Latest Drugwonks' Blog

The WSJ gave a lot of coverage to Leonard Saltz vitriolic attack on the cost of new immunotherapies for cancer.   Saltz call the prices for immunotherapy for advanced melanoma insance and immoral, some the WSJ article: High Prices for Drugs Attacked at Meeting
Cancer specialist criticizes new-treatment costs in high-profile speech


Dr. Leonard Saltz bases his fear about the unsustainability of cancer drug costs on emotion, not fact.   He claims that if we treated everyone with metastatic forms of cancer with treatments costing $295000, we would spend $174 million each year and that cost would be unsustainable.

Actually, it would be a bargain.   Dr. Saltz is assuming everyone who dies of cancer each year (580000) would get a combination of immune therapies.  The combination in question -- nivolumab (Opdivo) and ipilimumab (Yervoy) adds about a year of life to people with advanced forms of cancer.   So let’s stick with melanoma in explaining the incredible amount of value generated and money saved by such therapies.

The most recent estimate of the direct cost of treating advanced melanoma is $160,000 per person.  (The direct costs of treating metastatic colorectal, breast and lung cancer are about the same.) A good portion of this cost would be eliminated by using immunotherapy because the treatments displace the use of existing medicines and hospitalization.   I don’t count the amount of money saved from avoiding surgeries to remove tumor masses since the immune therapy shrinks tumors by 80 percent.   But if we treat everyone with such therapies in end stage cancers, we could save $92 billion a year on less effective forms of treatment. 

Further, stage IV melanoma currently has two-year survival rate of only 15 percent when treated with conventional chemotherapy.   Immune therapies allow 90 percent of patients to live 2 years.

If we assume that 90 percent of people who otherwise die of cancer in a given year lived two years that would add 1.1 million life years for each group of patients. An early study estimates the productivity loss of cancer death at about $250 billion.  Thus adding 1 million life years would generate $500 billion.   A more conservative estimate (valuing an additional life year at $150000) would be $150 billion.  And even if we assume a 60 percent response rate under either scenario, our society more than breaks even with a jump in two year survival.  Of course, if 90 percent of people who live two years, wind up living 5 years, both savings in medical spending and life year value soar.

Dr. Saltz said cancer drug prices are insane and immoral.   I’d say the same about someone who said – given these benefits – we shouldn’t perhaps pay even a little more.

From the pages of Politico

21st Century Cures up against FDA’s 20th century communication

When it comes to communication, the 21st Century Cures Act is stuck in the 20th century.

The sweeping biomedical innovation bill aims to speed up development of medical treatments by taking advantage of the latest in science and technology. But provisions meant to update the FDA’s regulations on drug advertising were dropped.

The agency’s current marketing and promotion regulations don’t even mention the Internet. They focus instead on brochures, file cards and, inexplicably, lantern slides — a mid-1800s invention that was supplanted decades ago.

In the era of Facebook, Twitter and YouTube, drug and medical device makers contend a social media reboot is critical.

The first draft of the House Energy and Commerce’s bill did make an attempt. Among other changes, it would have forced the FDA to let drug companies communicate truthful “introductory” information in character-limited settings such as Twitter so long as they hyperlinked to a webpage with more safety and efficacy information.

That “one-click” concept is gone from the legislation that cleared the committee on May 21 and is now headed to the House floor. Also gone is a measure directing FDA to revise all regulations and guidances that could apply to online communications so that drug and medical device makers can use the Internet “in a meaningful way” to disseminate truthful and non-misleading information.

In Rep. Billy Long’s view, these provisions would push FDA “to update its regulatory approach to communications to keep up with today’s technology.” The Missouri Republican quickly introduced them as a separate bill after they were cut from Cures, and an E&C staffer signaled late Friday that members remain supportive and that more work could take place later this year on proposals that didn’t garner a bipartisan consensus before the committee’s vote.

The social media debate involving FDA, the pharmaceutical industry and Congress is taking place in what is quickly becoming a free speech powder keg. Companies are pushing the agency to align its policies with recent court decisions that have upheld their right to communicate certain information regardless of whether it appears on an FDA-approved product label — the regulatory standard for what is widely marketable.

Without faster change, the industry warns, FDA instead risks a complete overhaul of its advertising and promotional regulations by the courts.

Richard Samp, chief counsel at the nonprofit Washington Legal Foundation, which defends the free enterprise system as its mission, has worked for decades on these issues. Though he doesn’t foresee the courts taking over FDA’s authority to set limits on pharmaceutical marketing, he does expect continued legal challenges that could complicate the regulatory environment.

“FDA has been on a pretty long losing streak when it comes to First Amendment issues, and the longer FDA continues to do nothing, the longer it will be that they continue to have these losses and the more confusion that will be created,” he said.

The agency should see the Internet as unique from older, static forms of communication, drug makers argue.

“Right now, FDA essentially treats a web page or even a banner ad or a tweet as if it were a print vehicle, when patients and health care professionals who are online treat the Internet differently,” said Jeff Francer, vice president and senior counsel at the Pharmaceutical Research and Manufacturers of America.

Unlike a print ad, the web allows a company to constantly update information. It also lets consumers quickly jump from one page to additional product details or third-party content, and companies want to know how much they’re on the hook if a third-party site later adds information about a drug’s unapproved use.

