The Avastin Decision: Bad For Genentech, But Good For Industry?

On its face, FDA Commissioner Margaret Hamburg’s decision to rescind Avastin’s breast cancer claim is a clear (though likely not unexpected) blow for Genentech, which waged an aggressive, creative and undoubtedly expensive battle to maintain its blockbuster VEGF-F inhibitor’s accelerated approval for first-line metastatic disease.

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 

FDA's Sharfstein On Avandia: "An FDA Decision"

FDA Deputy Commissioner Joshua Sharfstein was asked repeatedly during a briefing with media: Who will make the final decision on Avandia?

His answer: "It will be an FDA decision."

In the context of the question being asked, it wasn't a seemingly helpful response. But it gets to the heart of who carries the burden when the dust settles from the two-day advisory committee review on July 13-14.

If FDA chooses to pull the drug, the agency will have to explain to patients and prescribers why the drug, which an advisory committee voted overwhelmingly was linked to increased cardiovascular risks in 2007, has remained on the market for three years and counting. One could make the argument that it's been 12 years.

If FDA chooses to keep Avandia on the market--more restrictions or not--they'll have to explain to patients and prescribers why a drug linked to increase heart attack risks is still available.

Regardless, they have to explain the decision to their overseers in Congress and the public at large.

The gravitas of that decision and subsequent fallout means there is one person at "FDA" who will indeed make the final decision on Avandia: FDA Commissioner Margaret Hamburg.

So whether or not Hamburg literally makes the decision, it's hers.

Can a Biomarker Salvage Novartis' Joicela (AKA Prexige?)

In the "History of Troubled Drugs" playbook, lumiracoxib (Prexige, now called Joicela) is only a footnote, hardly a Vioxx or Avandia.

Prexige, however, may make a mark after all in pharma annals, far beyond its missed revenue opportunity or beneficial impact on patients. The drug, which is made by Novartis, is a selective COX-2 inhibitor, indicated for symptomatic relief of pain from osteoarthritis. COX-2s --as in the infamous Vioxx--are all but off the market in the US because of their cardiovascular side effects, but lumiracoxib binds to a different site on the COX-2 receptor, which may give it advantages that lift it from under the Vioxx shadow: minimal CV side effects, high selectivity, rapid cleansing from the blood and absorption into the inflamed joint.

The drug received European marketing authorization in November 2006 and launched in parts of Europe the following year. It has its own demons, however – rare but potentially fatal risk of liver failure at higher doses, and the FDA never approved it. In 2007, Novartis began under pressure from regulators to withdraw it from the market in the EU and elsewhere.

Now, as Joicela, lumiracoxib linked to a lab test may make a comeback. Novartis scientists have come up with a genetic marker, which they say can identify patients who are potentially at risk for lumiracoxib-associated hepatotoxicity. In essence, Novartis argues, patients who test negative for the marker aren't at high risk of liver side effects and can take the drug. Those who test positive for the marker should not get the drug.

It's an interesting case study in the murky, fragile world of companion diagnostics, which is starting to show up as more than a blip on pharma's radar. One indicator: Roughly a dozen or so diagnostic-drug companies deals with the aim of bringing a diagnostic and drug that are linked through to commercialization, were signed in 2009 --compared to seven in 2008. Novartis itself started a Novartis Molecular Diagnostics business unit--which is developing the diagnostic for Joicela and has 10 projects in the works --only little more than a year ago.

If Joicela makes it back on the market, pharma is likely to take note. For pharma, a biomarker strategy for rescuing flawed drugs holds tremendous appeal (think Exanta, Galvus, etc.), even if the ultimate market is nowhere near the original projections--especially if regulators accept data based on analysis of archived samples from previously completed studies. That's the approach Novartis has taken in Europe, where it submitted an application for marketing authorization in December 2009.

Novartis' next step in the US is less clear cut because the FDA has yet to propose a regulatory pathway for companion diagnostics --and the agency's paralysis has been a hurdle to say the least. Yet some good news happened on Feb. 25: Commissioner Margaret Hamburg for the first time publicly stated a timeframe: She expects the agency will propose companion diagnostics guidance this year.

Conspicuous Consumption: FDA Makes TB a Priority

Margaret Hamburg has only been on the job as commissioner of the Food & Drug Administration for two days, so it is obviously too early to pronounce on winners and losers in the Hamburg era. Except in one case: it already looks like the Hamburg years will be good ones for companies pursuing new therapies or vaccines for treatment of tuberculosis.

After all, Hamburg’s role two decades ago in combating drug resistant TB as New York public health commissioner was one of the defining elements of her resume when she emerged as the nominee for FDA commissioner. As she told the Senate HELP Committee during her confirmation hearing earlier this month, New York’s “rapid response to an epidemic of drug-resistant tuberculosis became the model worldwide.”

But it’s not just Hamburg talking about TB.

FDA’s new chief scientist—Jesse Goodman—highlighted a TB vaccine as an example for the need to focus on global public health priorities during a keynote address at the Food & Drug Law Institute annual meeting in April.

“There are billions around the world who clearly need an effective TB vaccine,” he said, citing an analysis by BIO Ventures for Global Health indicating that the market for such a vaccine would exceed $1 billion—even without sales in the US or other developed economies.

That’s not all: “If we had a highly safe and highly effective TB vaccine it would probably make sense to use it in this country,” Goodman added, noting “the chaos” that followed one traveler returning to the US with extremely drug resistant TB. That’s music to the ears of companies like Sanofi and GSK, which are developing TB vaccines. (You can read more of Goodman’s remarks to FDLI in The RPM Report.)

Then there is an upcoming meeting of FDA’s Anti-Infectives Drugs Advisory Committee June 3 to discuss “issues related to the development of drugs for the treatment of tuberculosis, including drug resistant tuberculosis.”

“Areas of discussion include diagnosis, treatment duration, study design (such as endpoints and duration of follow up) and safety issues,” the meeting announcement says. (We’ll have coverage of the meeting itself in The Pink Sheet next week.)

The meeting was announced by FDA March 12, one week after we broke the story of Hamburg securing the White House nod for FDA. We missed the coincidence at the time, but in hindsight it’s a clear indication of one priority for the new FDA leadership. (Yes, the TB meeting was being planned before Hamburg was picked—but then again, Hamburg was on the HHS transition team…)

A search of our Inteleos database shows at least 34 drugs and vaccines in development for TB. The Hamburg years should be good for those projects.