RE: snip: ODAC minutes - single arm studies for AA

[Guest guest]

For discussion:

I wonder if delaying the need for therapy with a targeted or immunotherapy

agent (that has no significant toxicity) would meet regulatory standards for

addressing an " unmet need? "

Such an agent given in a maintenance schedule, if truly low-toxic, could be

compared ethically to observation in the setting where there's no need to

treat, which is common for the indolent lymphomas.

The primary endpoint would be PFS with consideration of the magnitude of PFS

and adverse events, relative to observation (needed to objectively test

safety and efficacy). A secondary endpoint would be the clinically relevant

but " fuzzy " Time to Next Treatment, . this as the basis for AA approval.

And with much longer follow up, a benefit in OS would be the basis for full

approval . following the same population.

This similar to the recent Rituxan vs. observation study design, but with an

agent with a better risk profile (assuming one exists), and not used as part

of standard therapy, which raises concern about becoming refractory to a

component of standard care with regular use when not clinically needed.

What agents might be appropriate for such as study? CAL101, the btk

inhibitor, lenalidomide? .?

What are the reasons we should not propose such a model for AA approvals to

FDA, or encourage investigators to consider such a design?

Karl

Greetings,

Copying section that frames this important question and the issues

surrounding it.

===

DR. KLUETZ: So we're going to talk about four nonvoting questions to be

posed to the committee members. Again, these are designed to facilitate

discussion on ways to improve the accelerated approval process. And, to

remind everyone, discussion of specific drug indications should only be made

in order to make a broader point in the accelerated approval process.

So for the first question, with respect to single-arm trials to gain

accelerated approval[AA], single-arm trials have formed the basis of 29 out

of 49, or over half, of our accelerated approvals for oncology to date. And

while they often require less resources and time to complete, they provide

limited data on clinical benefit and safety.

Single-arm trials for accelerated approval have usually been performed on

refractory populations where no available therapy exists. But as a greater

number of drugs are approved, identification and documentation of the

refractory population is becoming increasingly problematic.

In addition, marginal response rates observed in single-arm trials in a

refractory setting make it difficult to determine whether the findings are

reasonably likely to predict clinical benefit.

Some alternatives to single-arm trials in a refractory population include

randomized trials in a less refractory population against an active control

using a surrogate endpoint analyzed at an earlier time point or a randomized

trial on a refractory population comparing the investigational agent to

either best supportive care or a dealer's choice of various agents selected

by investigators. Randomized trials provide the opportunity to look at a

wider variety of endpoints and allow for an improved characterization of

safety.

So the committee members are asked, given the problems with single-arm

trials, discuss scenarios where randomized studies should be required for

accelerated approval. Alternatively, please discuss situations where

single-arm trials may be appropriate to support an accelerated approval.

DR. PAZDUR: If I could just mention a few things here that perhaps we did

not mention on the slide, and that is really the need to really define the

population very well in a single-arm trial.

Remember, by law, these have to be controlled trials, adequate and

controlled trials that lead to an approval of a drug. And in a single-arm

trial, what we're looking at is really a situation where no other therapy

exists, so the response rate in the control arm, this make believe control

arm, is basically zero, because there's other effective therapy for this

disease.

Let me give you an example of this. One of our very early uses of a

single-arm trial was in irinotecan or CPT-11 for colon cancer, when only

there was 5-FU for that disease. So it would make sense that a single-arm

trial of X percent, I think it was about 15 percent in that situation, would

be a situation where one might consider an accelerated approval, the control

being there is no control. There is no other active drug in this disease, so

if one did a randomized study, one would expect to see a zero percent

response rate.

Some of the problems that you get into, especially with more and more drugs

being approved in other disease settings, is that it might not be that

cut-and-dry, especially for some of the hematological malignancies,

lymphomas, Hodgkin's disease, myeloma, et cetera, leukemias, where you might

get response rates even by retreating patients with drugs that they've had

in the past or drugs that are on the market that may not have a specific

indication but are widely used in oncology.

Here, again, the other issue that I think people have to understand is that

we're probably one of the very few therapeutic areas that takes single-arm

trials for drug approvals. Most other therapeutic agencies, the agencies go

right away to randomized studies. And this use of a large single-arm trial

of 100 to 120 patients really is a manifestation of the accelerated approval

process.

One could say an alternative would be, right after the Phase 1 study, if you

see some really interesting level of activity, high level of activity, maybe

you want to start a randomized study very early on rather than basically

just accruing large numbers of patients to a single-arm trial.

Sometimes when you get to some of the single-arm trials that have two

single-arm trials with 150 patients, you're well on your way already of

randomized study, and you might have been better off by just doing a

randomized study relatively early on. And that's some of the issues that we

really wanted to discuss.

As with everything, we feel that there is a role for single-arm studies,

particularly in unique diseases or where one has very, very high response

rates. But as with everything in medicine and advice that we give, water

tends to seek its lowest level and we frequently find sponsors coming in

saying, " Dr. Pazdur, what's the fewest number of patients and the lowest

response rate that you'll take? " Okay, that's problematic for us, and that's

where we're going with this question.

? end snip