Social media triggers other scenarios. Companies say they need more guidance on when they must report adverse drug experiences patients share with them through a posting on their Facebook page, for example.

At the same time, FDA is itself engaging online — in ways that only accentuate the gap between its lack of guidance for industry, critics say.

While the agency uses Facebook and Twitter to make short announcements on medical products, companies that do the same risk legal repercussions for not including enough risk and efficacy specifics in their post. Even retweeting the FDA’s own communication would be in violation of the agency’s advertising policies.

“The FDA uses Twitter to link its announcements to more comprehensive information. It is commonsense for the federal government to allow drug manufacturers to use these platforms in a similar fashion,” Long told POLITICO.

FDA first held a public meeting to discuss promotion of agency-regulated products on the Internet nearly two decades ago. Joy Liu, who specializes in drug advertising and promotion at the Washington law firm Ropes & Gray, remembers officials discussing the use of chat rooms and news groups, “sort of a precursor” to social media, she said.

But that 1996 meeting failed to translate into substantial policy changes. In 2009, Liu said, the agency reconvened another public meeting, asking how drug makers could fairly balance benefit and risk information for consumers, how they could embed hyperlinks and how they should correct inaccurate information on the Internet about a product.

Not until last year, however, in response to the FDA Safety and Innovation Act of 2012, did the agency release a pair of Internet-specific draft guidances.

“Is this as important as curing cancer? Maybe not, but it is I think important,” Liu said. “Getting information out about your products, understanding what are the rules of the road, have become critical to companies because they have been prosecuted for allegedly doing the wrong thing.”

Others maintain that the FDA has given industry sufficient direction. The agency’s former associate commissioner for external relations, Peter Pitts, says its current guidance on the Internet and social media is fairly good — but that industry has chosen not to pay attention.

“I think it’s a bit of an excuse for industry not to engage,” he said, adding that companies may find it “very frightening” to take part in such immediate, two-way communication with consumers and do the 24/7 monitoring that social media can require. “It takes guts and chutzpah” to engage online, Pitts said.

FDA did not respond directly to a question about its pace in adapting advertising regulations to evolving technology, instead highlighting its two recent guidances and the projected release of further regulations this year.

“FDA sees social media as an important resource for industry and is committed to developing additional guidance for drug and device manufacturers that outline the agency’s current thinking,” a spokesperson said. “We do all of this work with the best interest of patients in mind.”

The 21st Century Cures bill does expand what industry can say about its products when communicating with health insurers and asks for FDA to issue specific guidance on communication related to a drug’s off-label use.

Yet even as the 2014 draft documents make their way forward, the technology continues to evolve and trigger new questions, said Mark Senak, a lawyer who focuses on pharmaceutical and device marketing at the communications firm FleishmanHillard.

For instance, given that many people use a cell phone as their primary means for accessing the Internet, do companies have to make sure any website advertising is optimized for a mobile device? Senak says it is unclear whether a site that’s fully compliant with FDA regulations when it appears on a larger computer screen could face FDA enforcement because of how mandated information displays differently, and perhaps far less accessibly, on a small device.

One of FDA’s hurdles is that “they are an organization that’s really into understanding data,” Senak said. FDA wants to fully research an issue in a scientific manner before creating policy. “The whole process of them issuing a guidance document is just too slow for this environment.”

FDA’s drug center director, Janet Woodcock, testified at an April 30 congressional hearing on the 21st Century Cures legislation that the difference between FDA’s social media use and what industry is permitted to do stems from the different stakes each has — one is a government public health entity, the other markets drugs for profit.

What Woodcock didn’t note is how flexible FDA already is on direct-to-consumer drug advertising compared to the rest of the world. New Zealand is the only other country that allows drug companies to directly market to consumers.

There’s little chance that the U.S. public will stop using the Internet as a go-to resource on health concerns. According to a 2012 Pew survey, 72 percent of Internet users said they had looked online for health information within the past year. Much of that info is unregulated, a reality that also frustrates drug manufacturers.

Aaron Kesselheim, an associate professor of medicine at Harvard University, says FDA’s slow approach to releasing Internet and social media policy may be due to industry’s response to its past guidances on drug and device promotion.

After the agency issued guidance on print media in the 1980s, “investment in print media advertisement exploded,” Kesselheim said. The same thing happened after FDA put out guidance on broadcast media in the late 1990s, revising the parameters on the risk information companies had to include in TV ads. Virtually overnight, direct-to-consumer advertising spiked. It went from $579 million in 1996 to $1.3 billion in 1998. A decade later, it had again more than doubled to over $4 billion.

“You can understand why the FDA may be wanting to cover all of the bases … and is being deliberative about this,” Kesselheim said. “When these kinds of guidance do come out, they lead to a substantial expansion of advertising — which can have bad outcomes for patients because some drug companies take advantage of it.”

Fierce Pharma has long been a reliable source of misleading information about the cost of medicine because it never mentions value. 

The latest post by Tracy Staton -- essentially a rewrite of an Express Scripts blog complaining about the cost of medicines --  lives up to that proud journalistic heritage.   Staton once again obsesses about the amount of money spent on two or three cancer drugs without mentioning their impact.  I think it’s because no matter the value of such innovative medicines, the profits and prices are too high for Staton.  

