Re: FDA criteria & Non-Inferiority trials

[Guest guest]

Hi Al, Thanks for your comphrehensive and thoughtful review.

I agree 100% regarding the need for advocates to first have at least a working

understanding of the regulations that guide the drug review process, including

the rationale for independent review.

The Endpoints in Oncology report I posted earlier comes closest to providing

general principles, which is important because it shows there can and have been

different ways to get to the same place: persuasive evidence of clinical benefit

- to either conditional or full approvals.

.... So because each disease, population and drug is unique, I don't think the

process can be regulated by strict formula in legislative code.

From my perspective, a public hearings (similar to an advisory committee review

involving independent experts and patient representives) would be helpful to

address disagreements between the sponsor and FDA regarding trial design for

marketing approval - endpoints, level of evidence, patient characteristics ..

the methods used to objectively judge if a new drug or protocol provides

meaningful clincal benefit

.... - as reasonable people will have honest disagreements about how you define

refractory CLL, for example - if the application is for accelerated approval -

to address an unmet clinical need.

However, the main obstacle to a public resolution of such disputes is probably

the drug sponsor, not the FDA -- I suppose because the sponsors do not want to

communicate too much to shareholders regarding the uncertainty about the

potential of their investigational products?

As you know, having a control group (active or placebo) is usually essential to

science-based assessments, and so it follows that most studies for marketing

approval will also require this type of study design to meet the criteria. And

as you note, there can be ethical issues when using a placebo control in a

population in need of effective therapy.

But, hypothetically, a new " home run " drug with virtually zero side effects

would NOT require a control to win marketing approval - the random control is

needed only to assess agents which have signficant risks and uncertain benefit -

which so far, describes almost all cancer drugs - because of the nature and risk

of the disease.

For an excellent overview -- for advocates and investigators: Cancer therapy and

the randomized clinical trial good medicine? Dwight Kaufman M.D., Ph.D. Deputy

Director

http://onlinelibrary.wiley.com/doi/10.1002/1097-0142(19931101)72:9%2B%3C2801::AI\

D-CNCR2820721505%3E3.0.CO;2-N/pdf

Karl

> 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.

>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

[Guest guest]

The link Karl referenced to the Kaufman article is broken.

This one works for the .pdf

http://onlinelibrary.wiley.com/doi/10.3322/canjclin.44.2.109/pdf

~chris

CLL CANADA