Comparative Effectiveness Research

[Guest guest]

Greetings,

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

- an authority on the subject within FDA. Copying:

= Law

1. Safety

Demonstration of safety, shown by " all tests reasonably applicable "

to show whether drug is safe when used as labeled. (Unchanged since 1938).

" Safe Safe " generally understood to mean benefits outweigh risks.

2.. Effectiveness

" Substantial evidence " that it will do what is claimed.

Substantial evidence means convincing evidence from " adequate and well -

controlled studies " (generally > 1, but with exceptions).

3. Labeling

Adequate directions for use and not false or misleading.

There is NO requirement (and this is explicit in legislative history) that a

new drug be superior to, or even as good as, existing therapy; i.e., no

" relative efficacy " requirement.

It could be asked, however, whether in some cases adequate directions for

use could include comparative information. This is not a settled issue.

.. " FDA's ability to require comparative data is relatively limited, but we

are very interested, and fairly experienced in how to do it, and aware of

potential errors. "

==

Comment: We often see sponsors of new drugs, understandably, take the path

of least resistance - often a narrow indication (refractory whatever) to win

Accelerated Approval for their new drug (Ofatumumab for CLL refractory to

fludarabine for example

http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm188221.htm ).

.. This with the expectation?, perhaps, that it will be used off-label more

broadly without the need for traditional marketing (which would be illegal),

and this is particularly easy to accomplish if the new drug is easier to

administer and perceived as being less toxic by patients and physicians.

The sponsors may then follow with single arm studies for other clinical

settings as a way to show doctors (again, without advertizing) that the

broader off-label use is reasonable -- while avoiding head-to-head

comparative research, which is needed to know which is really better for

patients.

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.

All the best,

~ Karl

Patients Against Lymphoma

Patients Helping Patients

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