Randomized Controlled Trials and Covid-19

 Usually drug trial are divided in four phases:

 - (optional: phase 0): initial studies in animals and low doses for humans

 - phase 1: basic exploration. How does the medicine work? Is it safe? What dose is optimal?

 - phase 2: small scale test (25-100 patiënts): does it work?

 - phase 3: in a Randomized Controlled Trial the medicine is compared to placebos or existing products.

With the corona epidemic only phase 3 studies are done. The excuse is that we are in an emergency and that speed is essential. 

Sounds reasonable. Problem is that even if it results in a workable solution it may not be the optimal solution. We saw that illustrated when AstraZenica accidentally found that giving half a dose in the first round worked better. It may very well be that doses for other vaccines are far from optimal too. And although the claims of 90+% effectiveness for some vaccines may seem to leave little room for improvement both their need for a second dosage and their considerable side effects suggest otherwise.

The New York Times published an article "How the Search for Covid-19 Treatments Faltered While Vaccines Sped Ahead". According to the article:

The government poured $18.5 billion into vaccines, a strategy that resulted in at least five effective products at record-shattering speed. But its investment in drugs was far smaller, about $8.2 billion, most of which went to just a few candidates, such as monoclonal antibodies. Studies of other drugs were poorly organized.

But even given the 8 billion dollar expenditure, the results are very meager. Seeing how promising treatments like HCQ and Ivermectin are maltreated one has to wonder whether other motives play a role. Robert F. Kennedy, Jr. suggests that the interests of the vaccine producers play a role. If there is a medicine against Covid-19 it would no longer be possible to approve the vaccines according to the emergency rules.

What also plays a role that - given the absence of independent government institutes (many government paid experts have strong ties with the pharmaceutical industry) - it is hard to get the high volume research that would take away all doubts.

The British variant of the corona virus: a sidestep?

There is a lot of noise about the B1.1.7 variant of the corona virus. This new "British" variant is claimed to be more contagious and more deadly. However, the evidence is mixed.

It started a few months ago when in most of Britain the number of infections was falling fast. There was one place that showed the opposite trend. Then some people noticed a new variety of the virus that included a mutation on the spike. A laboratory study that suggested that this variant is more contagious closed the deal. The hype about the British variant was born.

This evidence for a new dangerous variant is rather thin. There could have been other explanations for the increase in infections in this one place. Maybe they just had some superspreader event, like a big wedding or funeral or a bunch of youth partying.

England has nowadays a new wave of corona infections. But the great majority of those cases have the "normal" variety of the virus and it is usual assumed that lots of socializing around Christmas was the main cause and not the new variant.

Yet the new version is becoming more common. The question whether it is a second epidemic - as some publications suggest - or that it is actually replacing the old variant. My impression is the latter.

There are different models of how a flue epidemic works. And despite that corona is a more serious disease than the average flue my feeling is that such a model applies here too:

Every day we encounter some viruses. If it is a small quantity our immune system will deal with them. If there are too much we will get sick. It is well established that people will get more sick when they got a heavier dose of virus. The big question is whether when we meet a small dose that doesn't make us sick our immune system will build some resistance. My feeling is that it does. That would also explain why flue epidemics tend to disappear after one or two years. 

Already this summer we saw reports that corona seemed to have become less deadly. This showed that we were building up some immunity. This situation favors any variation that is just different enough to at least partially evade this immunity. Reports from Moderna that antibodies built by their vaccine were six times less active with the British variant confirm this image. For the strong immune reaction by the vaccine in a healthy person this may not be relevant as there is still enough residual resistance to avert infection. But for people who have built less immunity it can make the difference.

So the answer to the question whether the British variant is more contagious and more deadly is ambiguous. In the present situation it is - because we have less resistance against it. But if it had appeared in February it might well have been less dangerous than the variant that then became dominant. 

This might seem an academic discussion but it goes against the common narrative that the virus is becoming more and more dangerous with all those new variants (British, South African and Brazilian). As I see it the virus is mainly making sidesteps to evade the immunity that we have built. And my expectation would be that most of these sidesteps will be less serious than the original. The fact that they arise at such a late stage suggest that in an earlier stage they were less competitive. 

These new variants arise in former hotspots. Those are the places where people have built most resistance and as a consequence making a sidestep is the most profitable for the virus.

I don't see this as two separate epidemics. As I mentioned: the quantity of virus that you encounter determines how sick you become. Quite likely the two variants work together. So if you had already received 60% of your quota to become sick from the common variety you need only the remaining 40% filled in by the British variant. And as the British variant encounters less resistance in your body it has a better chance to become dominant once the illness starts.

So when one sees an effective reproduction number R of 0.9 for the common variant and 1.3 for the British (to mention just some of the many numbers that have been thrown around) one can take it with a grain of salt. The gap is mainly caused by the replacement effect.

Seeing the British variant as a sidestep changes how one evaluates it. No longer is it a sign that the epidemic is getting worse and worse. Instead it signals that the virus is under pressure and making an evasive maneuver. It is a first sign of weakness and as such reason for hope.

Sure, much of this is speculation. But it might explain a lot.