Re: FDA criteria & new types of therapies

[Guest guest]

Karl, thanks very much for the links. These are quite useful, e.g.

in that many of the FDA's new/revised guidelines reference earlier

guidelines, rather than repeating details.

Dr. Furman, or anyone, can you cite a link that describes the more

recent FDA guidelines for the requirement that new therapies must

demonstrate greater benefit than a currently approved therapy in

head-to-head comparisons? If those guidelines have not yet been

released, anything (e.g. press releases) that discusses what is being

considered would be helpful.

For example, are those head-to-head guidelines directed at oncology

drugs in general? or are they directed at a more specific subset of

oncology drugs?

Al Janski

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

>I'd read this first, as it provides principles and a comprehensive

>list of examples:

>End Points and United States Food and Drug Administration

>http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResour\

ces/CancerDrugs/ucm094587.pdf

>

>Guidance for Industry

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

ances/ucm071590.pdf

>

>Accelerated Approval and Oncology Drug Development Timelines

>http://jco.ascopubs.org/content/28/14/e226.full.pdf

>

>Slides FDA Oncology Drug Approval

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

[Guest guest]

Alot of what the FDA intends is based upon statements made during the evaluation

of other agents. Much of this is not published, but the ODAC briefing reports

is one source.

> >I'd read this first, as it provides principles and a comprehensive

> >list of examples:

> >End Points and United States Food and Drug Administration

>

>http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResour\

ces/CancerDrugs/ucm094587.pdf

> >

> >Guidance for Industry

>

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

ances/ucm071590.pdf

> >

> >Accelerated Approval and Oncology Drug Development Timelines

> >http://jco.ascopubs.org/content/28/14/e226.full.pdf

> >

> >Slides FDA Oncology Drug Approval

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

>

>

>

[Guest guest]

Al,

My understanding is that non-inferiority trials can also be used to win

marketing approval for the same indiation - such as if the drug is easier to

administer, or safer, but with at least the same efficacy. (I'm not aware of any

examples tho)

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida\

nces/UCM202140.pdf

I recommend that you mine also

Comparative Effectiveness FDA Activities

J. Temple, MD

Associate Director for Regulatory Policy

FDA/Center for Drug Evaluation and Research

http://www.nhpf.org/library/handouts/Temple.slides_09-26-08.pdf

While a bit dated, Temple is an authority within FDA on regulations and statutes

for drug evaluations - and much of it is covered in outline form here - and I

don't think much if anything has changed in respect to level of evidence.

Best,

Karl

> >I'd read this first, as it provides principles and a comprehensive

> >list of examples:

> >End Points and United States Food and Drug Administration

>

>http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResour\

ces/CancerDrugs/ucm094587.pdf

> >

> >Guidance for Industry

>

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

ances/ucm071590.pdf

> >

> >Accelerated Approval and Oncology Drug Development Timelines

> >http://jco.ascopubs.org/content/28/14/e226.full.pdf

> >

> >Slides FDA Oncology Drug Approval

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

>

>

>

[Guest guest]

At 03:03 PM 1/3/2011, rrfurman@... wrote:

>Alot of what the FDA intends is based upon statements made during

>the evaluation of other agents. Much of this is not published, but

>the ODAC briefing reports is one source.

I have a long-time friend, and former research colleague, who spent

about 30 years, as an industry scientist, negotiating with the FDA on

clinical protocols for pharmacology/toxicology studies. A couple of

years ago, he moved to an FDA job. I'll see whether he can track

down an ODAC briefing that covers these expected FDA changes and what

he knows about what might be coming.

A couple decades ago, when I was a project leader for I new type of

drug, for which our company was the leader, some of the results of

our negotiations with the FDA on experimental protocols became the

FDA expectation for similar drugs throughout the industry,

expectations that were later, slowly publicly communicated by the FDA

in oral presentations, followed by written guidelines.

Evidently, something similar is the case now, and specific answers to

questions may be difficult to obtain at this stage. Although that

lack of specificity makes the job of advocacy more difficult, it is

also an opportunity to educate and influence the process before

definitive decisions are made.

Al Janski

[Guest guest]

Al,

I've served on three ODAC deliberations ... the instructions provided to

committee members are fairly basic: does the study provide clear and convincing

evidence of clinical benefit - sufficient to win accelerated or full approval -

depending on the type application. It boils down to evaluation of the outcomes

(weighing toxicities against efficacy measures, and study methods, etc.

knowledge of the natural history - just as in any deliberation, except the

sponsor has an opportunity to present it's case again and address specific FDA

concerns.

Each committee member is vetted for conflict of interest. Each receives

detailed documents - from the sponsor the FDA reviewers, the agency highlights

the areas of controversy, such as methods that may have led to biased results.

