverse events and still be considered acceptably safe because the older ones have safety issues undetected by MHRA’s statistical analysis.
It’s surely time for radical reform. We won’t though. We didn’t in 2004 when the House of Commons Health Select Committee published its report on the ‘Influence of the Pharmaceutical Industry’. We didn’t in 2009 with serious problems with Pandemrix, the Swine Flu vaccine. We didn’t after the Cumberlege Report in 2020. And we haven’t now despite the tsunami of evidence of harms from the Covid vaccines. The pharmaceutical industry is now too lucrative and too many doctors, the public and politicians are now addicted to ‘a pill for every ill’ that it now seems unstoppable. Depressing, isn’t it?
What’s the next ‘scandal’ going to be (apart from the Covid vaccines)? God knows. Perhaps it’ll be ‘SSRI antidepressants’. Serious concerns have been swirling around those for over a decade – which is, coincidentally, the average time it takes MHRA to wake up! Google ‘SSRI PSSD’ and judge for yourself.
Whatever it is, you just know there will be yet another medicine scandal along soon.
The fact is that there needs to be root and branch reform of MHRA and how it manages medicine safety. Sadly, that doesn’t seem likely – for example, the Government is already lining up to allow MHRA to rubber stamp anything licensed by the FDA or EMA. You have been warned.
Until Nick retired a few years ago, he was a Senior Civil Servant in the Ministry of Defence responsible for the safety and effectiveness of ammunition used by the Armed Forces. He is co-author of the Perseus Group report on U.K. medicines regulator the MHRA.
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