From Snake Oil to Fish Oil. The Need for a New Approaches to Off-Label Communication

02/19/2016 08:45 AM | Peter Pitts

Yesterday the new Duke-Margolis Center for Health Policy (headed by Mark McClellan), held a conference titled, “Off Label Communication in 2016: Meeting Information Needs through New Policy Options.”

Those new options are detailed in an important new paper:

Policy Options for Off-Label Communication: Supporting Better Information, Better Evidence, and Better Care

I am honored to be one of the co-authors and to have had the opportunity to speak at the event.

Just about every speaker pointed to the need for FDA leadership – though bold action and … clarity.

This is urgent for many reasons: different federal agencies (FDA, FTC, DOJ) with different views on pathways and jurisdiction, and the extreme danger of allowing federal judges dictate regulatory policy. If existing policy has evolved to protect the public from snake oil, the recent Amarin decision is precarious precedent for communications about fish oil – and beyond.

The paper lays out what we refer to as Guiding Principles for Lasting Solutions. They are:

Promote well-informed clinical decision-making to improve public health.

Support FDA’s central role in reviewing, approving, and enforcing efficacy claims.

Reduce inconsistencies across agencies’ enforcement decision-making.

Avoid continued cycles of litigation through greater policy clarity.

Promote more evidence development and data submission to FDA.

Nature abhors a vacuum. All of the participants in the conference and all the authors of the white paper were in complete agreement that, absent strong and forward-looking FDA leadership, the off-label debate will result in public health chaos.

And, as many management gurus have written, one of the key tenets of successful leadership is the ability to delegate in order to get things done.
To that end, one of the more contentious policy recommendations made in the paper is for the FDA to pursue a strategy that embraces third party sanctioned communication.

This alternative, which did not have universal support within our working group, involves a more intramural approach based on the FDA’s partnering with an external entity charged with accrediting certain types of communication.

This organization could focus its efforts on reviewing not an NDA, but an NDI – New Drug/Device Information, consisting of a sponsor’s evidence and associated communications about off-label use, and then potentially approve them for broader distribution.

An NDI review could be given within a rank, score, or grade system that confers greater weight to better evidence, and could be given contingent upon continued evidence generation and resubmission to the clearing body.

For example, an off-label communication may be approved and given an initial grade or rating that sunsets within a specified number of years barring updated submission of relevant evidence. Continued off-label communication at the current evidentiary grade and after the specified date would then be subject to additional evidence development by the sponsor.

The proposed reviewing body would operate outside of FDA but with FDA participation. To avoid First Amendment and other legal concerns, the body’s conclusions could not bind the FDA or otherwise hinder FDA’s ability to pursue enforcement action. While the reviewing body would not provide certainty to the regulated community, its recommendations could offer useful guidance to drug manufacturers.

An approach that involves an outside reviewing body might enable FDA to advance a model that more clearly differentiates between types and levels of communication, without modifying the FDA-approved product labeling. For example, the reviewing body might treat communication around off-label use that has become standard of care in a different manner than more tailored or less-well-established evidence on an off-label indication or within a specific patient subpopulation. Such a system could potentially play a more directed and focused alternative or supplement to the current role of peer-reviewed communications.

Any such entity will need to have participation from the FDA, and potentially other relevant agencies and will need to include a robust peer-review capacity. Incentives in the form of more rapid and predictable review and action would need to be in place to encourage sponsors to develop evidence and submit communication materials.

The end goal would be a process that augments the FDA’s capacity to review a diversity of communication types reflective of rapidly emerging evidence -- but does not change FDA’s ability to pursue enforcement action.

Such a third-party approach has precedents. In Canada, for example, the Pharmaceutical Advertising Advisory Board (PAAB) serves as an independent preclearance review agency for assessing the accuracy and evidentiary basis for promotional information on prescription, non-prescription, biologic, and homeopathic products. The PAAB process works within the Canadian regulatory framework with Health Canada as an ex-officio member of board leadership, conferring “approval” of advertising materials through a logo incorporated on cleared materials.

There also may be useful lessons for a third-party off-label communication entity from the Center for Disease Control’s Advisory Committee on Immunization Practices (ACIP), which develops recommendations on how and when to use vaccines within the United States. With FDA as a party to committee deliberations, ACIP relies on the body of clinical evidence, sponsor labeling, and data sources to issue formal, non-binding advice for immunization best practices – including potential off-label uses of vaccines.

While these examples differ in important ways from a third-party review system for off-label materials, they illustrate features and feasibility concerns that would need to be addressed to ensure a trustworthy, collaborative, and science-based process.

Might the USP be a good home for such a program. They already have a time-tested intramural relationship with the FDA. It's a thought worth further discussion.

All this to say that off-label communication is now on the health policy front burner and the flame is on high. As Everett Dirksen used to say, “When I feel the heat, I see the light.”  Read More & Comment...

Drug Price Transparency: The Full Monty For All

02/16/2016 12:45 PM | Robert Goldberg

I am all for “transparency in drug pricing.”  The question is transparency proponents have to answer is: why are they only focusing on how drug companies set their prices when the effective price consumers pay is set by PBMs, insurers and hospitals??
 
Take this story from Minneapolis. 
 
A major company has rolled back the price of a potentially life-saving prescription drug after a KARE 11 News investigation.
 
