FDA criteria & Non-Inferiority trials

[Guest guest]

Even if it is not known what the FDA is communicating to CLL drug

sponsors about expectations for head-to-head comparisons with

approved drugs, understanding FDA guidances related to such

comparisons is useful in developing strategies for advocacy.

At 08:13 AM 1/3/2011, " karlamonyc " wrote:

>Guidance for Industry Clinical Trial Endpoints for the Approval of

>Cancer Drugs and Biologics (May/2007)

>http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid\

ances/ucm071590.pdf

>

Unfortunately, the above guidance does not indicate in what

circumstances head-to-head comparisons with an approved cancer drug

would be required for approval of a new cancer drug.

However, this guidance does contain (on page 11) some general

guidance for the conduct of such comparative studies, which are

within the realm of " noninferiortiy " (NI) clinical studies (i.e.

" Studies Designed to Demonstrate Noninferiority " ).

The above guidance indicates: " A noninferiority (NI) trial should

demonstrate the new drug's effectiveness by showing that the new drug

is not less effective than a standard regimen (the active control) by

a prespecified amount (noninferiority margin)... "

Probably, of importance to design of CLL comparison trials is the

statement that " NI trials with endpoints other than survival are problematic. "

Specifically " This noninferiority margin should be a clinically

acceptable loss that is not larger than the effect of the active

control drug. The standard regimen should have a well-characterized

clinical benefit (survival benefit). If the new drug is inferior to

the active control by more than the noninferiority margin, it will be

presumed to be ineffective. "

At 04:22 PM 1/3/2011, " karlamonyc " wrote:

>Guidance for Industry Non-Inferiority Clinical Trials (March/2010)

>http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid\

ances/UCM202140.pdf

The reasons for why endpoints other than survival are problematic for

Non-Inferiority trials is probably evident somewhere in the details

of the above March/2010 guidance.

This guidance indicates (on page 6) possible reasons for the FDA

requiring new CLL drugs to be assessed in NI trials:

" The usual reason for using a non-inferiority active control study

design instead of a study design having more readily interpretable

results (i.e., a superiority trial) is an ethical one. Specifically,

this design is chosen when it would not be ethical to use a placebo,

or a no treatment control, or a very low dose of an active drug,

because there is an effective treatment that provides an important

benefit (e.g., life-saving or preventing irreversible injury)

available to patients for the condition to be studied in the trial.

Whether a placebo control can be used depends on the nature of the

benefits provided by available therapy. "

Additionally,

" There are, however, other reasons for using an active control: (1)

interest in comparative effectiveness.............. There is growing

interest among third party payers and some regulatory authorities, on

both cost effectiveness and medical grounds, in the comparative

effectiveness of treatments, and an increasing number of such studies

are being conducted. "

This document states (on page 2) " These active control trials, which

are not intended to show superiority of the test drug, but to show

that the new treatment is not inferior to an unacceptable extent... "

Taken literally, this would imply that a new CLL drug would not need

to demonstrate a greater benefit than an approved CLL therapy, just a

comparable benefit.

One general perception from this guidance: If it were used to guide

trials of new CLL drugs, it implies that a new CLL drug would be

required to be tested with the same parameters that were used in the

testing of an approved CLL therapy. In instances in which a new CLL

drug has a very different mode of action than any approved CLL

therapy, such a requirement might place the new drug in a significant

disadvantage because those parameters may not be optimal for the new drug.

To predict implications of this guidance for CLL studies, one would

have to invest considerable effort in studying it. However, this can

not be considered as absolute guidance, as evidenced by every page

being labeled " Contains Nonbinding Recommendations Draft; Not for

Implementation " .

Al Janski