No committee member can discuss the material with another.

That is, there is nothing in an advisory commmittee deliberation that is unique

- the purpose is to decide only a submission that's a close call - and most

applications are not reviewed by ODAC.

Karl

> >Alot of what the FDA intends is based upon statements made during

> >the evaluation of other agents. Much of this is not published, but

> >the ODAC briefing reports is one source.

>

> I have a long-time friend, and former research colleague, who spent

> about 30 years, as an industry scientist, negotiating with the FDA on

> clinical protocols for pharmacology/toxicology studies. A couple of

> years ago, he moved to an FDA job. I'll see whether he can track

> down an ODAC briefing that covers these expected FDA changes and what

> he knows about what might be coming.

>

> A couple decades ago, when I was a project leader for I new type of

> drug, for which our company was the leader, some of the results of

> our negotiations with the FDA on experimental protocols became the

> FDA expectation for similar drugs throughout the industry,

> expectations that were later, slowly publicly communicated by the FDA

> in oral presentations, followed by written guidelines.

>

> Evidently, something similar is the case now, and specific answers to

> questions may be difficult to obtain at this stage. Although that

> lack of specificity makes the job of advocacy more difficult, it is

> also an opportunity to educate and influence the process before

> definitive decisions are made.

>

> Al Janski

>

>

[Guest guest]

At 06:20 PM 1/3/2011, Karl wrote:

>I've served on three ODAC deliberations ... No committee member can

>discuss the material with another.

>......there is nothing in an advisory commmittee deliberation that

>is unique - the purpose is to decide only a submission that's a close call

If this is the case, it implies it is unlikely that ODAC briefings

will be a source of FDA guidance related to concerns that, for

approval, new therapies would need to demonstrate greater benefits

than an approved therapy in head-to-head comparisons.

Until something more definitive is identified that outlines, at least

generally, FDA desires for changes in how CLL therapies might be

approved, advocacy efforts to argue against such changes seems premature.

In my experience in negotiating with the FDA, it's hard enough to

argue one's position even when the FDA has issued very specific

guidances on their positions. When the FDA has not made a public

statement (oral or written), the FDA usually simply says it has made

no decisions on the issue, even though it may be confidentially

giving specific guidance to a sponsor on the same issues.

Reading between the lines of what's been posted on this list, my

intuition is that some things have been communicated between the FDA

and a sponsor(s) that lead sponsor(s) to believe that the FDA is

leaning toward changes for head-to-head comparisons. However, such

communications are usually confidential, and, even if the sponsor

chooses to disclose specifics, the FDA will not necessarily

acknowledge its position. The FDA is conservative about issuing

broad-based guidances until it is ready

For effective advocacy related to regulations, it is best to have

some specific details related to those regulations to design an

effective strategy. Those details do not yet seem to be public.

Although requirements for better efficacy than approved therapies in

comparative studies could have the effect of delaying initial

approvals of new types of therapies, there are scenarios in which

having results of head-to-head comparisons would provide important

value in the care of CLL. Karl discussed this value in a post today

on the list, a portion of which is below.

Al Janski

===========

From: " karls@lymphomation " <KarlS@...>

Date: Tue, 04 Jan 2011 11:43:55 -0500

Subject: Comparative Effectiveness Research

It seems evident that present regulations do not require that a drug

sponsor demonstrate that its new drug is superior to another - only

that it is proven to be safe and effective for the given indication.

See Comparative Effectiveness FDA Activities, by J. Temple, MD

<http://www.nhpf.org/library/handouts/Temple.slides_09-26-08.pdf>http://www.nhpf\

..org/library/handouts/Temple.slides_09-26-08.pdf

SNIP.............

So in the lymphomas and CLL we have an increasing menu of options to

choose from but little research being done to see which is better for

the larger patient population in the key indications (first line, etc).

This is not to understate the importance to patients of accelerated

approvals for those narrow indications - that prove to fill an unmet

need; only to highlight a limitation and to note why differences of

opinion will exist about the level of evidence needed to win such

approvals, such as how you define the patients in need, measure

efficacy, and so on. )

It should be noted that Accelerated Approvals are conditional and

based on surrogate endpoints, which may NOT predict clinical benefit

in the long term - for the narrow population, and even less certainly

when used more broadly in different clinical circumstances.

So sufficient follow up is needed to show if the study population

truly benefited (i.e., the drug activity and toxicities led to longer

survival or better quality of life) in order to make genuine progress

against the disease.

Finally comparative effectiveness research is urgently needed so

patients (consumers) can choose the best protocol (product) based on

objective information. Until then, expect when treatment is needed

for the decision to be yours, and opinions of oncologists to vary by

who you ask.