"As the American Society of Clinical Oncology meeting approaches, the pharmacy benefits manager released some numbers on cancer drug spending. The top line? Spending on cancer meds grew by more than one-fifth last year, with a 9% increase in use and almost 12% increase in prices.

Prime suspects for that increase? The leukemia treatment Gleevec, from Novartis ($NVS), which boasts the biggest share of the market at 12.5%. Fellow blood cancer treatment Revlimid--the multiple myeloma therapy from Celgene ($CELG)--came in close behind with 10.8% of pharmacy benefit spending.
She will never be convinced. " 

Let's take a look at those prime suspects and what they are guilty of.  

All Gleevec did was launch a revolution in personalized medicine and an array of medicines that allow people with CML to live full lives.  According to my colleague Tomas Philipson and his research group:  The TKI drug class in CML therapy has created more than $143 billion in social value. Approximately 90% of this value is retained by patients and society, while approximately 10% is recouped by drug companies...
The introduction of TKI drugs to treat CML has generated significant social value as a result of survival gains, the vast majority of which has accrued to patients.

What about treatments  for multiple myeloma developed by Celgene, Takeda and others since 1998:

Frank LIchtenberg concluded: 

"(A)lmost two-thirds (0.99 years) of the 1997-2005 increase in the life expectancy of American myeloma patients was due to an increase in the number of chemotherapy regimens now preferred by specialists. Based on a back-of-the-envelope calculation, this means that the cost per US life-year gained from post-1997 chemotherapy innovation is unlikely to have exceeded $46,000. We also investigate the impact of chemotherapy innovation on the myeloma mortality rate using longitudinal country-level data on 38 countries during the period 2002-2012. Countries that had larger increases in the number of chemotherapy regimens now preferred by specialists had larger subsequent declines in myeloma mortality rates, controlling for myeloma incidence.

Put another way,  people with myeloma added 360,000 life years since 1997, worth about $54 billion.  

Finally,  Staton ignores the contribtuion of cancer drug spending on total health expenditures.  

As the amount spent on new medicines increases, the cost of treating such diseases has declined
In 2011, 11.4 percent of total cancer expenditures were for prescription medicines as compared with 3.6 percent in 2001
The proportion spent on inpatient hospital stays declined from 47 percent in 2001 to 35 percent I 2011.

Cancer spending as a percent of total health care spending and GDP actually has declined.   Prescription drugs as a percent of total health care spending has remained at about 9 percent since 2000 and is projected to remain 9 percent for the next decade.  All the while cancer drugs make up more and more of spending on drugs and cancer care.

So maybe the takeaway is that more spending on the newest and most expensive drugs is a good thing.. or at least not portrayed as a criminal activity by FiercePharma.  

Fierce Pharma has to decide whether it has a responsibility to correct her bias by including other viewpoints or by providing greater editorial direction to include information that places the price and cost of medicines for cancer and other life threatening or disabling diseases in context.

My bet is that it will continue to demagogue an issue short on facts and chock fill of misplaced anger. 


Joint Meeting of the Drug Safety and Risk Management Advisory Committee and the Anesthetic and Analgesic Drug Products Advisory Committee


The meeting will be held on July 7, 2015, from 8 a.m. to 5 p.m. and July 8, 2015, from 8 a.m. to 4:30 p.m.


FDA White Oak Campus, 10903 New Hampshire Ave., Building 31 Conference Center, the Great Room (rm. 1503), Silver Spring, MD 20993-0002.


The committees will discuss the results of post-marketing studies evaluating the misuse and/or abuse of reformulated OXYCONTIN (oxycodone hydrochloride) extended-release tablets, supplemental new drug application (sNDA) 022272, manufactured by Purdue Pharma L.P. The committees will discuss whether these studies have demonstrated that the reformulated OXYCONTIN product has had a meaningful impact on abuse of OXYCONTIN.

FDA intends to make background material available to the public no later than 2 business days before the meeting. If FDA is unable to post the background material on its Web site prior to the meeting, the background material will be made publicly available at the location of the advisory committee meeting, and the background material will be posted on FDA's Web site after the meeting. Background material is available at Scroll down to the appropriate advisory committee meeting link.

And most importantly

Persons attending FDA's advisory committee meetings are advised that the Agency is not responsible for providing access to electrical outlets.

The complete notice can be found here.

 So let's see.. under the Express Scripts Bach (ESB) pricing scheme ESB would punish companies for investing in the hardest to treat cancers and diseases (by paying up to ten times LESS than list price) and reward them for picking the low hanging fruit.  
For example ESB would pay 5 times less to treat someone with pancreatic cancer with Tarceva than it does to treat  lung cancer because the average survival benefit is less.  ($1556 monthly compared to $6292)

My guess is that ESB would use $1556 as the reference price which means than any other company working on pancreatic cancer would see their good deeds penalized.  

Similarly,  ESB would price Erbitux for locally advanced squamous cell carcinoma of the head and neck at $10319 while it would pay only $471 for the much hard to treat metastatic forms. 

