23rd September 2021
With all medical eyes on COVID19, a cardiovascular drug with no proven benefit – at all – has been approved by NICE (The UK National Institute for Health and Care Excellence). Once a drug is approved by NICE it can, and will, be prescribed by doctors in England and Wales and Northern Ireland. Scotland has its own system.
NICE is also hugely influential beyond this small island. A NICE approval usually means a green light for approval in many other countries as well. Countries who assume that NICE will have carried out an in-depth ‘expert’ analysis using a set-up that they don’t have yet.
Which means that drug companies are always very keen to get NICE approval. It is a de-facto quality stamp. ‘This drug is both safe and cost-effective. You may now prescribe it everywhere in the world…’
Cost-effectiveness means that a drug does not just provide some clinical benefit. It must provide benefits that give you decent bang for your bucks. The ‘bang for your bucks’ measure used is the Quality Adjusted Life Year (QALY).
A QALY = one year of perfect health.
Of course, no healthcare intervention will ever give you one extra year of perfect health. Nothing is ever as clear cut as that. However, if you are suffering from a painful arthritic hip – and your quality of life is 50% perfect, or 0.5 – and you get a hip replacement, then your quality of life may rise from 0.5 to 0.9. So, you get 0.4 of a QALY/per year improvement.
After five years you have gained 0.4 (QALYs) x 5 (years) = 2 QALYs.
If the hip replacement operation has cost £10,000. The cost per QALY = £5,000. The cost per QALY obviously goes down if you live longer. That is a very simple example, most calculations become exceedingly complex. Measuring quality of life, for example, is fraught with difficulties.
In general NICE will approve a healthcare intervention if the cost per QALY is less than £30,000. This figure can never be pinned down. I often liken it to a blob of mercury. If you try to pick it up, it just slips, and slides, and fragments.
Indeed, this £30,000 figure never had any economic basis, or any other basis. It was simply plucked from the air because … well, because it seemed reasonable.
Here, from a discussion in the UK Parliament when NICE was first starting up:
‘There is clearly confusion about the cost per QALY threshold. Witnesses questioned whether there was any evidence to support the level that appears to be used. Professor Devlin told us that, “the threshold has no explicit basis or location in evidence”. Others agreed that it was “arbitrary”. Professor Smith confirmed…
Professor Rawlins admitted that the threshold was not based on “empirical research” as no such research existed anywhere in the world. He told us instead that the threshold was: …really based on the collective judgment of the health economists we have approached across the country. There is no known piece of work which tells you what the threshold should be.
No public discussion has ever taken place of the suitability of the threshold used. The American Pharmaceutical Group pointed out that the threshold has “never been the subject of public debate or Parliamentary approval. Cancer Research UK also argued that the threshold should be discussed openly and the reasons for its level should be determined in consultation with interested organisations.’ 1
I love it when people say things like ‘the threshold has no explicit basis or location in evidence.’ The short word – no – would have done nicely. As in, there is no evidence. Instead, we get the concept of no explicit basis or location in evidence. Listen guys, just get rid of the words: explicit, basis, or, and location. Why use five words when one will do?
Anyway, it has always amused me that NICE spends vast amounts of time and effort trying to establish with great accuracy whether a healthcare intervention meets a cost per QALY threshold… that was simply made up.
You might as well have got a cane with a hook on the end to pluck one of a thousand plastic yellow ducks floating in a pond with a random number written on the bottom. ‘Oooh look, it says thirty thousand… so that is the figure we shall use.’ Yes, really.
Anyway, as custom is king, this £30K figure – which has remained unaltered for twelve years [has anyone at NICE ever heard of inflation – or maybe a made-up figure cannot be affected by inflation] is unquestioned, and unquestionable. It is carved in stone. ‘And God did sayeth unto the multitude that thirty thousand pounds per QALY shalt be my law unto the end of time. Amen.’ Anyway, following that little history lesson, let us gaze upon the cost per QALY calculations that NICE used for Inclisiran – a new LDL lowering injection to be given twice a year. And below are the calculations [or at least the calculations that I could be bothered to copy]:
As you can see Inclisiran meets the cost per QALY criteria with ease. Well, actually, in truth, you cannot see anything because all the figures have been redacted. It amuses me further that NICE have decided that a table which contains no information of any use is ‘confidential’. Well, of course, it is not very confidential, because I can see it, and so can you, if you decide go to: https://www.nice.org.uk/guidance/gid-ta10703/documents/1
So, which part of that completely pointless table is confidential? It is clearly not confidential that it is confidential. Maybe this is some strange double-bluff. Perhaps you can scrape away the black areas to reveal the numbers beneath, and win a million-pound prize?