But the decision has some people asking how often we’re being overcharged on other medicines.
 
Curt’s Story
 
It started with Curt Burshem.
 
Back in November he told us CVS Caremark had jacked up the price for a prescription drug a family member needed for a kidney disorder.
 
 
Curt Burshem discovered that CVS was overcharging him on prescription drugs.
 
"When I see a company doing this crap, it makes me insane,” he said.
 
But, now, CVS has reversed the price high.
 
"Justice had been served,” Curt told us.
 
When Curt originally went to the CVS pharmacy in Maple Grove last Spring, the initial 30-day supply cost about $.87 per pill.
 
But when he followed his insurance company’s advice and ordered a 90-day supply through the mail, CVS Caremark increased the price to more than $6 a pill.
 
After KARE 11 called CVS they rolled the price back and gave Curt a refund.
 
Which raises the question: If transparency proponents were intellectually honest (some are, most are not) they would demand the same openness from every health care institution that shapes access to and the price of medicines.
 
Will PBMs and insurers reveal how they move from drugs that they acquire at 40-60 percent below pharmacy retail prices to charging consumers 30 percent of that retail price?
 
Will PBMs and insurers reveal how and why they decide when their customers are forced to fail first on medicines?
 
We need to know.  They claim drug costs are climbing at an unsustainable rate. That doesn’t square with data since 2000, spending on drugs has remained at 9-10 percent or HHS projections that overall drugs will remain at about 9 percent of total health spending through 2030.  So why are copays and co-insurance rates increasing??
 

Will hospitals reveal how they go from drugs acquired at the same rate to charging up to 700 percent of retail prices?  And while they are at it, will they explain why charges for hospital care increased faster than drugs, even as the use of these new medicines reduce hospital costs?  Why has hospital spending increased 6 times faster than drug spending between 2010-2013?
 
If I am a pharmaceutical company, I’d be for transparency for everyone.  I’d show them mine, if they showed theirs.  Let’s have the Full Monty for all.    Read More & Comment...

Issues in Indian PV

02/16/2016 07:51 AM | Peter Pitts

Within days of being given a diphtheria jab during a school vaccination drive, 5-year-old Meraj Shabbir Khan's leg became so swollen that he was hospitalised.

In a cramped Mumbai paediatric ward, third-year pharmacology student Nitin Shinde opens the boy's file and notes the vaccine, his age and the doctor's diagnosis of a skin infection. That information is later logged into a computer programme linked to a national database, part of India's fledgling efforts to track, analyse and ultimately warn patients about unknown side effects of drugs on the market.

India's six-year-old pharmacovigilance programme, which collects and submits suspected adverse drug reactions to a World Health Organisation (WHO) database, is key to improving drug safety in a country where medicine consumption is high, experts say.

But insufficient staff and equipment, and a lack of awareness among medical professionals mean many potentially dangerous drug reactions go unrecorded, hospital personnel across India told Reuters.

Gaps in the system mean the government has less data to determine whether drugs might have harmful side effects. Also, relatively little information flows from one of the world's largest pharmaceutical markets to the WHO database of over 12 million suspected adverse drug reactions.

"In a country of 1 billion people consuming so much medicine, obviously safety is a concern," said G. Parthasarathi, dean of the pharmacy school at JSS University in Mysore, adding the pharmacovigilance programme is still gaining traction. "We've made a good start," he said.

Last year, India contributed 2 percent of the 2.1 million suspected reactions added to VigiBase, the WHO's global database. China, with a comparable population, contributed 8 percent.

Indian health officials say the monitoring programme is a "high priority" and a $14.5 million annual budget is sufficient.

"We are going to develop a better pharmacovigilance system in India in due course," said G.N. Singh, India's drug controller. "Patient health will be assured."

Regarding doctors' lack of engagement, "the culture of reporting is improving," said V. Kalaiselvan, principal scientific officer at the Indian Pharmacopoeia Commission.

The full Reuters article can be found here.
   Read More & Comment...

What Do Jews and Pharma Have In Common?

02/15/2016 03:09 PM | Robert Goldberg

Much of what passes for journalism or commentary about the biotechnology/pharmaceutical industry is click driven hate mongering. Want to write about drug companies.  Start with this theme: Everything drug companies do is disgusting.  Nothing they do is beyond reproach.  Use h one example of unseemly behavior and claim every company does the same thing. Add some anger and sarcasm. 

Pharma sucks.  Ha-ha.  

Press send or post. 

Here’s some recent examples in order (mostly)  of idiotic magnitude:

Here’s what White House Chief of Staff Denis McDonough said in the wake of a Super Bowl commercial to raise awareness of opioid-induced constipation run two companies marketing a drug to treat it: “Next year, how about fewer ads that fuel opioid addiction and more on access to treatment.” commercialized and misused pharmaceutical knowledge,” he told a United Nations agency. 

Apparently McDonough never got the memo that people – including millions of cancer patients and individuals with digestive tract paralysis who safely use opioid based drugs to control searing pain – should have the same right to poop as White House staffers. 

Bill Maher tweeted (and this is evidence of why humor should be left to humorists) “Was that really an ad for junkies who can't shit? America, I luv ya but I just can't keep up.”

