Is clinical testing still needed in era of targeted drugs?

[Guest guest]

Is the need to test drugs in human subjects decreasing in the era of

targeted drugs?

While there is genuine reason for optimism in this era of targeted drugs,

there are at least two reasons clinical testing for efficacy is still

needed. The first being the toxicity of targeted drugs, which is generally

less but not always so. (Examples: Campath is a targeted drug. As is

Avastin - each have significant toxicities) .

..Other experience shows that the actual toxicity and efficacy of a targeted

drug (because of the unbelievable complexity of human and tumor biology),

can't be predicted by theories about mechanisms.

See for example: Review: Side Effects of Approved Molecular Targeted

Therapies in Solid Cancers

http://theoncologist.alphamedpress.org/cgi/reprint/12/12/1443

A second challenge is tumor resistance to targeted therapy, . (the pathway

the drug binds to might not be vital to the malignant behavior - or the

tumor cells may adapt) .

.. that is, the clinical effects may be found to be very modest or absent

when clinically tested . the responses short-lived and not significant

enough in relation to the toxicities. Again, these effects can only come

to light through clinical testing.

Copying comments from Dr. Ramaswamy Govindan, MD | August 1, 2007

: " For instance, about 20% of cardiology drugs succeed, whereas only about

5% of new oncology compounds go from first-in-human trial to FDA approval.

In non-small-cell lung cancer alone, between 1990 and 2005, a total of 1,631

new drugs were studied in phase II. Only seven of these new agents gained

FDA approval. "

http://www.cancernetwork.com/display/article/10165/62623

Thankfully, the potential for success seems much higher for drugs that treat

blood cancers! - some types can be cured or sent into durable remissions

often with available therapy - even at an advanced stage.

A third challenge is the need for therapies that actually help us to live

longer. There are many instances where responses are seen that do not

translate into clinical benefit, again, because the response can be modest

and not long lasting enough, or may be offset by toxicities (early or late).

The Accelerated Approval path is in place to allow for study drugs to win

conditional approval faster - based on surrogate (early, provisional)

endpoints (such as response rates, improved time to progression, etc.). But

such approvals will also require follow-up of the participants to determine

if the early positive effects translate into living longer or better -

needed to win full approval. (Or a second confirmatory study.)

Regarding the " home run " drugs that we all hope and expect to emerge in the

future: in the clinical-phase testing of such drugs (registration trials

intended to demonstrate clinical benefit), there will be independent data

monitoring boards (DMB) assigned to evaluate the outcomes, interim and

final.

.. One purpose of the DMB is to add credibility to the result and to avoid

sponsor and investigator bias.

.. The DMB can also stop a trial early when the evidence clearly shows that

one or the other protocol is superior.

.. At that time, the sponsor can then submit its data for FDA review -- if

it's a -- and start also to get up to speed with manufacturing - which is

needed to ensure the quality of commercial version of the study drug.

Regarding compassionate use of " home run " drugs or those that fill unmet

needs . I believe the Expanded Access policy is sound (and yes, I've read

it and provided input), but the main obstacles to using it remains:

* the commercial company can't be forced to provide a study drug and often

won't for various reasons (Concerned about liability concerns, for example,

perhaps a higher risk when a study drug is used outside of an

investigational setting), and

* the administrative burden on our treating physicians, who might also not

be confident that the study drug, perhaps when used as a single agent, could

be helpful in our circumstance. (About this process we have direct personal

experience, having made use of Expanded Access twice.)

There is nothing to prevent a drug company from setting up an Expanded

Access trial (and under the amended rules also receive compensation from

participants to mitigate costs). This to help meet the urgent clinical

needs of patients . until the independent FDA review is complete and the

manufacturing piece is also done.

Further, It may be that the current Expanded Access policy cannot force

insurance companies to reimburse for compassionate use of an investigational

drug, although health care reform (if it holds) might help to address this.

Is the FDA review time too long?

A comprehensive review of data submitted by the sponsor can take 6 to 9

months - and for Priority Reviews, have been completed by the agency in a

little as 2.5 months (Gleevec).

.. This might seem like too long, and perhaps it can be shortened??, but I am

hearing of concerns that required turnarounds (by law) may not be long

enough for the review team to carry it out reliably (these are often very

complex evaluations -involving tradeoffs of many kinds, and sometimes

requiring direct review of scans to ensure the integrity of the findings.)

Anyhow, this is my understanding of the rationale for need for clinical

phase testing and independent FDA review.

In short, human and tumor biology is very complex, and experience shows that

theories about mechanisms is not evidence.

All the best,

~ Karl

PAL www.lymphomation.org

Bcc: undisclosed advisors