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On CNBC this Tuesday, I called on HHS Secretary Sebelius to promise that CMS would continue to pay for Avastin as a treatment for breast cancer.
(The complete CNBC interview can be viewed here.)
And, late yesterday, Medicare confirmed it would do just that. According the CMS spokesman Don McLeod, “The label change will not affect our coverage.”
At least for now. As Andrew Pollack reports in today’s New York Times, “Mr. McLeod’s statement could allay those concerns, at least for women covered by Medicare. He said that Medicare commonly paid for off-label use of cancer drugs.”
McLeod said that while there were no plans for one right now, he could not totally rule out that Medicare might one day undertake a national coverage determination to decide whether to pay for Avastin. That process would take at least a year and involve public input.
In other words, the administration understands that, had CMS withdrawn reimbursement for Avastin’s use in breast cancer, it would have become a front-and-center election issue. Proof positive that ObamaCare equals denial of care.
A unique situation (at least as of late) where the right public health decision is also the savvy political move.
And hopefully it won’t be the last.
(Can you say “Adieu IPAB?")
I’ve just returned from the big BIO bash, where I was honored to moderate the panel discussion, "Lessons From In-Licensing Partnership: Biotech Company Partners with Global Pharma to Deliver Cutting-Edge Follow-On Biologics.” I was joined on the podium by joined by Arun Chandavarkar, Chief Operating Officer of Biocon Ltd.; Stephen Hoge, Principal at McKinsey & Co.; and Diem Nguyen, General Manager, Biosimilars, Pfizer.
Here’s how I opened the discussion:
Woody Allen said that, “Change should always be expected – except from vending machines.” But management guru W. Edwards Deming hits closer to the mark, “Change is not required. Survival is not mandatory.”
Many believe that the age of the blockbuster is over. Cost concerns are more challenging than ever. And we are struggling with what “personalized medicine” really means.
We are now in the era of post-patent medicine where advances in manufacturing, incremental innovation, and molecular diagnostics are as important as new molecular entities, and safety is as important (and as improvable) as efficacy.
The era of post-patent medicine is also the epoch of biosimilars. But will biosimilars really be as important an element of change as many believe. Will it be a game changer?
I believe the answer is “yes,” but I am not sure whether or not all the changes will positively affect the advancement of the public health. I fear the expectations that biosimilars will radically reduce costs are overstated. I fear that safety concerns are being understated and that the risks to innovation are real.
As Eli Lilly & Co. CEO John Leichleiter said, "Creating and maintaining the conditions for innovation to flourish is challenging and complicated work - work that is never finished.”
Case in point -- there seems to be general consensus that, with a clear FDA pathway still off in the future, BLAs are the way to go. Hence a redefinition of BLA as “Beat Legislative Ambiguity.” No aBLA biosimilar.
EMA and FDA recently announced that they are setting up a "cluster" on biosimilars to increase communications between the two agencies on the topic and the two agencies will discuss harmonization of regulatory requirements. Yet fundamental differences in the laws they administer make harmonization difficult.
Beyond a standardized regulatory pathway, there are many issues on the table:
* The role of “next generation biologics” (or, if you prefer, “biobetters”)
* Bioequivalence, interchangability, and therapeutic substitution
* The debate over distinguishable names and robust post-marketing surveillance
* GMP standards
* Reference products and clinical trial requirements and design
* And, last but not least, Patent Life vs. Data Exclusivity
And that’s not even considering PDUFA V. Nobody said it was going to be easy.
This morning’s panel won’t answer every question – and it is very likely to raise a few more. Our hope is that the panel will provide useful and timely insight on how global pharma and biotech companies can collaborate to develop, gain authorization, and globally commercialize cutting-edge follow-on biologics.
(And I believe we succeeded in delivering a thoughtful and thought-provoking discussion.)