In between the harsh sarcasm of the White House and Maher’s tweet is the much needed gap created by Samantha Allen of the Daily Beast:

Martin Shkreli Is Just One of Many Pharma A-Holes 

Nancy Retzlaff is not Martin Shkreli. She won’t inspire hundreds of news articles nor will she become the subject of any Internet memes. She won’t threaten Ghostface Killah and it seems unlikely that she will ever flirt with a minor on a YouTube livestream.
But the chief commercial officer for Turing Pharma is just as responsible for keeping the price of the life-saving drug Daraprim 5,000 percent higher than it used to be. And as long as the public eye is still trained on the Shkreli sideshow, she’ll get away with it.

….There are more Martin Shkrelis out there, and not all of them are acting like assholes on Twitter. And if the Shkreli Show overshadows the people who still need easy access to a once-affordable treatment, everyone loses. The Pharma Bro started out as a poster child for a pressing problem. He may end up being a red herring.”

Samantha Allen seems eminently qualified to cover the relationship between being an asshole and drug pricing. She has a PhD in Ph.D. in Women’s, Gender, and Sexuality Studies from Emory University.  She In 2013, she received the John Money Fellowship for Scholars of Sexology from the Kinsey Institute.  She used the money to “research a wide range of media (books, photos, videos, graphic art, tabloids, etc.) on several different sexual fetishes (shoe, foot, nylon, pantyhose, breast, spanking, hair, etc.) dating from across the 20th and 21st centuries.” 

Is this a great country or what? 

But Dr. Allen is also an asshole expert because she is a misandrist.  In case you are wondering, that means she hates men: 

“i hate men because it’s not my job to fix masculinity; it’s my job to heal from it and to be together with my sisters as we try to make it through a hostile world. and yet i am expected to patiently educate men on how not to be an asshole. here’s my only tip: stop spending so much time around men. they’re assholes.”

Finally, here’s someone attacking drug companies for changing all human and cultural concepts in the world so widely that treatment is completely considered as a business in the world today..We should revive our traditional medicine which is in harmony with our culture and is naturally cheaper and more useful.”

That last statement is from former Iranian President Mahmoud Ahmadinejad who blamed “Zionist medicine” for polluting our planet with profitable but useless medicines. 

You knew it had to come down to the Jews controlling Big Pharma this: 

“Martin Shkreli (pictured) is a Jewish businessman (he has relatives living in Albania, and is often referred to as an Albanian). Though his Wikipedia page says he is Albanian and Croatian, he was born and raised in Brooklyn, went to Baruch College, worked for uber-Jewish hedge fund manager Jim Cramer in his teens — and had his own hedge fund by the time he was 21. 
 When the Jews want to profit more from selling a drug needed to treat sick people, who otherwise would die, they don’t just raise the price by a factor of five or ten. They send someone to raise it by a factor of fifty, wait for the reaction to hit the press, then they pretend to back down… yessir, all the way down to where they had planned to put the price from the beginning.
… This is a Jewish business strategy. Whenever they want to do something that they know will antagonize the public, they have one of their own, or someone under their control, do something even worse, and then they pretend to “correct” their own agent by telling him to stop doing it, and start doing something that isn’t quite so bad instead.”

Or as Dr. Allen put it: 

Martin Shkreli became the public face of price gouging because he was so transparent. But Retzlaff’s cool, calm, and collected attempt to spin the same exorbitant price increase for an HIV drug as a net good is arguably more dangerous because it is less obvious.”


There’s no underlying similarity binding these anti-pharma and anti-Semitic rants except varying degrees of paranoia and this observation by George Orwell: “If thought corrupts language, language can also corrupt thought.”


  Read More & Comment...

Rheums with a View

02/09/2016 05:10 PM | Peter Pitts

Today the FDA’s Arthritis Advisory Committee heard presentations on whether or not the agency should approve a BLA from Celltrion Inc. for CT-P13, a biosimilar of Remicade infliximab from Johnson & Johnson.

From the very beginning of the hearing, it was clear the expert members of the committee didn’t understand what biosimilars really are, nor the pathway the agency uses to review them.

And yet, at the end of a long day they were asked to vote on this question:

Does the Committee agree that based on the totality of the evidence, CT-P13 should receive licensure as a biosimilar product to US-licensed Remicade for each of the indications for which US-licensed Remicade is currently licensed and CT-P13 is eligible for licensure (RA, AS, PsA, PsO, adult CD, pediatric CD, adult UC)?

Despite open public comment from patients and physicans concerned about extrapolation issues, the vote was 21-3 in the affirmative. It was the vote the FDA wanted. And they got it.

Infliximab is particularly relevant to the overall conversation regarding indication extrapolation because structural differences have been identified as potentially related to the treatment of inflammatory bowel diseases.  The EMA has granted the product full extrapolation including inflammatory bowel diseases, while Health Canada did not, citing uncertainty regarding the clinical impact of observed structural differences.

What does the FDA know that our European and Canadian regulatory cousins do not?

There was also much chatter amongst the panel members about this vote helping to lower prices. Maybe so. Maybe not. Either way it’s not an appropriate discussion for an FDA panel.
   Read More & Comment...

Opioids Minus the Politics

02/09/2016 10:29 AM | Peter Pitts

If you’re following the opioids debate and want to cut through the political rhetoric and get right to the meat of the policy debate, here’s a conference you should plan on attending the Abuse-Deterrent Formulations Summit.

