Re: trials for slowly progressed patients

[Guest guest]

At 01:10 AM 2/3/2011, Al Janski wrote:

>Have any trials ever been conducted that focus on slowly progressing

>CLL patients?

>If so, have these trials involved follow-up observation of these

>patients when the disease was not eliminated (e.g. not yet reached MRD)?

>If so, is there any data on the overall survival of these patients

>relative to patients who's original treatment resulted in

>elimination of disease?

Additionally, have any trials segmented analyses of results into a

subset of CLL patients whose disease progressed slowly prior to

needing treatment? and compared those results for that subset of

patients with the results for CLL patients whose disease progressed

rapidly prior to needing treatment?

Al Janski

[Guest guest]

Hi Al,

To your question I would hazard a guess, which is probably not.

My impression is that it's considered very challenging to

interpret the results of studies in low risk populations -

i.e., when observation is appropriate, so the focus is more

often on populations with relapsed and refractory disease -

where the clinical course is more predictable and so the

assessment of the intervention is more reliable (and also

affordable: faster/cheaper).

My hope is that the general policy of excluding this

population will change when agents with low and reversible

toxicities emerge - which may have modest activity, but may

be best applied to patients with lower risk disease. Such

studies will require larger numbers of participants and very

long follow up to provide reliable answers.

Karl

> >Have any trials ever been conducted that focus on slowly progressing

> >CLL patients?

[Guest guest]

Re: trials for slowly progressed patients

At 01:10 AM 2/3/2011, Al Janski wrote:

>Might that strategy then be an incentive for those pharmaceutical

>companies to propose study designs that would 'reduce' disease but

>not eliminate disease?

Re: Does Pharma want to hook you for life on a CLL drug?

At 10:49 AM 2/9/2011, S wrote:

>And now onto CLL. Once these kinase inhibitors such as CAL-101 and

>the catchy-named PCI-32765 are approved, maybe the drug companies

>will stop all research!

, I suspect you misunderstood my point.

The core of my point is that historically the development of CLL

drugs has been mostly directed toward clinical endpoints that involve

elimination of disease (e.g. " minimal residual disease negativity " ),

largely because such endpoints have become the expectation of the FDA

for approval of those drugs.

A drug sponsoring company can present its case to the FDA so as to

lobby for endpoints that require disease reduction to something less

than MRD negativity. However, that lobbying, then investment in the

associated clinical trials with lesser endpoints, requires major

(financial) risks by those companies, requiring proportional

(financial) incentives to take those risks.

For the biochemical reasons I've detailed in this and other recent

threads, I believe untreated CLL patients who's CLL disease has

slowly progressed to the point at which they now need therapy, may be

an ideal subgroup of CLL patients for treatment with drugs that do

not eliminate the disease but reduce it 'again' to being an indolent

or manageable disease. For related biochemical reasons, those

patients may actually have a longer overall survival with fewer

pathologies over that survival period than if their first treatment

had resulted in MRD negativity.

As such, drugs (e.g. CAL-101, PCI-32765) that provide such partial

disease reduction may be the ideal ('best') types of drugs for

initial treatment of these slowly progressed patients. The best

specific drug providing partial disease reduction for a specific

patient may vary depending on the exact biochemical nature of that

patient's CLL (e.g. of the dominant CLL clone), but those two drugs

would seem good candidates.

Because the fraction of CLL patients who slowly progress to needing

treatment is substantial, there would seem to be substantial

incentive for companies sponsoring such drugs to at least assess the

financial return for targeting slowly progressed patients, then, if

attractive, design a strategy to convince the FDA of a clinical

design that has endpoints representing disease reduction less than

MRD negativity.

Thus, my point is 'whether or not' there is financial incentive for

'whether or not' a drug is developed for a specific, but

unconventional, endpoint in a given patient subgroup. Of course, as

therapies with better overall values are developed for a specific

patient population, they will replace the therapies with lesser overall values.

When I had a leadership position in the R & D for a pharma company,

part of my job was to participate in presentations (to company

financial decision-makers) of the scientific basis for such

alternative strategies in seeking FDA approval, as well as the

subsequent negotiations with the FDA in defining the clinical

protocols for those alternative strategies.

Al Janski