But, look a little deeper and you’ll understand why the decision should be (and perhaps already is) being cheered by the larger biopharmaceutical industry.
Hamburg’s 69-page opinion is confirmation that the accelerated approval mechanism is alive and well, and this is because the regulatory pathway’s accelerated withdrawal mechanism has now been validated.
“The Pink Sheet” touched on this briefly in our initial coverage following the two-day Avastin hearing in June (“Avastin’s Breast Cancer Claim: Will FDA’s Hamburg Take A Middle Road?” “The Pink Sheet,” July 4, 2011). However, now that Hamburg’s verdict is in, we think the issue warrants further exploration.
Think of the chaos that would have been created for FDA and industry if Hamburg agreed with Genentech’s view that accelerated approval can and should be maintained until there is practically no hope of confirming clinical benefit?
How many CDER review division directors do you think would be willing to approve a novel therapy on the basis of an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint other than survival or irreversible morbidity, knowing that it would take an act of God to get a drug off the market when the sponsor ultimately either can’t (or won’t) confirm the benefit in post-marketing studies?
How many review division directors would want to go through the scrutiny, and at times embarrassment, that the oncology review division faced during the course of Genentech’s 11-month long battle?
Hamburg lays it all on the line on page 55 of her opinion:
“Withdrawal here is the essential counterpart to accelerated approval. When the accelerated approval pathway was established, it was done with full recognition of the risk that drugs might be approved and later found not to confer clinical benefit to patients. FDA deemed this risk worth taking for life-threatening illnesses in need of additional therapies, but also found it essential to mitigate that risk by providing for follow-up studies and withdrawal when benefit is not confirmed. The program has, on the whole, worked very well, making many new drugs available, particularly to cancer patients and AIDS patients, years before they would otherwise have been on the market. But when follow-up studies fail to confirm benefit, it is essential that approval be withdrawn in order to protect patients.”If the accelerated withdrawal hammer had been rendered meaningless, we predict you would have seen a lot fewer accelerated approval announcements coming out of CDER in the years ahead. Better to wait three, four, five years for survival data, or confirmatory evidence on some other “hard” endpoint, before making an approval decision than having to face both the embarrassment and time-consuming work of defending your revocation decision at a public hearing, all the while wondering if your own commissioner was going to back you up.
Hamburg’s comments highlight the strengths and weaknesses of progression-free survival as a surrogate endpoint. Though the agency is still reticent of giving hard targets, as sponsors would prefer, it lays out that in many first-line settings, it is the only practical option and one the agency is happy to review. The level of benefit that counts as “clinically meaningful” may be a matter of debate, but even Genentech acknowledged during the hearing that FDA’s granting the MBC approval was “progressive thinking” on the part of the agency. For other sponsors, the Avastin process has added some clarity on FDA’s expectations surrounding PFS – in particular, that quality of life benefits could serve as evidence that the benefit is clinically meaningful. So the Avastin withdrawal shouldn’t just dissuade sponsors from using PFS, it should encourage them to design trials with supportive measures that can themselves turn into additional claims. (Indeed, Incyte’s Jakafi (ruxolitinib) just cleared FDA with a patient-reported outcome based symptom claim.)
By withdrawing Avastin’s MBC indication, Hamburg has introduced some predictability into the accelerated approval regulatory pathway, both for agency staff and drug developers. We’d be surprised if industry, and its investors, didn’t see that as a good result. -- Sue Sutter