The event’s lead-off hitter is Dr. Doug Throckmorton, CDER’s Deputy Director for Regulatory Programs and the FDA’s point-man for opioids. His talk, “The Future of Abuse-Deterrent Formulations,” is a timely must-hear presentation.
   Read More & Comment...

Addressing Markey's Marker

02/08/2016 10:53 AM | Peter Pitts

From the pages of Drug Information Daily:

Does Califf’s Opioid Announcement Go Far Enough?

Sens. Joe Manchin (D-W.Va) and Edward Markey (D-Mass.) will maintain their holds on the nomination of Robert Califf for the top job at the FDA, despite the agency’s announcement Thursday that it would overhaul its opioid policies.

Specifically, the FDA said it would reexamine its approval, REMS and postmarket policies for opioids in response to a growing abuse epidemic and calls to action from lawmakers.

The senators — along with Sen. Bernie Sanders (I-Vt.) — in January placed holds on Califf’s nomination, with all three citing the FDA’s handling of approving prescription opioids.

A spokeswoman for Manchin tells DID that the senator’s plans have not changed, and he still plans to filibuster and hold Califf’s nomination. Manchin said the FDA’s announcement that it would re-evaluate its risk-benefit framework for the drugs will only “slightly improve” the agency’s response to the opioid epidemic, and that “sweeping changes” are still necessary.

Markey said in a statement that the FDA’s actions are “some important steps” but “fall short of what is needed.”

Andrew Kolodny, director of Physicians for Responsible Opioid Prescribing and the chief medical officer of Phoenix House, tells DID that many of the FDA’s “speaking points” are “meaningless.”

He criticized the agency’s announcement that it would convene an advisory panel before approving any new opioids that lack abuse-deterrent properties, asserting that these meetings should be held for all approvals regarding opioids.

Senator Markey also made that point: “By refusing to convene advisory committees to inform all of its opioid approval decisions, the FDA continues to ignore outside experts who could help stem the tide of tragic deaths and overdoses plaguing the country,” Markey said in a statement. He also said he would continue to hold off on Califf’s nomination “[u]ntil the FDA commits to convene advisory committees of outside experts for all its opioid approval decisions.

Peter Pitts, president and founder of the Center for Medicine in the Public Interest and a former FDA associate commissioner, tells DID that he thinks the FDA’s approach could make a difference, saying it will make the approval process “more complete.” 
“I think there will be a higher evidentiary standard on the one hand, but on the other hand there will be a clearly explained pathway as to how to achieve it. They're taking ambiguity out of the process.”

Pitts added that the approach is going to provide guidance on how to develop abuse-deterrent opioids and how to use real-world data to impact post-approval labeling.  Read More & Comment...

Biosimilar Sins of Omission

02/08/2016 09:12 AM | Peter Pitts

On Friday, FDA posted briefing documents ahead of the Feb. 9 meeting of its Arthritis Advisory Committee to discuss a BLA from Celltrion Inc. for its CT-P13, a biosimilar of Remicade infliximab from Johnson & Johnson. What's just as interesting is what's not in the package.

Celltrion conducted clinical studies of CT-P13 in rheumatoid arthritis (RA) and ankylosing spondylitis (AS), and is seeking extrapolation of CT-P13 across all seven of Remicade's approved indications including Crohn's disease, pediatric Crohn's disease, ulcerative colitis (UC), pediatric UC, psoriatic arthritis and plaque psoriasis.

In the briefing documents, FDA reviewers said the preclinical, clinical and manufacturing data submitted by Celltrion suggest that it is "highly similar" to Remicade. Agency officials noted that while there were differences in the binding of the Fc regions between Remicade and CT-P13, "it is reasonable to extrapolate conclusions regarding the similar efficacy and safety of CT-P13 and U.S.-licensed Remicade to IBD."

In brief, the FDA recommends approval for all indications mostly based on analytical studies along with some clinical (primarily for RA and AS data). Emphasis on analytics is not surprising based on the FDA biosimilar pathway – but what is interesting (and disturbing) is the absence of available real world data. More on this important patient safety issue shortly.

Infliximab is particularly relevant to the overall conversation regarding indication extrapolation because structural differences have been identified as potentially related to the treatment of inflammatory bowel diseases.  The EMA has granted the product full extrapolation including inflammatory bowel diseases, while Health Canada did not, citing uncertainty regarding the clinical impact of observed structural differences.

AdComm members will be asked to discuss the similarity of CT-P13 to Remicade, whether there are clinically meaningful differences between the two mAbs, and whether there are sufficient data to support extrapolation to the approved indications beyond those studied in clinical trials. The panel will vote on whether CT-P13 should be approved as a biosimilar of Remicade for each of the seven indications.

Interestingly, the FDA has will not ask the panel to discuss any of the comparative real world data available that speaks to relevant clinical outcomes. This is particularly disturbing since (on page 11 of the briefing package) the agency FDA made statements on switching (per RA and AS) that would support the safety of a one-time switch from innovator to biosimilar. This is particularly important since Celltrion is NOT seeking interchangeability.
Should “defacto interchangeability” be an acceptable regulatory pathway?

