Ann: Botanix Announces BTX 1503 Data and Progression to Phase 3, page-275

I put this little conundrum (why placebo differences between US versus Aussie) into my brain last thing last night … and woke up this morning with the obvious answer.

Compliance.

Imagine you are a teenage boy (girl) with a hot date Saturday night. Confidence is going to be everything and bad acne is hardly helpful for that. The treatment you are on (the placebo) is doing bugger all and so despite strict instructions to the contrary you will start experimenting with alternative approaches.

Its an emergency after all.

But why would compliance be lower in the US compared with Australia? Boys / girls are equally randy the world over.

Therapeutic alliance.

In the US the sites are predominately contract research centres. Conducting trials is their business. The Australia sites are predominately dermatology clinics – their business is treating people.

One is motivated by purely money the other business is motivated by helping people (and making money).

Teenagers are a particularly tricky clientele for clinical trials - because their altruism levels are low. The world revolves around them … as opposed to older people who take part in trials to feel useful and contribute something back to society.

So you are at great risk with younger people for poor compliance. They don’t care. Which is the opposite for older people who sometimes care too much … and worry excessively about doing the wrong thing and ruining your good work.

That existing relationship with a treating health care professional is what gets you good recruitment and good compliance in a clinical trial. Subtract that – as what occurs in these US research units and you lose that element of not wanting to let your doctor / health professional (who has cared about you) down.

So that’s the theory – how would you confirm it? It’s difficult because you do not have a objective measure of compliance.

But I would expect higher US attrition (drop-outs). And baseline participants differences between the US / Australia – with the US lower SES.

Many trials include a measure of allocation blinding – can participants correctly guess what treatment they were receiving. I would expect this to be above chance for the placebo group – hence increasing the risk the people wandering off protocol.

People have pointed to parallels with RAP. Good Aussie results poor US results. It is similar but not quite the same.

In the RAP Ausssie trials the research team was the clinical team. In the US through a CRO in a tier one hospital there is a strict separation between the research team and the clinical team. Naturally this produces poorer quality data (the clinical team care very little for getting good data – they care about getting good patient outcomes) … which the US adjudicators then find difficult to make consistent diagnoses on.

Here you don’t have that problem … but it is the same in that the context of the implementation is having a big impact on outcomes.

This might all seem insightful. But in fact its only learned through error.

I have recently been part of a US research group that has just made this same mistake and lost several million dollars. In upscaling we moved to a good research group. But we lost the therapeutic alliance element that we had had with participants in our earlier trials. We sort of took it for granted – not fully appreciating how vital it was for compliance. So compliance dropped through the floor and on an ITT basis the results are terrible.

So take this with a big pinch of salt … but there is probably a better story here. Albeit you would like a confirmation of something somewhere of what I am saying. But none of us can pick up the phone and chew the fat with the PIs here for a hour. So big uncertainty … not for the faint hearted … but perhaps worth a punt that the mob is going to get this wrong.