Re: Arzerra takes on physicians' choice of therapy

[Guest guest]

Unfortunately, this is part of the FDA's move to make approvals harder.

Ofatumumab was approved based upon a single arm phase II study (no comparitor).

The comparitor was not used because the approval was based upon response rate.

They used historical controls as what they might have expected. The FDA appears

unlikely to allow for any other single arm, phase II approvals.

This is in part the higher standards that oncoloyg drugs are held to. In other

areas, there are allowed to be many drugs that are proven effective, but not

necessarily better than what is already out there. This is not true in

oncology, where you have to be either better or in an area where nothing is

proven effective (unmet medical need). The rationale for this is hard to come

by.

Rick Furman, MD

>

> The objective of this Phase III clinical trial is to confirm the response rate

and disease control in the refractory setting through a controlled trial

comparing ofatumumab with the physicians' choice of therapy in

fludarabine-refractory, bulky lymphadenopathy patients.

>

> This study will compare ofatumumab with the physicians' choice of therapy.

>

> The purpose of this study is to confirm the clinical benefit observed in the

pivotal registration study, Hx-CD20-406.

>

> The Committee for Medicinal Products for Human Use (CHMP) required that a

randomized study be conducted in CLL patients with bulky fludarabine-refractory

disease as a specific obligation for grant of conditional approval for ARZERRA

in the European Union (EU).

>

>

> I find this rather strange...

>

>

> ~chris

>

[Guest guest]

Dr. Furman, My understanding is that a control is generally needed to provide

an objective reference in oncology trials ... for judging efficacy and toxicity,

and that for non-oncology indications a placebo control can be ethical

(withholding treatment for the control) ... and this is one reason we have som

many drugs for the same lower-risk indications, requuiring no head-to-head

comparisons.

For Arzerra, a control wasn't required because eligibility selected for

refractory CLL - an urgent unmet need with no satisfactory standard therapy.

If FDA is saying that this, or a similar study design, is no longer appropriate

for refractory CLL, please feel free to send me the details privately of the

submitted design and FDA objections and I'll be happy to draft a patient

perspective letter ... I will be happy also to sign a non-disclosure agreement,

.... assuming you think this might help.

All the best,

Karl

See also for FDA guidelines, Kane

http://www.fda.gov/downloads/aboutfda/centersoffices/cder/ucm103366.pdf

>

> Unfortunately, this is part of the FDA's move to make approvals harder.

Ofatumumab was approved based upon a single arm phase II study (no comparitor).

The comparitor was not used because the approval was based upon response rate.

They used historical controls as what they might have expected. The FDA appears

unlikely to allow for any other single arm, phase II approvals.

>

> This is in part the higher standards that oncoloyg drugs are held to. In

other areas, there are allowed to be many drugs that are proven effective, but

not necessarily better than what is already out there. This is not true in

oncology, where you have to be either better or in an area where nothing is

proven effective (unmet medical need). The rationale for this is hard to come

by.

>

> Rick Furman, MD

>

[Guest guest]

Not certain how the FDA got involved in this.

As I understand it the 'Arzerra ~ physican's choice trial' is required by the

Committee for Medicinal Products for Human (CHMP) to meet European approval

requirements.

This trial is a specific obligation for grant of conditional approval for

ARZERRA™ in the European Union (EU)

This clinical trial to take place in Sweden... Centrala Etikprövningsnämnden

NCT01313689

Link: http://clinicaltrials.gov/ct2/show/NCT01313689

[Guest guest]

At 07:27 AM 3/15/2011, Rick Furman, MD wrote:

> Ofatumumab was approved based upon a single arm phase II study (no

> comparitor). The comparitor was not used because the approval was

> based upon response rate. They used historical controls as what

> they might have expected. The FDA appears unlikely to allow for any

> other single arm, phase II approvals.

Is this new FDA perspective partially a result of the Feb.8 ODAC

meeting? Link & SNIP below.

Al Janski

FOOD AND DRUG ADMINISTRATION

Center for Drug Evaluation and Research

Oncologic Drugs Advisory Committee

DRAFT QUESTIONS

February 8, 2011

http://tinyurl.com/4a9t8a6

Accelerated Approval & Oncology Experience:

The Oncologic Drug Advisory Committee will discuss the accelerated

approval process. To focus the discussion, the following non-voting

questions will be posed to committee members. The first question

pertains to studies supporting the initial accelerated approval. The

remaining questions apply to post-marketing studies designed to

confirm clinical benefit.

1. SINGLE ARM TRIALS TO GAIN ACCELERATED APPROVAL

Single arm trials have formed the basis for 29/49 or over half of the

accelerated approvals for oncology drugs to date. While single arm

trials 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 in

refractory populations where no available therapy exists. As a

greater number of drugs are approved, identification and

documentation of a refractory population is 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.

Alternatives to a single arm trial 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 in a refractory population comparing the

investigational agent to best supportive care or 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.

DISCUSS: Given the problems with single arm trials, discuss scenarios

where a randomized study should be required for accelerated approval.

Alternatively, please discuss situations where single arm trials may

be appropriate to support an accelerated approval.

CONTINUED AT: http://tinyurl.com/4a9t8a6