Specifically absent from the FDA AdComm package is data from a study, from Mercy University Hospital, University College Cork, Centre for Gastroenterology, Mercy University Hospital, Cork, Ireland, which studied the clinical impact of both the innovator product (Remicade) and CT-P13, the Celltrion biosimilar. The findings are important. Specifically, the rates of surgery of the groups were significantly different.

80% of biosimilar patients required hospital readmission versus 5% of the Remicade) group. (p=0.00004). 60% of patients in the biosimilar group needed steroid augmentation of standard steroid tapering protocol with 50% requiring multiple increases in steroid dose versus 8% of those patients on Remicaide  (p-value = 0.0007). Over the course of 8 weeks, 93% of patients in the biosimilar group had an increase in CRP with 7% remaining unchanged whereas 100% of patients in the Remicade group had a decrease in CRP (p=<0.001).

The study’s conclusion is not ambiguous, “Our results suggest that biosimilars may not be as efficacious as the reference medicine. The results found reflect the ECCO statement position that the use of most biosimilars in IBD will require testing in this particular patient population and cannot be extrapolated from other disease populations."

The complete poster can be found here.

An American College of Rheumatology abstract of CT-P13 data shows important differences between adverse events in patients with rheumatoid arthritis and those with ankylosing spondylitis depending on whether or not they were switched.

The ACR abstract can be found here.

The efficacy data was good. But the safety data is concerning. But the FDA AdComm won’t be discussing this study either.

Biosimilarity and measurement of efficacy is only one dimension. Attention must be paid to effectiveness relative to real-world patient outcomes data. Regulatory sins of omission are dangerous when it comes to the public health.  Read More & Comment...

FDA's Opioid Manifesto

02/05/2016 07:49 AM | Peter Pitts

The FDA has announced a far-reaching action plan to reassess the agency’s approach to opioid medications. The plan will focus on policies aimed at reversing the epidemic, while still providing patients in pain access to effective relief.

Importantly, the FDA’s strategies and tactics are not adverse to the well-being of pain patients and avoid measures (such as mandatory advisory committees for abuse deterrent formulations) that would have the negative consequence of chilling investment in the science of abuse deterrence.

The FDA will:

• Re-examine the risk-benefit paradigm for opioids and ensure that the agency considers their wider public health effects;

• Convene an expert advisory committee before approving any new drug application for an opioid that does not have abuse-deterrent properties;

• Assemble and consult with the Pediatric Advisory Committee regarding a framework for pediatric opioid labeling before any new labeling is approved;

• Develop changes to immediate-release opioid labeling, including additional warnings and safety information that incorporate elements similar to the extended-release/long-acting (ER/LA) opioid analgesics labeling that is currently required;

• Update Risk Evaluation and Mitigation Strategy requirements for opioids after considering advisory committee recommendations and review of existing requirements;

• Expand access to, and encourage the development of, abuse-deterrent formulations of opioid products;

• Improve access to naloxone and medication-assisted treatment options for patients with opioid use disorders; and

• Support better pain management options, including alternative treatments.

As one of the cornerstones of this plan, the FDA will seek guidance from outside experts in the fields of pain management and drug abuse. For example, the FDA has already asked the National Academy of Medicine to help develop a framework for opioid review, approval and monitoring that balances individual need for pain control with considerations of the broader public health consequences of opioid misuse and abuse.

“We are determined to help defeat this epidemic through a science-based and continuously evolving approach,” said

Per Rob Califf, the FDA’s Deputy Commissioner for Medical Products and Tobacco “This plan contains real measures this agency can take to make a difference in the lives of so many people who are struggling under the weight of this terrible crisis.”

In addition, the FDA will convene independent advisory committees made up of physicians and other experts when considering for approval any new opioid drugs that do not contain abuse-deterrent properties. The FDA will also convene a meeting of its standing Pediatric Advisory Committee to make recommendations regarding a framework for pediatric opioid labeling and use of opioid pain medications in the pediatric population.

The FDA is also strengthening the requirements for drug companies to generate postmarket data on the long-term impact of using ER/LA opioids. The agency expects this to result in the most comprehensive data ever collected in the field of pain medicine and treatments for opioid use disorder. The data will further the understanding of the known serious risks of opioid misuse, abuse, overdose and death.

The FDA’s full announcement can be found here.

  Read More & Comment...

Biosimilar BLA Blah Blah

02/04/2016 09:13 AM |

From today's edition of Morning Consult:

Tricky Road Ahead For Safe Approval of Biosimilars

On February 9^th, the FDA’s Arthritis Advisory Committee will discuss biologics license application (BLA) 125544, for CT-P13, a proposed biosimilar to Janssen Biotech Inc.'s REMICADE (infliximab), submitted by Celltrion, Inc.

If the Adcomm gives a thumbs up and the agency approves the product, this will be the second biosimilar approved in the U.S., but the very first monoclonal antibody, a much more complex molecule than filgrastim.

Apart from the product issues, there are many important policy issues that should be discussed. For example:

Labeling, naming, coding, substitution, non-medical switching and interchangeability are all-important policy issues that FDA has the authority to impact and are appropriate to raise at a high level AdComm.