I suspect that written beneath them will be the phrases. ‘How much?’ ‘You’re having a laugh.’ Or ‘We will not release your family unless you pay this as ransom.’ And suchlike.
Enough of this. NICE is a public funded organisation that is supposed to work on our behalf. They have decided that Inclisiran is cost-effective, yet they will not let anyone see the figures that they used? You would think they would be shouting it from the rooftops. ‘Look how fantastic it is. Look at the size of that discount. Gaze with wonder on the magnificent cost-effectiveness of Inclisiran.’ No, instead, they are very shy about it. Like little meercats sensing danger and scurrying down into the darkness.
Without any figures, the NICE appraisal is essentially hundreds of pages of utterly meaningless guff. As I used to say, once upon a time, when teaching my children to count. ‘One two, miss a few, ninety-nine, one-hundred’.
How much are we paying for Inclisiran? Nobody knows. Because NICE won’t tell us. We know it should be/could be around £4,000/year ($5,000). So, some sort of discount has been negotiated. How much … well, that’s a secret. A secret. Why? In case we all rush round to Novartis headquarters and try and buy some at a bigger discount?
Secret or not, the truth is that I do not need to know the exact cost of Inclisiran. Because I already know that whatever it costs, the cost per QALY current stands at infinity i.e., ∞. I know this because, at present, there is no evidence that it provides any benefit, on any clinical outcome. By which I mean no evidence that it prevents strokes, heart attacks or, in fact, anything.
Based on this knowledge the Cost per QALY equation goes something like this:
Cost per year of Inclisiran/benefit in QALYs = cost per QALY
With Inclisiran let us set the cost per year at £4,000, and benefit at zero:
£4,000/ 0 = ∞ (infinity)
Let us set the cost at £1 and run the equation again
£1/0 = ∞ (infinity)
You see how simple it is to work out the cost per QALY when there is no benefit. It always ends up at infinity. If it cost one Turkish lira, the cost per QALY would still be infinity. I certainly did not need several hundred pages of guff to tell me this. You ought to try reading an endless NICE report sometime. My advice is, don’t bother.
Anyway, if you do read what NICE has to say about Inclisiran you will find the following key sentences in the NICE appraisal documentation.
‘There is also no long-term evidence on whether Inclisiran reduces cardiovascular events. This means the clinical evidence and the cost-effectiveness estimates are very uncertain.’2
Let me rephrase the first sentence.
THERE IS NO EVIDENCE THAT INCLISIRAN WORKS
Let me rephrase the second sentence
THIS MEANS, THE CURRENT COST-EFFECTIVNESS ESTIMATES ARE NONSENSE
Yes, it lowers LDL (low density lipoprotein), we do know that. We do not know if this will have an impact on cardiovascular deaths, or overall mortality. NICE assumes that if you lower LDL, you will reduce cardiovascular death – and suchlike.
However, this is not necessarily true. Repatha (evolucamab) is a drug which has exactly the same mechanism of action as Inclisiran but needs to be given every two weeks instead of twice a year. Both Inclisiran and evolucamab are PCSK9-inhibitors. [They block the breakdown of LDL-receptors in the cell, which means that more LDL receptors are available to pluck LDL molecules from the blood, thus reducing the blood levels]. Both drugs reduce the LDL level by pretty much the same amount.
In the FOURIER study on Repatha the results were the following
Cardiovascular mortality – total numbers:
Repatha = 251
Placebo = 240
Overall mortality
Repatha = 444
Placebo = 4263
Yes, Repatha lowered LDL to the same degree as Inclisiran and yet slightly more people died taking Repatha than died taking placebo. Repatha has been approved and launched, although you may wonder how or why.