That is not only economically peverse, it's immoral.  If ASCO embraces this approach with it's value app it will kill innovation in cancer care overnight.  There is still a lot of chatter from ASCO about paying for value, but also paying doctors more for using cheaper drugs.   

This is disturbing. Lowell Schnipper,MD who runs the ASCO Value app project has made it clear that one goal of the app is to push down drug prices. And from Schnipper has said previously, the ESB pricing scheme is something he wants oncologists to endorse and discuss with patients.   “My guess is that something like this can have a modulating effect,” he said. The increased transparency may make it more difficult for pharmaceutical companies to attach significantly higher price tags to drugs that confer only a small benefit.

Those hot TV lights must be affecting Mike Huckabee’s cognition or, di minimis, his awareness of sloppy staff work.

"Americans should have the freedom to purchase safe drugs from Canada," Huckabee wrote in the Orlando Sentinel. "It just makes sense."

Alas not.

Let’s start here – there is a difference between the high quality, well regulated medicines Canadians get from their local pharmacies and those products sold to Americans via wildcat Canadian internet pharmacies.

Canadian internet pharmacies -- by their own admission -- are sourcing their drugs from the European Union. And while they may say their drugs come from the United Kingdom, let's not conveniently forget that 20 percent of all the medicines sold in the UK are parallel imported from other nations in the EU -- like Spain, Greece, Portugal and Lithuania.

Recently EU officials seized over 34 million fake pills in just two months. Irish drug enforcers confiscated over 1.7 million pounds of counterfeit and illegal drug packages. So if American customers start buying drugs over the Internet from Canadian pharmacies, they could easily wind up with tainted medicines of unknown European origin.

It’s also important to note that drugs from anywhere in Europe aren’t even legal for sale in Canada. So, when politicians say we can get “the same drugs” that Canadians get, they’re just plain wrong.

Even more worrisome is outright fraud — many “Canadian” pharmacies are actually headquartered somewhere else.

A 2005 investigation by the Food and Drug Administration looked at 4,000 drug shipments coming into the United States. Almost half of them claimed to be from Canada. Of those, a full 85 percent were actually from countries such as India, Vanuatu, and Costa Rica.

As part of another investigation, FDA officials bought three popular drugs from two Internet pharmacies claiming to be “located in, and operated out of, Canada.” Both websites had Canadian flags on their websites. Yet neither the pharmacies nor the drugs were actually from Canada.

As an FDA official told Congress, “We determined there is no evidence that the dispensers of the drugs or the drugs themselves are Canadian. The registrants, technical contacts, and billing contacts for both web sites have addresses in China. The reordering website for both purchases and its registrant, technical contact, and billing contact have addresses in Belize. The drugs were shipped from Texas, with a customer service and return address in Florida.”

And in laboratory analysis, every pill failed basic purity and potency tests.

The on-the-ground reality of state and local importation schemes have been dismal and politically embarrassing. Remember Illinois' high profile "I-Save-RX" program? Over 19 months of operation, a grand total of 3,689 Illinois residents used the program—which equals approximately .02 percent of the population.

And what of Minnesota's RxConnect? According to its latest statistics, Minnesota RxConnect fills about 138 prescriptions a month. That's for the whole state. Minnesota population: 5,167,101.

Remember Springfield, Massachusetts and “the New Boston Tea Party?” Well the city of Springfield has been out of the “drugs from Canada business” since August 2006.

And, speaking of tea parties, according to a story in the Boston Globe, “Four years after Mayor Thomas M. Menino bucked federal regulators and made Boston the biggest city in the nation to offer low-cost Canadian prescription drugs to employees and retirees, the program has fizzled, never having attracted more than a few dozen participants.”

The Canadian supplier for the program, Winnipeg-based Total Care Pharmacy, sent a letter to city officials saying the firm was terminating its agreement because there were so few participants. In 2006, Boston saved $4,300 on a total of 73 prescriptions. When Total Care decided to end its relationship with the city, only 16 Boston retirees were still participating.

And such programs won't do any better on a national basis. A study by the non-partisan federal Congressional Budget Office showed that importation would reduce our nation's spending on prescription medicines a whopping 0.1 percent—and that's not including the tens of millions of dollars the FDA would need to oversee drug safety for the dozen or so nations generally mentioned in foreign drug importation schemes.

 Calling foreign drug importation “re-importation” is a clever way to sell the idea to the American people. But the term simply doesn’t fit with the facts. In reality, Americans would end up jeopardizing their health by purchasing unsafe drugs made in foreign countries – while not saving money.

Note to Governor Huckabee – Get better staff.

Yesterday the WSJ ran an article about how Express Scripts wants to tie the cost of cancer drugs to how well they work.  

Let's deal with how hypocritical and self-serving this ploy is.

1.   Health outcomes are a function of adherence to medication.  Why doesn't Express Scripts tie what it makes in rebates to how well they help keep people on medicines.   To do this, it would have to eliminate cost sharing for specialty medicines that are shown to discourage compliance. 

2.   Health outcomes are a function of getting the right medicine at the right time as soon as possible.  Why doesn't Express Scripts invest in precision medicine profiling and eliminate cost sharing for medicines that are best for patients?   Why doesn't Express Scripts refund copays when drugs dont work under a fail first or step therapy approach? 