While extrapolation was allowed for filgrastim, the questions of extrapolation for this product are not as simple or straight forward for the following reasons:

Complexity and Stability

Filgrastim is generally not used as a long-term product for a life-long, chronic disease like infliximab and is much less complex than infliximab, which is nearly eight times larger.  Monoclonal antibodies are used in patients with moderate to severe diseases like Crohn’s or ulcerative colitis and disease stability is critical.  With biosimilar entry the risk of switching the patient to a new, similar product must be carefully considered due to the complexity of the product and disease state.

Regulatory Authorities Split

Because biosimilars are not identical copies of their reference products, even slight differences in structure can affect the biosimilar’s mechanism of action.  Without clinical data in each therapeutic area, it may be challenging to understand the impact of these differences on clinical outcomes.  Infliximab is particularly relevant to the overall conversation regarding indication extrapolation because structural differences have been identified which are thought to be potentially related to the treatment of inflammatory bowel diseases.  The EMA has granted the product full extrapolation including inflammatory bowel diseases, while Health Canada did not, citing uncertainty regarding the clinical impact of observed structural differences. 

Quality Attributes

Biosimilar sponsors compare the structure and function of their products to the reference product using a range of laboratory (i.e., analytical tests) tests.  Because of the complexity and uncertainty with regard to monoclonal antibodies, we can’t always tell which product attributes (or parts of the structure) will be relevant to ultimate clinical outcome and which won’t be.  This is why it’s critical that FDA take a conservative approach and ensure that the biosimilar and reference product are as highly similar as possible, across a wide variety of structural and functional attributes.

Studies Suggest Different Response in Different Disease States

An American College of Rheumatology abstract of infliximab biosimilar data shows difference between adverse events in patients with rheumatoid arthritis (RA) and those with Ankylosing Spondylitis (AS) depending on whether or not they were switched with a 22.5% difference in AS patients that were switched:

* Ankylosing Spondylitis (AS) TEAEs - 48.9% on biosimilar; 71.4% switched from innovator to biosimilar

* Rheumatoid Arthritis (RA) TEAEs – 53.5% on biosimilar; 53.8% switched from innovator to biosimilar.

Pharmacovigilance

Regulatory authorities recognize the importance of robust post-marketing safety monitoring for all drugs including biosimilars.  What make biosimilars different from other drugs however is that unlike generic small molecule medicines where safety can be assumed to be identical as its branded counterpart, a biosimilar is not identical to its reference drug.  Another defining difference with biosimilars is that all biologic medicines may trigger the human immune system to react in undesirable ways such as rendering the medicine ineffective.  Small difference between products may result in different effects on the body’s immune system.   

* Post-marketing safety monitoring is heavily dependent upon voluntary reporting of adverse events by health care professionals and patients.  Unfortunately, this system does not have the capability to effectively monitor and accurately identify adverse events as a result of triggering the body’s immune system.   It is unclear how regulators can or will implement robust ways to compare the safety of a biosimilar to its reference product once approved.

It may be February in Maryland – but the heat is on the FDA. 

  Read More & Comment...

BIO's Value-Based Values

02/04/2016 08:45 AM |

BIO released a set of voluntary principles that include a set of commitments by the trade group and its member companies to support "comprehensive and sustainable solutions to improve patient access to and affordability of innovative medicines."
The principles include a commitment to work with payers, healthcare providers and policy makers to maximize patient benefit and drive "smarter" healthcare spending via "value-based and outcomes-based contracting arrangements, patient adherence and education programs, alternative financing and payment mechanisms, or other similar options." 


Thee BIO PRINCIPLES ON THE VALUE OF BIOPHARMACEUTICALS begins as follows:

BIO member companies are committed to investing in,  developing, and delivering innovative biopharmaceuticals that are transforming how we treat and cure patients with once-devastating diseases – giving them hope, extending survival, and saving millions of lives. The value that these innovative medicines offer to patients and their caregivers, the healthcare system, and society at large is truly a game-changer. The critical issue is how best to ensure that these medicines are accessible to patients in need, while continuing to foster the risk-taking required to sustain the promise of future treatments and cures. This issue is the subject of vigorous public policy debate, and we welcome it.

Per a report in BioCentury, Ron Cohen, president and CEO of Acorda Therapeutics Inc. and chairman of BIO, the trade group is putting the final touches on a media and lobbying campaign emphasizing the value of biopharmaceuticals and the high costs of other healthcare products and services.
BIO's new principles also include a commitment to work with policy makers to "remove legal barriers that currently limit the ability to engage in value-based contracting and communications."

Stakeholders also told BioCentury that regulatory barriers to outcomes-based pricing contracts include FDA's prohibition on discussion of off-label uses of drugs and agency regulations that prevent companies from working with payers prior to approval to develop creative payment strategies. The FDA has listed these issues as key topics for the agency to address in its 2016 guidance agenda process.

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The Real Story Is Generic Price Increases (Not Really)

02/03/2016 01:20 PM |

Lots of headlines about the pricing practices of Turing and Valeant, which are the subject of an investigation lead by  Democrats on the House Oversight Committee .  The large retail price increases of these two companies are, we are told by mainstream reporters at Bloomberg, Wall Street Journal, etc media and Congressman Elijah Cummings, is indicative of what is going on in almost every company. 