In short, just because a drug lowers LDL does not mean it does any good. Just to give another example, the drug evacetrapib lowered LDL by 37% (and increased HDL by 132%). It, too, had absolutely no impact on cardiovascular mortality.
‘Although the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease.’ 4
Just in case you are wondering, Evacetrapib did not launch. Nor did another three drugs in the same class that all had ‘favourable effects on established lipid biomarkers’ but achieved nothing. One of them, torcetrapib, increased cardiovascular death by 50%.
In short, approving drugs, or launching drugs before you have any evidence that they do anything – other than having a favourable effect on an established lipid biomarker – is ridiculous. But never mind, longer term studies on Inclisiran will be completed by 2023, and 2026. When will they actually be published?
Who cares, by the time they are published, Inclisiran will have made billions, and no-one will care if the results are positive, or negative, as it will have become established as ‘standard’ treatment.
A number of us found the NICE approval of Inclisiran so ridiculous that we wrote them a letter. (See below). I do not imagine it will have the slightest impact.
To: Sharmila Nebhrajani OBE,
Chair: National Institute for Health and Care Excellence
2nd Floor, 2 Redman Place
London E20 1JQ
cc. The Right Honourable Sajid Javid, MP Secretary of State for Health and Social Care Department of Health
Richmond House 79 Whitehall London, SW1A 2NS
15th Sept 2021
Concerns about the latest NICE draft guidance on Inclisiran
Introduction:
We are concerned about your draft final guidance recommending the novel anti-cholesterol drug inclisiran (Leqvio and made by Novartis) for people with primary hypercholesterolaemia or mixed dyslipidaemia who have already had a cardiovascular event such as a heart attack or stroke.
We would ask for this decision to be over-turned immediately until there is enough data to support any hard outcome benefit of Inclisiran, namely the prevention of heart attacks, strokes or death.
Our main concerns are addressed in six key areas:
1. Inclisiran is an investigational drug in the UK
Inclisiran gained approval by the European Medicines Agency in Dec 2020, however, the drug remains unapproved in the UK (which is not part of the European Union) since 31 Jan 2020 and other major nations. The novel PCSK-9 inhibitor has not been approved by the US Food and Drug Administration.
We would recommend however, that a full appraisal of the Inclisiran trial data and marketing license be obtained by UK’s Medicines and Healthcare products Regulatory Agency prior to rolling out the drug to patients in the NHS.
2. Lack of transparency in NICE decision making process
The decision for NICE follows an agreement on a population-level commercial deal between NHS England and NHS Improvement and Novartis which will make inclisiran available with a discount to its list price.
The full details to the pricing agreement have been kept confidential and not available for independent scrutiny. This lack of transparency should be of concern to the British public, prescribing doctors and taxpayers who fund NICE.
3. No long-term data on effectiveness or safety
To date, the trials are short term, only 18 months. NICE’s daft guidelines acknowledge this issue. “The committee was concerned that there was a lack of long-term data on cardiovascular outcomes from the clinical trials that compared Inclisiran with placebo. However, it noted that ongoing clinical trials would provide more data on these outcomes.”
We propose that more long-term data on safety and efficacy is accumulated before recommending Inclisiran, even as an adjunct to statin therapy.
4. Decision based on a surrogate marker (LDL-C)
Inclisiran, the novel PSCK-9 inhibitor is effective at lowering Low Density Lipoprotein cholesterol (LDL-C), however, mounting evidence demonstrates that it is a weak surrogate marker of cardiovascular disease.
The push to lower cholesterol with statins to prevent heart disease has been hugely influenced over the years by meta-analyses performed by the Cholesterol Treatment Trialists Collaboration at Oxford University researchers.
The CTT suggests that there is a linear relationship between LDL-C reduction by statins and the reduction in risk of cardiovascular disease. The individual patient data, upon which they make these claims, is not accessible to third parties for independent scrutiny.
NICE justifies its decision to be guided by the CTT in its recommendations “The clinical experts stated that the CTT meta-analyses were appropriate and that a similar relationship between LDL-C lowering and a reduction in cardiovascular event risk as seen with statin use could be expected with Inclisiran.”