Avastin Fight Highlights Limits Of Big, Random Trials
An FDA advisory panel on Wednesday unanimously rejected arguments from Genentech that its anti-cancer drug should continue as an approved therapy for... View Enlarged Image
A Food and Drug Administration special advisory panel voted 6-0 on Wednesday to withdraw approval of the drug Avastin for treating late-stage breast cancer, sticking to its usual scientific standards despite some patients' pleas to disregard them.
The recommendation was based on the best scientific evi dence currently available, but the controversy highlights the limits of the science the FDA uses to determine drug effectiveness.
"Large, randomized-controlled trials are the 20th century," said Peter Pitts, president of the conservative Center for Medicine in the Public Interest. "The 21st century is the age of personalized medicine, where we need better molecular diagnostics to determine which subpopulation reacts to which treatments."
Avastin blocks the growth of new blood vessels to tumors, and is already FDA-approved for late-stage colon and lung cancer.
In 2008 the FDA granted accelerated approval of Avastin for use in late-stage breast cancer based on one randomized trial that found it slowed the progression of late-stage breast cancer.
In late 2010, the FDA withdrew approval based on two trials that found Avastin did little to slow progression, did not improve overall survival from late-stage breast cancer, and that it posed serious health risks, including death.
Randomized-controlled trials often involve large samples of patients. Such studies determine if a drug has a widespread benefit. But this is also a limitation. A treatment may work for a subpopulation in the sample, but since it doesn't work for most people in the sample, the average shows that the treatment is ineffective.
"The concept that you're looking for one magic bullet that cures a ton of patients at once is the wrong idea," said Terry Kalley, who founded Freedom of Access to Medicines in response to the FDA's 2010 decision on Avastin. "Cancer is likely to be cured by several therapies that target different subpopulations."
Kalley says his wife Arlene has been taking Avastin, along with chemotherapy, for 27 months.
Roche asked the FDA to extend its approval of Avastin until it conducts a study that "would include a biomarker component to identify patients who may be more likely to derive a more substantial benefit from Avastin."
But that is in the future.
"Unfortunately, the data we have right now (don't) allow us to know if there is such a subpopulation," said Karuna Jaggar, executive director of Breast Cancer Action.
Jaggar is concerned that Roche is using this as a stalling tactic to keep Avastin on the market. The Swiss drug giant could lose nearly $1 billion in sales, analysts say.
"We must insist that breast-cancer patients are receiving drugs that have been demonstrated to work," Jaggar added.
Others say regulators should keep Avastin approved for now.
"The FDA should say the evidence isn't there right now, but we will work with Genentech and patient groups to develop the appropriate diagnostics," said Pitts. "But the FDA needs to leave the indication on the label so people can still use it and be reimbursed for that."
If the FDA rescinds Avastin for late-stage breast cancer, at least until subpopulations are studied, then Genentech/Roche cannot market the drug for that purpose.
Doctors could still prescribe Avastin for the off-label use. But it's unlikely that government programs like Medicare and Medicaid or private insurance will cover Avastin — which costs $80,000 or more per year — for breast cancer.
An estimated 17,500 women suffer from late-stage breast cancer.
Many people like Terry testified at the hearings about Avastin. But without better data, such stories are little more than anecdotal.
The flip side is that if it turns out that Avastin does help some subpopulations, such women today will suffer as long as the FDA does not approve the drug for late-stage breast-cancer treatment.
What the FDA advisory panel (stacked by Richard Padzur, who heads up the Office of Cancer Drugs, with 6 advisors who wanted to yank Avastin last year) said was that based on the FDA's read of the data, Avastin despite causing a doubling in median progression free survival and objective response in tumors as well as an overall medial survival of two additional months in a subgroup of patients who were the most likely to die without Avastin (that's my take) and were more likely to die of cancer should not be used for breast cancer because it caused too much hypertension, bleeding and swelling.
