Advisory committee notes: keeping an open mind

[Guest guest]

Yogi Berra: " In theory there is no difference between theory and practice. .

In practice there is. "

Because of the complexity of human biology and disease, not all effects of a

drug can be accounted for or measured. Unanticipated and delayed effects can

offset measurable benefits, such as tumor shrinkage.

Thus survival is the most reliable endpoint for comparing strategies to treat

disease. But surrogate endpoints are required when use of survival is not

practical or ethical - such as for indolent lymphomas that have a long median

survival. For indolent lymphomas, the surrogate of choice seems to be

progression free survival (PFS). However, the totality of captured effects

must also be considered, such as treatment-related mortality, effects on bone

marrow reserves, effects on quality of life ....

(But, what happens when you have two, or ten protocols for a condition approved

in this way, and you don't know which improves survival, and the sponsors are

not inclined to do the expensive comparative studies? Isn't this the current

landscape for indolent lymphomas?)

Back to the reviewer's task: The data you are reviewing is likely the most

complete and comprehensive data that's available for this drug for this

indication. The design of the trial for marketing approval - it's size, how

patients are selected/randomized - was pre-approved as capable of providing

reliable comparison of benefits and risks to the participants - an objective

comparison of the agent against an active control ... such as CVP+Rituxan versus

CVP.

So as a reviewer, the basis for your decision is in this data, not the

expectations of different stakeholders - influenced, perhaps, by theory, biased

and selective sponsor reporting, testimonials, or outcomes from small single arm

studies.

~ Karl