Well sort of.   As Adam Fein has noted,  most generic drug price increases are a response to shortages, of which we have way too many.  In most cases, the price increases can be blamed on drug shortages. "For example, the NADAC per unit for doxycycline hyclate (100 mg tab) increased from 5.6 cents to $3.65 (+6,351%). The increase is most likely due to a nationwide shortage. I presume there’s also an active gray market, as in generic injectables. For context, see Drug Shortages and Gray Market Profiteering."

And the retail price, once again, is not the real price.  Again, Adam (drug)channels Mr. Spock in his logical analysis of the gap between retail and acquisition cost.



Adam's columns on pricing are more educational and authoratative than the turgid reports from some members of Congress. 

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Drug Price Reporting Reaches New Low

02/03/2016 11:58 AM |

Apparently the quality of journalism – if it can be called that – about the cost of medicines has not hit bottom.

Two new lows were hit by Robert Langreth (with Rebecca Spalding) at Bloomberg and  USA Today's Jane O’Donnell. 

Langreth and Spalding wrote a predictably predictable article on the eve of Martin Shkreli’s no show congressional flogging.   Predictable and derivative since it recycled the same stuff written by other low achieving reporters.  The headline says it all: Shkreli Was Right: Everyone's Hiking Drug Prices.

So I will respond by recycling a previous blog on a ‘me-too’ pricing article in noting that Langreth fails to put drug price increases (net price or otherwise) into perspective.  Langreth states that U.S. prescription-drug spending rose 12.2% in 2014, accelerating from 2.4% growth in 2013. But “price increases for protected brands increased spending by $26.3 billion, contributing 8.2% to total market growth on an invoice price basis; estimated net price growth was substantially lower as rising off-invoice discounts and rebates offset incremental price growth and reduced net price contribution to growth to 3.1%.” 

That’s an increase in spending of about $7.1 billion.  Total US health care spending increased by $100 billion from 2013-2014.  So brand drugs were 7 percent of that amount. 


O’ Donnell takes reporting on drug prices to a new low in "Patient groups funded by drugmakers are largely mum on high drug prices"  She accuses patient groups that receive support from biotech firms from blocking efforts to impose price controls.  The headline is the tipoff.   To be more precise, she let’s Zeke Emanuel do the smearing.  If you want a job done well, hire a pro:

"It is worrisome because it is a conflict of interest even if you can’t prove it changes their position," says Ezekiel Emanuel, an oncologist and professor who chairs the University of Pennsylvania's department of medical ethics and health policy. "The patient voice carries a disproportionate amount of weight."

So if someone alleges it changes your position, that’s a conflict of interest.  

By that standard, the patient groups she cites as conflict free should also be suspected of conflict. More specifically, the Patient Voice Institute works with the Leapfrog Group which also gets money from large employers, health purchasing groups and AARP.   All three are quoted in the article.   But applying Zeke’s conflict benchmark, the fact that I can’t prove any connection means it is a conflict. 

The j’accuse of getting funding from corporations is a diversion.  O’Donnell, like many of her colleagues fail to look at the cost of new drugs relative to what insurance companies spend.  It’s about 3 percent.  And that spending makes treating illness less expensive by reducing hospitalization, saves lives and improves quality of life.  

The question O’Donnell ignores is the one the Leukemia and Lymphoma Society answered about a year ago:  How much would it really cost to pay for the drugs insurers scream are too expensive? 

They commissioned a Milliman study and found that it would cost on average about 50 cents per patient per month.  If drugs were driving up overall costs (as opposed to reducing them, which they do) why such a small increase to make people whole?

O’Donnell had the opportunity and column space to look at this issue.  Instead she went down a darker, more deceptive road.   What a shame.  Then again, it's not surprising.    Read More & Comment...

Compound Fracture

02/01/2016 06:16 AM |

Mark Baum’s  self-serving op-ed in the Wall Street Journal (New Prescription for Lower Drug Prices) that compounded-drug makers can bring inexpensive, off-patent medicines to market, “if the FDA will let them” omits a key issue in the debate – public safety.

Just last week, two Alabama pharmacists agreed to plead guilty to criminal charges in connection with the 2011 deaths of nine Birmingham-area patients who allegedly received a contaminated compounded drug.

According to federal prosecutors, the drugs were contaminated from being prepared, packed or held in unsanitary conditions. The Centers for Disease Control and Prevention found the same bacteria on a water faucet in an open container of amino acid powder, and on the surface of mixing equipment that had been used to make the drug, according to federal prosecutors.

Also last week, Dr. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, said she has ruled out the use of compounding to combat spikes in generic drug prices. 


Woodcock told the U.S. Senate Health, Education, Labor and Pensions (HELP) Committee that "there are very great risks" from FDA allowing mass production of compounded drugs to reduce the cost of a generic drug. 
Woodcock said that while recent legislation gives FDA additional power to enforce quality standards on pharmacies that compound sterile injectable drugs, FDA has limited oversight authority over compounding of tablets and pills. She said FDA has recently withdrawn compounded vitamin and hormone products after pharmacies distributed potentially fatal super-potent formulations. 


Despite Mr. Baum’s rosy commercial projections, compounded drugs may be sub- or super potent, contaminated, or otherwise adulterated. Additional health risks include the possibility that patients will use ineffective compounded drugs instead of FDA-approved drugs that have been shown to be safe and effective.