The answer: all this would get in the way of their profits.  Discrimination against sick people by designing benefits in way that put all meds in the highest cost sharing tier is good for business.  

Next, what about the feasbility and clinical impact of the Express Scripts proposal to tie payment to impact in specific uses or indications.  The company borrowed this idea from Peter Bach who has been noodling about ways to control drug prices for years. 

"Express Scripts’ approach would be similar to that proposed by Peter Bach, director of the Center for Health Policy and Outcomes at Memorial Sloan Kettering Cancer Center.In an article published last year in the Journal of the American Medical Association, he suggested that in an indication-specific arrangement, the monthly price for Eli Lilly & Co.’s cancer drug Erbitux (cetuximab) would plummet from $10,320 a patient to about $470 a patient for its least effective use, treating recurrent or metastatic head and neck cancer. The drug also is used to treat locally advanced head and neck cancer, as well as colorectal cancer."

So let's look at how this would work.  Not only does Express Scripts want to do use the Bach approach, the Amercican Society for Clinical Oncology wants to use the it in telling cancer doctors what medicines.  

Bach claims that the use of Erbitux for head and neck cancer is a "least effective use".  Let's set side the curious math used to arrive at the $470 figure.  It is more important to note that Bach ignores not only individual differences in response but the impact of Erbitux relative to existing need and treatment protocols.     Bach uses an average 2.3  months more of survival as his benchmark.   The price controllers love to focus on that number because it sounds so small.  Express Scripts and Bach dishonestly ignore context.

Here's what we know about pre-Erbitux treatment of recurrent, metastatic squamous cell carcinoma of the head and neck (SCCHN):

"None of the trials performed in the past, even those with a reasonable sample size, have shown that aggressive platinum-based combination chemotherapy leads to survival benefit when compared to single agent methotrexate, cisplatin or 5-fluorouracil.

What difference does Erbitux makes?  

After decades without real progress, a recent European randomized trial showed that adding cetuximab, the first clinically available EGFR-directed monoclonal antibody, to a standard chemotherapy regimen (platinum/5-fluorouracil) leads to an important survival benefit and this, with support of an additional smaller study in the US, has changed practice."  J. B. Vermorken and P. Specenier Optimal treatment for recurrent/metastatic head and neck cancer. Ann Oncol (2010) 21 (suppl 7): vii252-vii261 doi:10.1093/annonc/mdq453

Hence, the Bach-Express pricing approach would whittle away payment for the hardest to treat cancers for patients that have had no real advances in care for decades.  Maybe Bach supports paying doctors less for people who are the farthest gone because the relative health gains are well, not worth it??

Second,  the use of Erbitux, which targets the overexpression of EFGR associated with poor outcomes in SCCHN has lead to the development of biomarkers that that identify individuals that will have 4 times greater survival than the one size fits all studies Bach and Express Scripts would use to price treatment 

Thanks to research done with the drug, we now have assays measuring evidence that Hypermethylation of the p16 gene is associated with KRAS mutation and response to Erbitux .

So now we have groups of patients that Patients with p16-unmethylated tumors had significantly longer time to progression (TTP, median 9.0 vs 3.5 month; and overall survival (OS, median 44.9 vs 16.4 months than those with p16-methylated tumors. Patients with both KRAS and p16 aberrancy had markedly shortened TTP (median 2.8 months) compared to those with either KRAS or p16 aberrancy ...  Cancer Res Treat. 2015 Apr 24. doi: 10.4143/crt.2014.314. [Epub ahead of print]    p16 Hypermethylation and KRAS Mutation are Independent Predictors of Cetuximab Plus FOLFIRI Chemotherapy in Patients with mCRC.
Kim SH1, Park KH2, Shin SJ3, Lee KY4, Kim TI3, Kim NK4, Rha SY3, Roh JK3, Ahn JB2.

In the studya above, hypermethylation of the p16 gene was detected in 14 of 49 patients (28.6%) which means an even smaller group of patients then the number of patients in one size fits all studies.  Following the Express Scripts logic, using a drug for a smaller group of patients that have had no progress in treatments and limited 5 year survival prospects should be priced LESS than $470.

Heaven forbid looking at the effect of 'even' 3 months of survival -- or 25 months of survival in a small subgroup -- this way:

Each year 60000 people are diagnosed with head and neck cancer each year.    Fifty three percent have recurrent metastatic types. 

Running the numbers for the 28.6 percent of high responders with metastatic (31800 x.286=17160) we get 20008 years of additional life worth $3.01 billion.

For the benefit, Express Scripts and Bach would pay $17 million.  Meaning that they think an additional year of life for such patients isn't worth more than $583.

I didn't get into how patients receiving Erbitux spend about 30 fewer days hospitalized or in nursing homes and hospice.  Or that total costs per treatment is lower with Erbitux.  I don't have the time or patience right now to walk people who don't care or don't want to know through the economics.  

Too bad no one in the media has run the math instead of running with this as a novel way to deal with health care costs.  This is madness. As Isaiah Berlin put it, ‘disregard for the preferences and interests of individuals alive today in order to pursue some distant social goal that their rulers have claimed is their duty to promote has been a common cause of misery for people throughout the ages.”