However, it should be noted that statins have pleotrophic effects – anti-inflammatory and anti-thrombotic – that may be responsible for the benefits seen in secondary prevention patients.
Further, there is conflicting evidence that LDL-C is a causal factor in heart disease. A 2020 recent study published by Danish researchers, for example, demonstrated that LDL-C the lowest risk of all-cause mortality was found at an LDL-C concentration of 3.6 mmol/L (140 mg/dL).
In comparison the highest association with all-cause mortality was actually at LDL-C levels of less than 1.8mmol (70mg/dL).
Notably, NICE recommendations suggest that people with LDL-C concentrations persistently 2.6 mmol/l or more, despite maximum tolerated lipid-lowering therapy, should be on Inclisiran. This has no independent scientific basis.
Although the NICE recommendation is specific to patients with either previous cardiovascular disease or FH such a well-publicised recommendation feeds into a false narrative that the lower the LDL-C the better when it comes to overall health and/or managing cardiovascular disease. It’s instructive to note that there is also no difference in levels of LDL-C in patients with FH who developpremature heart disease versus the one’s that don’t suggesting that LDL-C is not the main driving factor for the development of coronary artery disease in these patients.
Furthermore, an independent peer reviewed systematic review of drug trials carried out by three cardiologists in 2020 published in BMJ Evidence Based Medicine revealed that there was no clear relationship with reduction in LDL in both high risk and low risk patients in reducing cardiovascular events.
5. No evidence for cardiovascular benefit with Inclisiran lowering LDL-C
Low Density Lipoprotein cholesterol (LDL-C) has been the primary outcome of the clinical trials. While we agree that Inclisiran demonstrates effective reduction in LDL-C, we find that the clinical data to support the benefit of cholesterol lowering is absent.
An analysis by the European Medicines Agency (EMA) found there was a “lack of cardiovascular outcome data” in the regulatory documents sent to the drug agency.
It also found that “the number and percentage of deaths was comparable between the placebo and the Inclisiran group, but numbers are too small for clear conclusions.”
“In addition, no definite data on cardiovascular morbidity and mortality are currently available,” the report stated.
NICE’s own guidelines state, “there is also no long-term evidence on whether inclisiran reduces cardiovascular events. This means the clinical evidence and the cost-effectiveness estimates are very uncertain”.
Given that Inclisiran has not proven to reliably reduce major cardiovascular events, cardiovascular morbidity, or mortality, we believe a decision to recommend this drug based is premature.
Two studies, ORION-4 in secondary prevention and ORION-17 in primary prevention are currently underway.
6. Loss of professional confidence
The lack of transparency in the decision-making process may undermine professional and public confidence in NICE and its decision-making processes. This could be critically damaging to professional confidence in the delivery of evidence-based healthcare in the UK
In light of our concerns, we urge you to withdraw the current guidance on Inclisiran for people with primary hypercholesterolaemia or mixed dyslipidaemia who have already had a cardiovascular event such as a heart attack or stroke until further important clinical data with clear cardiovascular benefits are made available.
Your Sincerely,
Dr Aseem Malhotra FRCP, Consultant Cardiologist, Professor of Evidence Based Medicine and Chairman of The Public Health Collaboration.
Sir Richard Thompson, Past President of The Royal College of Physicians
Dr JS Bamrah CBE, Consultant Psychiatrist and Chairman of BAPIO (British Association of Physicians of Indian Origin)
Dr Campbell Murdoch, General Practitioner and Royal College of General Practitioners – Clinical Advisor
Dr David Unwin FRCGP, General Practitioner, Vice Chair – The Public Health Collaboration.
Dr Malcolm Kendrick, General Practitioner and author.
Sherif Sultan, Professor of Vascular Surgery, President of International Society of Vascular Surgeons. Shahriar Zehtabchi, MD, Professor of Emergency Medicine, State University of New York
Postscript:
The Cholesterol Treatment Triallists Collaboration (CTT) in Oxford is the group that hold all evidence from cholesterol lowering trials that have been done on statins. They will not release this evidence, or allow anyone else to come into their unit see it.
