In principle, conceptually, the comparison is the same as for a conventional therapy. The difference is about the level of certainty or uncertainty, the risk that what you observe in the trial is not actually going to be observed in practice when you roll it out to more patients.
The challenge of the orphan drugs to HTA is how to deal with that uncertainty. Intellectually, conceptually, the way to deal with it is to recognize the price, the value of that uncertainty. Health care is very much like laying a bet. We think something is going to work, but it doesn't work in everybody, so we take odds, like five to one, and we are willing.... If I were going to bet $5, I would probably quite happily do it on a hundred-to-one bet.
If I have to bet $10,000, I am probably not going to go more than 1.1 to 1. This reflects that uncertainty has a value, and there are mechanisms for calculating the value of the uncertainty.
What that information allows payers to do is negotiate down the price to reflect the uncertainty at the time of introduction, and as the evidence is accumulating, because the technology is on the market and being used, there is then the possibility for the price to increase to reflect the reduced risk, but actually you are buying something that doesn't work.
That is why we need, for these types of technologies.... Orphan drugs are one extreme, but also for precision medicines there is a large overlap. We are going to be moving into a world where decision-makers are going to have to be much more sophisticated. It is not going to be a simple yes or no. It is frequently going to be yes with conditions. Those conditions will reflect the nature and the magnitude of the uncertainty that is in play. Does that help?