Considering the paucity of biosimilar-specific data on the label for Sandoz’s filgrastim-sndz biosimilar, should sponsors be able to discuss their products’ analytical and clinical data with health care providers and payers? And what about with physicians?

When it comes to biosimilars, is off-label now on the table?

Zarxio was approved with labeling that was almost identical to that of Neupogen except for some differences specific to the products’ formulation and presentations The Zarxio label contains all of the same clinical data as that found in Neupogen labeling but none of the clinical or analytical data that supported the finding of biosimilarity to the reference product. But neither the word “biosimilar” nor the name of the reference product are found on Zarxio’s labeling.

Here’s the rub – the FDA has posted on its website hundreds of pages of review documents detailing its findings that Zarxio is highly similar to Neupogen with no clinically meaningful differences. However, the data analyzed in those reviews is nowhere to be found in the Zarxio labeling. The argument is that the absence of such data will hinder a biosimilar sponsors’ ability to use their analytical and clinical data in marketing and promoting the products.

Is this contrary to existing guidance? Technically no. Per a 2012 draft guidance document on scientific considerations in demonstrating biosimilarity, FDA said biosimilar labeling should include all the information necessary for a health professional to make prescribing decisions. This would include a “clear statement” advising that the product is approved as a biosimilar to a reference product, and whether the product has or has not been deemed interchangeable with the reference biologic.  BUT, the labeling-related language was from the final version of the scientific considerations guidance (issued in late April 2015). 

That lack of granularity is particularly irksome to biosimilar manufacturers since being able to discuss the data underlying approved biosimilars will be critical to building support for biosimialrs amongst doctors, patients, and (critically) payers. Can you say FDAMA 114? 

Beyond marketing and formulary concerns, there are also questions over who bears responsibility for updating a biosimilar’s labeling to reflect post-marketing adverse events. And what about the fact that the Sandoz product is not (at least not yet) deemed interchangeable by the FDA?

A side-by-side assessment of biosimilars and their reference product is a logical and appropriate exercise. Will it be considered violative, off-label communications?

Should it be specifically called out in 21st Century Cures? Should it await PDUFA VI? Or will the agency revise it’s current position of it’s own accord. And what will the impact of this issue be on biosimilar nomenclature?

Inquiring minds want to know.

I am putting in a lot of miles on behalf of international regulatory fraternity.

Over the last few months I’ve visited Egypt, Indonesia, Vietnam, Taiwan, Mexico, and Brazil, where I’ve had the distinct privilege to meet with regulatory and healthcare officials. (And boy, are my arms tired.)  Many things were discussed and shared, but the red thread was the urgency of quality.

I’ve learned many things and met many remarkable people. Perhaps the most important thing I’ve come to appreciate is that we need to stop talking about regulatory “harmonization” and focus our time and attention on regulatory “convergence.” Just as every nation has it’s own unique culture and cuisine, so too must it design it’s own regulatory philosophy and structure. It’s not about replicating the USFDA or the EMA – it’s about converging towards best practices.

Beware the danger of regulatory imperialism. Expecting other nations with less experience and resources to “harmonize” with the USFDA or the EMA isn’t the right approach. Rather we should seek regulatory convergence, because that gives us a pathway to improvement – with the first step being the identification of specific process asymmetries that can be addressed and corrected.

And at the top of the list is quality.

Without quality, safety and effectiveness are non-starters. Without quality, healthcare spending is not just wasteful – but harmful. Without quality it’s al about price without any consideration for value. Without quality, regulation is a sham.

In April I spent three fascinating days in Sharm El Sheikh, Egypt at the Second Arab Conference on Food & Drugs. It was all business – and I didn’t even mind not getting any time to enjoy the Red Sea beaches.

Delegates from the Levant to Morocco had a lot to say and share. The fundamental take-away was that the Arab world is serious about coordinating their efforts in healthcare in general and in regulatory affairs specifically. “Convergence” and “harmonization” were the two key words of the event.

(The Middle East/North Africa Region – MENA – consists of 22 nations – but just 2% of global pharmaceutical sales.)

I was honored to present a plenary address on “Advancing Medicines Quality via New Strategies in Bioequivalence Regulations, Pharmacovigilance Practices, and the Identification and Management of Substandard Pharmaceutical Events,” as well as chair the event’s panel on pharmacovigilance, sharing the panel with governmental thought leaders such as Dr. Amina Tebba (Morocco), Dr. Amr Saad (Egypt), Dr. Emad Munsour (Qatar), and leading global policy experts Dr. Hisham Aljadhey (King Saud University), and Michael Deats (WHO). I also participated on a panel discussing the urgency of IP, as well as another on biosimilars – specifically calling out the vexing debate over nomenclature, physician notification, and therapeutic substitution.

With healthcare policy (as with life in general) – wherever you go, there you are.

Not surprisingly, much of the conversation centered on controlling costs – specifically pharmaceutical costs, without (alas) the appropriate balance of time spent on the pennywise/pound foolish consequences of many of these policies. The IP panel tried to add balance to that debate by strongly presenting the facts on the value of innovation.

