November 16, 2022

expert reaction to NICE draft recommendations on the use of treatments for COVID-19

The National Institute for Health and Care Excellence (NICE) have released their draft guidelines on therapeutics for people with COVID-19.

Dr Lennard Lee, Academic Clinical Lecturer and Medical Oncology Consultant, University of Oxford, said:

Does the press release accurately reflect the science?

“For the first time, NICE has reviewed drugs used to treat COVID-19.  They have recommended that five treatments are no longer used in the NHS.

“Without further R&D efforts, this will have most significant impact on patients at the highest risk, such as those who are immunocompromised, the elderly and the unvaccinated.

Is this good quality research?  Are the conclusions backed up by solid data?

“NICE declares that their recommendations are uncertain and that their key cost-effectiveness analyses are affected by hospitalisation rates.  Hospitalisation rates vary with different SARS-CoV-2 variants.

How does this work fit with the existing evidence?

“It is a summary of the existing evidence in the literature.

Have the authors accounted for confounders?  Are there important limitations to be aware of?

“The main limitation is that cost-effectiveness analyses are reliant on coronavirus being mild.  If case- hospitalisation rates, case-intensive care rates or case-death rates are higher in certain groups, then the calculations would be confounded.

“For example, if subgroups of patients are known to experience very high rates of hospitalisation, then the treatments may become cost-economic.  The authors were keen for this data and noted this as a limitation to their recommendations.

What are the implications in the real world?  Is there any overspeculation?

“The real world implication is that patients who have low protection from coronavirus vaccination, such as the immunocompromised and those with cancer, are critically dependent on getting access to timely coronavirus treatments following infection, in order to prevent more severe outcomes.

“Assessment of drugs based on effectiveness and cost-economic analyses needs to be holistically balanced with drug alternatives, clinical demand and disease severity.

“Many vulnerable and immunocompromised patients are still shielding as they face higher risk during the pandemic.  Taken in isolation, without further resourcing of new treatments for them, removing drug access is likely to add to ongoing concern by this group that they have been forgotten.

“There is no overspeculation in the press release.”

Dr Stephen Griffin, Associate Professor at Leeds Institute of Medical Research (LIMR), University of Leeds, said:

“Therapeutics are a major factor in the Government’s “living” with COVID strategy as they provide a safety net for those unable to make beneficial responses to vaccines.  Of course, prevention is always better than cure, but without appropriate provision of such medicines the current strategy will leave even more people open to disease than the >26K that have already died this year in the UK from supposedly “mild” Omicron infections…or the >2M people currently living with Long COVID symptoms, including children.

“NICE has a difficult job to do appraising the cost effectiveness of medicines.  However, I struggle with the logic applied to some of these decisions which are seemingly highly risk averse due to a lack of recent trial evidence and a general unease around viral diversity and the Omicron sub variants.  In particular, I am astonished at the decision not to approve the Evusheld combination antibody.  The Crick study mentioned in the report shows that the Cilgavimab component still displays neutralising activity against BA.5.  Moreover, it is important to note that this is primarily a prophylactic therapy, which could help clinically vulnerable people to make informed choices on how to de-risk their lives in the same way that those able to respond well to vaccines can.  I hope that the cost-effectiveness analysis takes this into account as the medicine is currently used effectively in many other countries.

“Sotrovimab is also a surprising omission, given that it too appears to retain activity against circulating strains.  It is important to remember that for all antibody therapies, whilst many do indeed show marked reductions in activity for newer Omicron subvariants in the laboratory, how this relates to the threshold of protection in real life is quite another question.  I appreciate that it may be difficult to cost up altered dosing regimens, but to ignore a potentially effective therapeutic seems short-sighted; I am similarly surprised by the WHO recommendations.

“The decision on remdesivir is also surprising.  Yes, as is the case for all direct-acting antivirals, this drug works best given early to at-risk patients to prevent hospitalisations – there is clear evidence of this from the PINETREE study mentioned in the report; it is well accepted that treating too late makes little difference, although seriously ill patients can benefit prior to the need for mechanical ventilation.  However, clearly the need for intravenous administration is a downside to this medicine.  Nevertheless, unlike Paxlovid, remdesivir can be used in juvenile patients off-label, plus it has nowhere near the number of contraindications regarding other medicines that Paxlovid has due to the inclusion of the ritonavir boost.  We are in danger of losing flexibility when it comes to clinical decision making.

“In this regard, it is clear from the Panoramic trial that Molnupiravir performed less well than in previous studies, but this may be because this was a different patient cohort that was recently vaccinated.  Whilst molnupiravir almost certainly is less effective than remdesivir or nirmatrelvir, there are still patients that may benefit.  Moreover, if we are to be left with a single antiviral small molecule (Paxlovid) it is only a matter of time before nirmatrelvir resistance emerges, especially if usage is broadened as it has been in the USA of late – the genetic barrier to this happening in the laboratory is low.

“At the same time, I am not aware of any indications that Omicron variants have changes in their polymerase (or the exonuclease) that would prevent either remdesivir or molnupiravir from working as well as they do versus other variants – the argument is the same as for nirmatrelvir in this respect.

“My main concern at present is why we are not exploring whether combinations of direct antivirals, or indeed some of the monoclonals, provide not only improved activity, but also longevity, against SARS-CoV2.  There appears to be a paucity of new options coming through the therapeutic pipeline, which is very worrying indeed.

“If we limit the options available for such therapies, especially potential prophylaxis, then we are leaving those most vulnerable to infection high and dry, given the unmitigated prevalence and multiple waves we are experiencing at present.”

‘NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE, Draft guidance consultation: Therapeutics for people with COVID-19’ was published by NICE at 00:01 UK time on Wednesday 16 November 2022.

Declared interests

Dr Lennard Lee: “No conflicts of interest.”

Dr Stephen Griffin: “Member of Independent SAGE.”