Yes substantial, but the point I'm trying to make is the part above that, that describes the not follow rule, says:
" . . . the Agency will not later alter its perspective on the issues of design, execution, or analyses unless public health concerns unrecognized at the time . . . "
This overrides the following which are just bullet point examples. The need to protect public health is the reason to breach a SPA, not patients might be wasting their money.