Dr. Rasha Ziada (Egyptian Ministry of Health) made the important point that if a pricing authority doesn’t take outcomes into consideration, it will lead to overall price distortions. Amen. And Dr. Ola Ghaleb (Ministry of Health, United Arab Emirates), spoke about the UAE’s strategy of performance-based risk-sharing arrangements – but also how politics can derail any decision-making process. Her honesty was refreshing. Net/Net -- Outcomes is now capitalized and bolded in the international lexicon of healthcare policy.

While many of the presenters discussed the value of sharing pharmaceutical economic data across borders, there was not an equal counterbalancing discussion of the value of sharing clinical data for approvals and outcomes-based decision-making processes. But there was certainly an effort (both on many of the panels as well as during the breaks and after hours) to stress the urgency of this agenda. The good news is that many, many speakers (sometimes in passing and other times passionately) made the point that it mustn’t just be about “getting the lowest price,” but also appropriately pricing the most clinically effective treatments. Bravo.

Many of the delegates said (from the floor as well as in conversation) that the conference was useful – but that action is required. In short – talk is cheap. My feeling (speaking privately with senior government officials from many of these nations) is that there is serious momentum for change (and even reinvention). But only time will tell.

As Deming said, “Change is not required. Survival is not mandatory.”

At the closing plenary session came “The Sharm El Sheikh Declaration.” The full document (in English translation) can be found here, but let me focus on the aspects that pertain to quality:

·      Investing in training and qualifying inspectors of pharmaceutical factories and ensuring the application of good manufacturing practice (GMP).

·      Strengthening drug post-marketing regulation through the establishment and activation of pharmacovigilance centers, while working on qualifying and training their workforce.

·      Urging Arab countries to invest in training inspectors of pharmaceutical factories to raise the quality of the inspection process and ensuring the application of current good manufacturing practice (cGMP).

·      Urging Arab countries to authorize performing bioequivalence studies and ensuring that they conform to the technical requirements of Good Clinical Practice (GCP) through regular inspection visits.

·      Urging international drugs regulatory authorities in the Arab world to activate drug post-marketing monitoring programs through establishing pharmacovigilance centers and equip them with trained pharmacists and doctors.

(Pleased and proud to say that many of these recommendations came from the conference panel I chaired on pharmacovigilance.)

In May my regulatory travels took me to Asia. In Jakarta I met with senior hospitalists to discuss the impact of Indonesia’s new legislation (designed to provide universal access to healthcare) – and its impact on both the quality of medicines available and a physicians right to choose both therapy and brand.  Senior healthcare leaders are concerned that insisting that the lowest priced product be used will result in suboptimal outcomes for those patients unable to access private healthcare. They recognize that a system that provides broader access to low quality care is not a victory. Bioequivalent does not equal identical. Biosimilar does not equal identical. The stakes are high.

Next up was the Javanese capital, of Yogyakarta for a symposium on pharmacovigilance held by Ahmad Dahlan University. The senior Ministry of Health official shared the fact that for a nation of 250+ million, there are but 10 people focused on pharmacovigilance. Talk about the Java Jive! She spoke of the need to develop better risk-based assessment protocols and better coordinate efforts with other nations in the region in order to share information on adverse events, bioequivalence, API and excipient sourcing. Quality is a team effort.

Meetings in Hanoi and Ho Chi Minh City focused on quality with a more specific focus on the need for more regular bioequivalence testing on patients under treatment (as opposed to healthy volunteers) in order to better understand not adverse events, but the uptick in Substandard Pharmaceutical Events (SPEs). SPEs occur when a product does not perform as expected—perhaps because of API or excipient issues. SPEs can arise because of an issue related to therapeutic interchangeability. In Vietnam they are beginning to understand and appreciate that Small is the new Big. The need to focus on the individual patient rather than the general population and on long-term care rather than short-term cost.

The last stop on my Asian tour was Taipei, where I had the opportunity to speak to a colloquium of oncology physicians. Their fear and frustration was similarly directed towards a government healthcare program that mandates the use of lowest cost products. Nowhere does this cause greater angst and anger than with healthcare professionals treating patients with cancer. The unintended consequences caused by short-term, price-driven government policies on quality and clinical outcomes cannot be underestimated. Those on the front lines (physicians and pharmacists) understand this. And recognizing there is a problem is the first step towards solving it.

What have I learned? The only thing that’s grown more than my frequent flyer miles is my respect and admiration for those over-worked and under-appreciated civil servants toiling on the front lines of medicines regulation.

It’s a global fraternity of dedicated (and generally under-paid) healthcare and health policy professionals devoted to ensuring timely access to innovative medicines and quality generics drugs. It’s not easy and it’s not a job – it’s a personal public health mission.

There are many languages, priorities, pressures, and impediments (social, political, cultural) to consider, but one thing everyone agrees on is that quality counts. But what does “quality” mean – and does it mean the same thing from nation to nation and from product to product both innovator and generic? The good news is there’s general agreement that lower levels of quality for lower cost items aren’t acceptable. But the bad news is that there are gaps and asymmetries in how “quality” is both defined (through the licensing process) and maintained (via pharmacovigilance practices).

Can there be a floor and a ceiling for global drug safety and quality? Even as we move toward differential pricing, should we allow some countries to have lower standards than others “based on local situations?” Can one man’s ceiling be another man’s floor? Can a substandard medicine ever be considered “safe and effective?”