Hal Barron, Executive Vice President, Head of Global Development: Oncology, Inflammation, and Virology at Genentech -- Avastin's creator -- summed up the FDA's (Padzur) deadly decision: The FDA (Padzur) would have allowed the Avastin indication to stay if it was really treating an unmet medical need. In otherwords, the FDA (Padzur) would have not stacked the deck against Avastin if the FDA (Padzur) thought that giving thousands of women longer life and better health.
The FDA switched the endpoints and oncologists, health plans and patients know it even as The Gooz oozes glee over the Avastin decision and derides the additional benefit to thousands of patients as just in their minds. Here's what Padzur said in his summary of evidence against Avastin.
"AVADO showed a statistically significant improvement in PFS for the bevacizumab-containing arms, with a HR of 0.70 (95% CI 0.55, 0.90) for 7.5 mg/kg
bevacizumab arm and HR of 0.62 (95% CI 0.48, 0.79) for the 15 mg/kg bevacizumab arm. The magnitude of treatment effect, as commonly assessed by clinicians based on
differences in median PFS, was marginal."
Genentech had called out this shifting of evidentiary standards in a pre-hearing summary of evidence:
"Although it was clear that AVADO and RIBBON1 (the two studies FDA, I mean Padzur, wanted to confirm the benefit of Avastin) were not powered to show an OS benefit, the agency now cites the studies for failing to show a statistically significant OS effect. Then, CDER stated only after its decision to withdraw Avastin’s MBC indication that any PFS effect “must confirm the magnitude of treatment effect of E2100."
Also: " CDER also has not articulated a clear rationale for its view that a 5.5-month improvement in median PFS is clinically meaningful but lesser improvements are not."
www.gene.com/gene/news/news-events/avastin/documents/051311.pdf
FDA might believe it sent cancer drug developers a message, but I believe it's get tough approach will backfire:
1. Medicare and health plans will still continue to pay for Avastin.
2. Congress will hold oversight hearings and will rake Padzur over the coals (repeatedly) en route to amending FDA statute through one of many bills calling for faster access to new treatments.
3. The Obama administration will toss the FDA under the bus as the attacks target the President for presiding over the rationing of new drugs.
4. Cancer patients who moblilized to keep Avastin's label will become enraged and engaged long term.
5. The FDA has unleashed public sentiment that will overwhelm the medical progress haters -- Avorn, Angell, Wolfe, Goozner, Mahar, Soros, Furberg -- who will find their Congressional patrons have abandoned them.
First some facts, figures, and definitions:
- A “rare disease” (according to the IOM) is one that affects fewer than 200,000 people (in the United States)
- An estimated 25-30 million Americans suffer from a rare disease
- According to the NIH Office of Rare Diseases, there are more than 6800 “rare diseases”
- 80% of rare diseases are of genetic origin
- 50% of rare diseases affect children
- 85-90% of rare diseases are life threatening
And, most germane to this conversation …
- Only 10% of rare diseases have available treatments
So, what are we doing about it?
Well, of course there’s the Orphan Drug Act of 1983 which:
- Modified the Food Drug and Cosmetics Act to increase market incentives and reduce regulatory barriers for orphan drugs
- Provided the following incentives for industry to research, develop, and manufacture drugs for rare diseases:
- Seven years market exclusivity from the date of marketing approval of a drug with an orphan designation
- Tax credit of up to 50% for clinical research costs of a designated orphan drug
- Grants to support clinical development of products for use in rare diseases
- Waiver of PDUFA fees normally charged to sponsors
- Assistance with trial design for sponsors by FDA staff about nonclinical and clinical studies that could support approval of a rare disease drug
And the FDA Modernization Act of 1997 which:
- Provided additional incentives for industry to develop drugs for serious or life threatening conditions and which potentially address unmet medical needs (not exclusive to orphan drugs) including fast track, accelerated approval, and priority review designed to facilitate the development and expedite the review of new drugs that fall in the above category.
And what have these well-meaning pieces of legislation delivered?
