Saturday, August 22, 2009

Precancers 5: Regulatory justification of precancer as a surrogate marker for cancer

Precancers are the lesions from which cancers develop. Precancers can be easily treated, and when we eliminate precancers, we eliminate the cancers that would have developed from the precancers. This is the message in Precancer: The Beginning and the End of Cancer.

In the prior blog post, I discussed how precancers can be used as surrogate markers for cancers, in carcinogen assays. The example used was the increase in MGUS (the multiple myeloma precancer) in occupational exposure to pesticides. An increase in MGUS after human exposure is an indicator that pesticides can cause multiple myeloma.

Because precancers occur earlier than cancers, the use of precancers as surrogate markers for cancers, in animal studies and in human epidemiologic studies, can save enormous time and money in carcinogen assays.

Is there regulatory justification to use surrogate markers (instead of the ultimate disease end-point) in assays that test the effectiveness of interventions (to decrease the incidence of disease or to treat disease).

The Food and Drug Modernization Act of 1997 specifically allows and encourages the use of surrogate markers and end-points in drug evaluations (from the Act):

(1) IN GENERAL.-The Secretary may approve an application for approval of a fast track product under section 505(c) or section 351 of the Public Health Service Act upon a determination that the product has an effect on a clinical endpoint or on a surrogate endpoint that is reasonably likely to predict clinical benefit.
(d) AWARENESS EFFORTS.-The Secretary shall-
(2) establish a program to encourage the development
of surrogate endpoints that are reasonably likely to predict
clinical benefit for serious or life-threatening conditions for
which there exist significant unmet medical needs."

An early use of a surrogate marker for disease response was the use of MRI evaluation of brain images for betaseron effectiveness as a treatment of multiple sclerosis. Wherease previous FDA requirements would have expected a clinical trial showing that betaseron produced a clinical treatment response, the Modernization Act permitted the use of MRI brain scans (showing improvement in MS lesions) to serve as a surrogate end-point for clinical data. The drug was approved largely on the basis of surrogate end-points.

Similarly, precancers might serve as surrogate end-points for cancers. A drug that increases the number of precancerous lesions would be expected to increase the number of cancers. Likewise, a drug that decreases precancerous lesions would be expected to reduce the incidence of cancers.

-© 2009 Jules J. Berman

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