The meta-analyses carried out by the Cholesterol Treatment Triallists Collaboration (CTT), using the data that only they can see, using the evidence only they hold, has established that the risk of cardiovascular event is reduced by a set amount, for every 1mmol/l that LDL is lowered. (1mmol/l = 38.67mg/dl. Mg/dl is the form of measurement used in the US)
‘The CTT Collaboration has shown that lowering LDL cholesterol using statin therapy reduces the risk of major vascular events (heart attacks, stroke or coronary revascularisation procedures) by about one fifth for each 1 mmol/L reduction in LDL cholesterol achieved.’5
This was the evidence used by NICE to establish that LDL lowering can be used as a ‘surrogate end-point’ i.e., the CTT ‘know’ that if LDL is lowered this will – for certain – result in a known reduction in cardiovascular end-points.
‘The company (Novartis) used the Cholesterol Treatment Trialist Collaboration (CTT)meta-analyses, which reported change in cardiovascular event risk per1 mmol/l reduction in LDL-C by statin use. The ERG agreed that these analyses were appropriate and noted that earlier versions of this source were used in past NICE technology appraisals in this disease area.’
It should be noted that the Cholesterol Treatment Triallists Collaboration (CTT) is part of the Clinical Trials Service Unit in Oxford (CTSU) 6. This unit has received hundreds of millions of pounds in funding from pharmaceutical companies, primarily those who market cholesterol lowering drugs.7
The Clinical Trials Service Unit (CTSU) in Oxford is currently running, and co-ordinating, the various ORION studies that are being done on Inclisiran. For example, ORION-4, as can be found on the CTSU website:
‘ORION-4 is a research study which aims to find out if a new cholesterol lowering injection safely reduces the risk of heart attacks and strokes in people who have already had one of these conditions, or who have had an operation or procedure to unblock their arteries.’8
Thus, NICE are using the meta-analysis created by the CTT to make the decision that Inclisiran will reduce cardiovascular events, purely due to the effect on LDL lowering.
The CTT hold all the data that make up the meta-analysis used by NICE – and will not allow any independent researchers to see it.
The CTT are part of the CTSU which has run, and continues to run, many pharmaceutical company sponsored studies on LDL/cholesterol lowering drugs. For which they have received hundreds of millions in funding. The CTSU is the group primarily responsible for running the clinical trials on Inclisiran.
Yet, and yet. If you look at the final stakeholder list of consultees and commentators for the Single Technology Appraisal:
NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE
Single Technology Appraisal
Inclisiran for treating primary hypercholesterolaemia or mixed dyslipidaemia
[ID1647]
Final stakeholder list of consultees and commentators
…if you look closely, the CTT and CTSU do not get a mention 9. It is as if they simply do not exist. And there are literally hundreds of stakeholders. Running from the British Cardiology Society, to the Cochrane Cystic Fibrosis and Genetic Disorders Group, and NHS Bradford City CCG.
Yet, the CTT/CTSU hold on the data for the meta-analysis upon which the entire approval process rests. They are the people running the clinical trials on Inclisiran. And no-one at NICE thought it might be a good idea to speak to them? Are they not, stakeholder number one? Why so coy?
One could even argue that NICE have breached their own guidelines by failing to speak to the most important stakeholder of all.
1: https://publications.parliament.uk/pa/cm200708/cmselect/cmhealth/27/2707.htm
2: https://www.nice.org.uk/guidance/gid-ta10703/documents/final-appraisal-determination-document
3: https://jcbmr.com/index.php/jcbmr/article/view/35/75
4: https://pubmed.ncbi.nlm.nih.gov/28514624/
5: https://www.ctsu.ox.ac.uk/research/ctt
6: https://www.ctsu.ox.ac.uk/research/ctt
7: https://www.zoeharcombe.com/2014/08/ctsu-funding-from-drug-companies/
8: https://www.ctsu.ox.ac.uk/research/orion-4 9: https://www.nice.org.uk/guidance/gid-ta10703/documents/final-matrix
Dr. Malcolm Kendrick 