Latest Drugwonks' Blog
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.
From the pages of the Des Moines Resister.
(Why Iowa? You know why.)
Our shortsighted plan for dealing with Medicare
By: Peter J. Pitts
First, HHS announced it would be making $42 million available to enhance coordination efforts between primary care physicians and other health care providers treating Medicare patients. An Emory University study concluded that better coordination in Medicare could save $125 billion over the next 10 years.
Second, HHS launched a $40 million effort to help states combat chronic disease.
Chronic diseases are responsible for 75 percent of our health care costs. Diabetes, heart disease and strokes alone account for nearly a trillion dollars in medical spending annually.
Both those initiatives have the promise to save money and lives. Unfortunately, they represent exactly the opposite approach to Medicare cost control set forth in last year's health care reform law.
Deep in the heart of the 2,700-page law is the creation of something called the Independent Payment Advisory Board (IPAB), a panel tasked with reining in soaring Medicare costs.
Here's how IPAB will work. The president will appoint 15 "experts" to serve on the board. Starting in 2014, they will be charged with keeping Medicare annual spending in line with designated targets. Any time spending looks to exceed its target, IPAB must draw up cuts to bring it in line.
Incredibly, IPAB's Medicare spending recommendations automatically become law whether a majority of Congress approves of them or not. Overriding IPAB requires a three-fifths majority vote in the Senate, a very high legislative hurdle. There's also no way for doctors or patients to legally or administratively challenge IPAB's decisions.
There are numerous legal problems with IPAB. A lawsuit is challenging the board's constitutionality, arguing that it has been improperly delegated authority over the federal budget (about 13 percent of the total) that constitutionally belongs to Congress.
The policy repercussions of IPAB are even worse. In meeting its spending targets, IPAB is ostensibly not permitted to ration care or adjust Medicare premiums and fees. Its main tool for cost-cutting is to lower Medicare reimbursement rates to doctors and other health care providers.
Unfortunately for Medicare patients, reimbursement rates are already well below market rates. Because of this, the number of doctors limiting or refusing Medicare patients is at an all-time high. IPAB threatens to make doctor access a major problem for Medicare.
Worse still, the scramble IPAB will produce each year to meet spending targets will deflect policymakers' attention from innovative new programs such as the two announced by HHS.
Even though the HHS primary care coordination and chronic disease initiatives are comparatively inexpensive and could eventually yield major savings, it will likely take years to measure their impact, let alone demonstrate that they're reducing costs. Not only that, they increase health care costs in the short-term.
On one hand, these two new HHS initiatives show that the Obama administration is making credible efforts to target the areas of the health care system that could produce the most savings. On the other hand, the Affordable Care Act through IPAB seeks to devalue efforts such as these in favor of squeezing doctors and other providers.
The right way forward is to get rid of IPAB and substitute for it a Medicare cost-savings plan that encourages long-term strategic thinking along the lines of these HHS studies.
The partisan acrimony over health care reform in Washington would seem to make all-new Medicare legislation unlikely. Fortuitously, though, bipartisan concern about IPAB's obvious shortcomings might prove to be the catalyst for a new and improved reform initiative.
House Budget Chairman Paul Ryan, R-Wis., has made repealing IPAB a major part of his high-profile budget proposal. Politico reports that several House Democrats have signed on to repeal IPAB. The repeal legislation's House sponsor, Phil Roe, R-Tenn., has floated the possibility of attaching repeal to the must-pass increase in the debt ceiling.
Support for IPAB is rapidly and rightly collapsing as citizens become better informed about the danger this all-powerful panel of unelected bureaucrats poses to their health care. It's time to urge Congress to get rid of IPAB and stand up for real Medicare reform.
In France the Ministry of Health has outlined a proposal to overhaul the country’s regulations on reimbursement, marketing, and safety of prescription drugs.
Details are incomplete, but Xavier Bertrand, the Minister of Health, highlighted these provisions:
- A new law on transparency and conflict of interest, to be called the “French Sunshine Act”;
- Pharma companies will be “held responsible for off-label use management with financial consequences”;
- For reimbursement, new drugs will be required to have an active comparator in Phase 3 studies,
- Products that have been on the market for some time will need to have a benefit/risk valuation prepared;
- A new tax will be created on pharma to finance physician medical education;
- A limit on sales reps beginning in hospitals (no personal detailing - only in group meetings) that may be extended to physician offices.
We’ll see. As General De Gaulle said, “How can you govern a country which has 246 varieties of cheese?”
Or, perhaps more to the point, “I have come to the conclusion that politics are too serious to be left to the politicians.”
Bien sûr -- and especially when it comes to healthcare.
Please pass the cheese.
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.
