How Tested and Approved Are Our Covid Treatments?

The glib smarties need to rethink their attacks on unproven, off-label drugs that might prevent or treat Covid-19. When it comes to compounds like Ivermectin, what we’ve got is a screamingly inconsistent standard of evidence.

Take a look at the current treatment guidelines (image below) for hospitalised Covid-19, recommended by two separate groups: the NSW Therapeutics Advisory Group (NSWTAG), and the NSW Agency for Clinical Innovation (ACI).

Of the five drugs shown in the ACI/NSW TAG Hospitalised Guideline, the TGA has approved only one (Dexamethasone) for respiratory illness. NSWTAG Guideline 13 April 2021 TGA Product Information

Three of the other four are neither approved nor provisionally registered for treating Covid. They are all arthritis or dermatitis drugs and are being prescribed off-label (for other than approved indications). Only one is Covid-specific, provisionally registered, but still in ongoing phase 3 clinical trials with onerous reporting and review conditions.

Baricitinib is not approved, not even provisionally registered, for the indication of Covid-19. It is prescribed off-label. It is an arthritis and dermatitis drug. It is conditionally recommended based on two trials “suggesting that baricitinib probably reduces the risk of death” [my emphasis] NSWTAG Guideline 6 August 2021

Tocilizumab is not approved, not even provisionally registered, for the indication of Covid-19. It is prescribed off-label. It is an arthritis and arteritis drug. The conditional recommendation is based on the view that “in patients hospitalised with COVID-19 who require supplemental oxygen, tocilizumab probably reduces the risk of death” [my emphasis] NSWTAG Guideline 15 July 2021

Sarilumab is not approved, or provisionally registered, for the indication of Covid-19. It is prescribed off-label. It is an arthritis drug. There is a limited supply and not directly recommended by NSW TAG any longer.

Remdesivir is not approved, but only provisionally registered. It is an antiviral that “is currently being evaluated in ongoing phase 3 clinical trials for COVID-19”. NSWTAG Guideline 15 March 2021. Compared with many drugs, it has a heavy, liver-related and kidney-related adverse event profile.

NSW Agency for Clinical Innovation Guidelines; based on NSW Therapy Advisory Group

National Covid-19 Clinical Evidence Taskforce

The National Covid-19 Clinical Evidence Taskforce (NCCET) gathers and reviews evidence for different Covid-19 treatments for different stages of disease. It then categorises them into recommended, conditionally recommended for/against, consensus recommended, not recommended.

The Taskforce’s recommendations inform the NSW TAG and ACI’s recommendations. Those recommendations are not exactly the same as the NSWTAG’s.

For example, the NCCET recommends use of REGEN-COV (Casirivimab plus Imdevimab) and Sotrovimab for some types of moderate-to-severe Covid illness, while NSWTAG/ACI do not. Note, however, that the NCCET in their evidence review state that REGEN-COV only “probably reduces the risk of death” [my emphasis].

Early Treatment Recommendations

Both the National Clinicial Evidence Taskforce and the NSWTAG conditionally recommend Sotrovimab (Xevudy) for early treatment for specific groups of at-risk people who don’t need oxygen therapy. For everyone else, it’s Paracetamol or Nurofen.

Sotrovimab is a monoclonal antibody drug that targets the SARS-CoV-2 spike protein. It has no long-term safety or efficacy data. NSWTAG Guideline 2 September 2021

The TGA has only provisionally registered Sotrovimab as a treatment of Covid-19 as at 20 August.

The two organisations recommended the treatment on the basis of short term efficacy and safety data from one trial. The trial is described on page 8 of the TGA Product Information.

Continued approval of this indication depends on the evidence of longer term efficacy and safety from ongoing clinical trials and post-market assessment

TGA Product Information p6

How Strong Is the Evidence that the Evidence Taskforce Relies On?

We can see from the drugs listed above that the evidence is far from overwhelming. Clearly there is clinical effect, and in the fog of medical war our doctors do need to charge ahead with lower levels of certainty than in other situations.

But let’s not pretend that there is a proven protocol with proven, tested drugs. That would be a lie. The TGA hasn’t approved most of them. Most rely on a very limited number of trials with suggestive rather than conclusive findings.

So what type of evidence does the NCCET rely on?

The evidence presented is based on research papers and then the Taskforce makes judgement calls on seven aspects:

  • Benefits and harms
  • Certainty of evidence
  • Patient preferences and values
  • Resources
  • Equity
  • Acceptance
  • Feasibility.

Realistically, the only ones that matter are the first two.

You can see just how certain the NCCET must be when NSWTAG has to quote words like “probably” to justify treatment options.

Weak Evidence to Shut Down Ivermectin

So, let’s consider the evidence that the NCCET used to shutdown Ivermectin use, and to advise the TGA Advisory Committee on Medicines Scheduling to support restrictions on doctors prescribing it. To be fair, it’s nicely transparent that they list those papers.

If we consider harms, for Ivermectin they are minimal and well-understood, because the drug has been around a long time. You could describe the listed harms of diarrhoea, nausea and dizziness as bog-standard short term side effects.

If we look at the certainty of the evidence criterion, the NCCET only addresses treatment after progression from mild disease. Many of the claims for Ivermectin refer to protection from symptomatic infection or progression to moderate-to-severe illness. The NCCET does not address that type of claim in the Certainty of Evidence.

NCCET, Ivermectin Certainty of Evidence

As for the papers on Ivermectin, if you believe these are all the relevant ones, I have a bridge for you. What’s more annoying is that 12/20 papers study effect on hospitalised cases rather than the prevention and protection from hospitalisation. Two references were not papers but general. More than half were from 2020 and there was only one meta-analysis. The vast majority were poorly designed or too small to show statistical significance, but 13/18 did show non-statisically-significant benefit from Ivermectin. None showed overall worse outcomes or major adverse events.

Again, I’m not in a position to make a call on Ivermectin. Nor any of the other non-recommended therapies the NCCET considers.

What I can see is slanted behaviour. What I can see is a bureaucracy in action.

I can also see spin-doctoring that allows ordinary people to think that there are only proven therapies and the rest is quackery. Yet any honest scientist would accept that in this fog these papers provide no reason to exclude from off-label prescription a well-tolerated, available drug with promise for an under-serviced patient population (asymptomatic and mild or non-hospitalised cases).

I guarantee decisionmakers never thought anyone would read through their reference list. And discover it doesn’t address the key issue, and that it is so limited as to be embarrassing. Well, we’re in a different world now.

List of Papers Used by NCCET on Ivermectin, accessed 16 Sept 2021

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