Aristotle said, “Quality is not an act, it is a habit.” Habits are learned and improve with iterative learning and experience. And nowhere is that more evidently manifested than through the many and variable methodologies for generic medicines licensing and pharmacovigilance practices. From paper-only certification of bioequivalence testing and questionable API and excipient sourcing, the safety, effectiveness, and quality of some products are, to be generous, questionable.

Is this the fault of regulators; of unscrupulous purveyors of knowingly substandard products; of shortsighted, overly aggressive pricing and reimbursement authorities? While there are many different and important avenues of investigation, the most urgent area of investigation should focus on the asymmetries in how quality is defined, measured, and maintained. That which gets measured, gets done.

National 21st century pharmacovigilance practices must also take into consideration the realities of funding, existing staff levels, training programs, and existing regulatory authority. Accessing increased regulatory budgets is problematic. Should licensing agencies consider user fees for post-market bioequivalence testing of critical dose drugs? That’s a contentious proposition– but agency funding is an often-overlooked 800-pound gorilla in the room and deserves to be seriously discussed and openly debated.

Another uneven issue is that of transparency. While regulatory standards are undeniably an issue of domestic sovereignty, shouldn’t there be transparency as to how any given nation defines quality? “Approved,” means one thing in the context of the MHRA, the USFDA, and Health Canada (to choose only a few  “gold standard” examples), but how can we measure the regulatory competencies of other national systems? Is that the responsibility of the historically opaque WHO? What about the regional arbiters? Should there be “reference regulatory systems” as there are reference nations for pricing decisions? And how would this impact the concept of regulatory reciprocity?

In our globalized healthcare environment of SARS, Avian Flu, and Ebola, it’s important to remember that a rising tide floats all boats.

And so home again, home again, jiggity jig to an American healthcare system debating many of the same issues – bioequivalence, biosimilarity, interchangeability, physician notification, substandard pharmaceutical events, patient/physician/pharmacist education, the price/value equation, short-term savings vs. long-term patient outcomes.

It’s a small world after all.

Oils well that ends well.

Reporting from The Hill ...

Bipartisan House committee leaders on Thursday announced a $13 billion deal to pay for the cost of a measure to speed the approval of new medical cures

The 21st Century Cures measure, aimed at streamlining the FDA’s approval process for new drugs, has received bipartisan support in the Energy and Commerce Committee, easily passing a subpanel last week on a voice vote. 

But the major remaining question was how to pay for the bill’s cost, most of which comes from more than $10 billion over five years in new funds for the medical research at the National Institutes of Health. The bill also includes $550 million over five years for the FDA, a key point for Democrats, who pushed to have the funds added. 

Committee leaders in both parties worked intensely over the past few days to come to an agreement. 

The deal puts the bill on track to be a rare bipartisan achievement. After a markup Thursday morning, committee leaders hope to have a full House vote in June. 

“The policies in this package are long overdue and will pave the way for a new generation of health care innovation,” the bipartisan committee leaders said in a statement. “Too many patients and families have been waiting too long for cures — this bill will make a difference

The offsets include selling 8 million barrels of oil each year for eight years from the Strategic Petroleum Reserve, which the Congressional Budget Office says will bring in $5.2 billion. 

A second change modifies the timing of government payments to insurance companies under the Medicare Advantage program so that the government can keep interest earned on the funds rather than the insurer. This measure will bring in between $5 billion and 7 billion. 

A $2.8 billion change reduces Medicaid payments for certain medical equipment. It does this by lowering Medicaid payments to match the lower rates that Medicare pays for the same equipment. Medicare currently pays less because it uses a competitive bidding process.

The bill would also make $200 million by limiting payments for x-rays on film, incentivizing the switch to digital imaging. 

The markup had been scheduled for Wednesday morning, but it was delayed for 24 hours at the last minute after Democrats asked for more time to review the offsets and work through changes.  

Top Democrats on the committee had only seen the full offset proposals this week. 

Rep. Jan Schakowsky (D-Ill.) said Wednesday that the offsets had been “sprung” on Democrats. 

A Democratic committee aide pointed out it would be more customary to work out offsets later in the process after the bill passed committee, but attributed the faster timeline to Republican leadership wanting the bill to be paid for early on. 

The committee’s chairman, Fred Upton (R-Mich.), said Wednesday that leadership wants “us to get our ducks in line,” and that offsets had to be worked out so that the bill could be scored by the CBO. 

In a positive signal from leadership, the bill was given the number H.R. 6. Bill numbers 1-10 are typically reserved for the Speaker. 

Committee leaders sent proposal back and forth this week, winnowing down a list of possible offsets. 

Upton had a final meeting with the other leaders on the bill, Reps. Joe Pitts (R-Pa.), Frank Pallone (D-N.J.), Gene Green (D-Texas) and Diana DeGette (D-Colo.) on Wednesday before the group broke to brief the members in their respective parties. 

Upton said Wednesday evening that committee Democrats had met at 5:30 p.m. that afternoon to go over the deal. 

“We haven't heard any blowback, so I'm sensing that what we discussed earlier is going to hold,” he said. “So we're there.”


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.

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