Well, as of January 2011:
- There are 460 rare disease drugs in development in late stage clinical trials or awaiting FDA approval
- More than 350 medicines have been approved to treat rare diseases since 1983 (compared to 10 in the 1970s
- 2,313 medicines have been designated orphan drugs by the FDA
- Between 2000 and 2008:
- Orphan drugs comprised 22% of all new molecular entities (NMEs) and 31% of all significant biologics (SBs) receiving market approval
- Orphan drugs receiving priority review status rose from 35% of all orphan NMEs in 2000 to 50% in 2008; orphan SBs receiving priority review status rose from 17% to 67%
- Big Pharma’s share of orphan drug approvals grew from 35% to 56%
- Average total development time for orphan products dropped by 2.3 months for NMEs and 37.5 months for SBs
Mazel tov. All good things. Solid and important achievements – as intended.
Why the success? Many reasons – not the least is which is that investment in innovation was rewarded.
But now comes the unintended part – reimbursement problems.
Scuttlebutt across the industry is that payers are beginning to, increasingly, question Tier One formulary status for many new drugs designed (and designated on label) to treat rare diseases. And these conversations are, increasingly, taking place well in advance of FDA review. The result is that Big Pharma is (increasingly and not surprisingly) recalibrating go/no-go decisions on rare disease development programs. It’s yet another unintended (and dire) consequence of short term cost-centric care trumping patient-centric medicine.
Stifling for innovation. Worse for patients.
Widows and Orphans is not an option.
Attention must be paid.
tinyurl.com/3cthlwf
"There seems to be this perception that there are all these kinder, gentler treatments for metastatic breast cancer, but I'm not aware of those treatments, said Dr. Kimberly Blackwell of Duke Cancer Institute.
Blackwell helped conduct the trials of Avastin in breast cancer and believes the FDA is "moving the goal posts" on the drug's effectiveness, which could discourage drugmakers from pursuing new drugs.
"If the label is withdrawn, we will not see a new drug for metastatic breast cancer for another decade," said Blackwell, who directs Duke's breast cancer program.
Watch these discussions of Avastin's use in HER-2 positive metastatic breast cancer underscores just how misleading is the claim that there is no scientific evidence to support what patients are saying."
www.ecancermedicalscience.com/tv/video-by-category.asp
tinyurl.com/6b5o8pz
www.foxnews.com/opinion/2011/06/28/fda-panel-is-deciding-life-or-death-for-my-wife/
According to a report in BioCentury, “A few weeks after finishing negotiations with FDA over a PDUFA V deal that seeks to tweak drug oversight with changes to the review process, BIO now plans to propose sweeping changes to the U.S. regulatory system.”
For example:
A progressive approval pathway to get new therapies for unmet conditions to patients rapidly; with intensive surveillance and limits on off-label prescribing if necessary
A revamping of the advisory committee process to ensure that conflict-of-interest rules do not prevent FDA from gaining access to needed expertise
A fixed term for the FDA Commissioner to insulate the agency from political pressure. BIO takes political independence a step further, calling for FDA to be removed from HHS and turned into an independent agency with a head who reports directly to the president, like the Environmental Protection Agency.
A refining of FDA’s mission to emphasize its role in biomedical innovation. To bolster FDA’s capacity to advance scientific innovation, BIO wants Congress to lift restrictions on funding the Reagan-Udall Foundation.
Further, BIO calls for the FDA to have a “chief innovation officer with “authority to pilot and develop strategies for implementation of promising scientific and regulatory approaches in review divisions.”
Underscoring the connection between regulatory innovation and PDUFA, a member of BIO’s board of directors will present the organization’s recommendations at a July 7 House Energy and Commerce Committee hearing about PDUFA.
Bravo BIO.
Center for Medicine in the Public Interest is a nonprofit, non-partisan organization promoting innovative solutions that advance medical progress, reduce health disparities, extend life and make health care more affordable, preventive and patient-centered. CMPI also provides the public, policymakers and the media a reliable source of independent scientific analysis on issues ranging from personalized medicine, food and drug safety, health care reform and comparative effectiveness.
