ODAC - single-arm studies for accelerated approval

[Guest guest]

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

All the best,

~ Karl