His company, Imprimis, has had challenges with its compounding facilities in New Jersey and Southern California, both of which have been issued letters from the FDA citing Common Good Manufacturing Practices (CGMP) violations that could call into question the safety and effectiveness of the drugs compounded there.

Putting price before patient safety is bad medicine and worse policy

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Hoosier Healthcare Hospitality

01/30/2016 09:21 AM |

Sleeping with the Enemy? Hardly. Eli Lilly & Co. has announced an important collaboration with an unlikely bedfellow – their Hoosier neighbor, Anthem. The goal is to help develop common ground on policy solutions related to cost and value. Finally – two important players understand that they are, in fact, on the same team.

Bravo.

More information can be found here.

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Wockhardt and get ahead?

01/30/2016 08:28 AM |

FDA finds Indian drug maker Wockhardt hid failed tests

MUMBAI | BY ZEBA SIDDIQUI

Indian drugmaker Wockhardt hid the results of failed tests and deleted data from its systems at a plant in western India, according to a report by the U.S. Food and Drug Administration sent to the company earlier this month and seen by Reuters.

Issues around "data integrity", maintaining accurate and consistent databases, are key to the U.S. watchdog, which regulates the world's largest market for generics producers.

Wockhardt is the latest of several major players in the $15 billion Indian drugs industry to be hit by U.S. regulatory action over the past few months.

It makes around a fifth of its $670 million in annual revenues from the United States and had said the Shendra plant, the site that prompted the FDA report, would boost its U.S. business. Shendra makes lucrative injectable medicines, which analysts say are key to Wockhardt’s U.S. plans.

Wockhardt did not return several telephone calls and emails requesting comment on the detailed report.

The FDA did not immediately respond to a request for comment on its report. It issues such reports, known as a 'Form 483', when its staff believe that conditions at a manufacturing site could lead to products that are harmful to human health.

In the report, dated Jan. 12, the FDA said that among other violations, the audit showed that the results of 22 failed tests had not been recorded. It also found multiple data files had been deleted from some machines.

The FDA did not detail whether the files or tests related to specific drugs, or whether the violations could impact the quality of medication produced at a plant which still exports to Britain and Ireland.

FDA inspectors also reported finding pharmaceutical ingredients that were not stored or labeled properly. A rejected drug batch was stored in the "approved material" area, and some batches did not carry expiry dates, the report said.

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Califf feels The Berne

01/27/2016 08:11 AM |

Citing his “extensive ties to the pharmaceutical industry,” Senator Bernie Sanders has placed a hold on the nomination of Rob Califf to be FDA Commissioner.

What are those “extensive ties?” Working to design and field innovative clinical trials for FDA review. You want the best and the brightest to work with industry on such matters – because industry is the one that does them. Not academia. Not NIH. Not physicians. And not the FDA. The pharmaceutical industry. And well-designed and executed clinical trials provide important insights into the benefits and risks of potential new therapies. To those reading this column this isn’t a surprise – but to many others it is.

If Senator Sanders thinks that having one of our nation’s keenest clinical trial design experts working with industry is a reason to place a hold on his nomination, then it’s time for him to step back and reconsider his position. When it comes to clinical trials that investigate safety and efficacy, we can't afford to use only the second best and almost brightest.

Yes, Bernie has other things on his mind at the moment, but facts as pesky things.

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The Biosimilar Qualifier

01/27/2016 07:32 AM |

Somewhat different (but similar) from the FDA's "Filgrastim SNDZ" naming decision, the World Health Organization has posted a final version of its proposed biologics naming policy. It proposed that each biologic, including biosimilars, would be assigned a four-letter “biological qualifier” (BQ) that would make it possible to trace the compounds globally. BQs could be used for pharmacovigilance and to facilitate transferring prescriptions among countries.
WHO would generate BQs. The qualifiers would consist of random consonants, would be separate from non-proprietary names, and could be assigned retrospectively or prospectively.

It's BQ IQ.

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Friends with (Pharmacy) Benefits

01/26/2016 07:19 AM |

A new report by the Pharmacy Benefit Management Institute (PBMI) makes some very interesting points about the value of PBMs to employers and employees. Some highlights include:

* PBM generic copays are in line with overall inflation, only increasing from $9.85 to $10.85 over a 15-year period in inflation-adjusted dollars.

* Preferred and non-preferred brand copays (preferred brand from $19.43 to $31.08 and non-preferred from $37.58 to $56.65) have outpaced inflation considerably.

* Plan sponsors increased use of prescription drug benefit deductibles by 157% in 2015 compared to 2014.

* In 2014, only 14% of plan sponsors reported having a deductible for prescription drugs compared to 36% in 2015.

* There is considerable opportunity for employers who are willing to implement additional strategies to control costs and utilization without shifting additional costs to members.

* Mail order in particular can save members an average of over four monthly copayments per prescription per year (annualized). For a member taking a preferred brand in a three-tier plan design, this equates to yearly savings of $138.88 for a single maintenance medication.

The complete report (sponsored by Takeda Pharmaceuticals) can be found here.

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Who Are the Real Data Parasites?

01/25/2016 02:41 PM |

In his Forbes.com blog David Shaywitz comments on an editorial in the New England Journal of Medicine (NEJM), written by editor-in-chief Jeff Drazen, along with Dan Longo. "that a new class of research person will emerge—people who had nothing to do with the design and execution of the study but use another group’s data for their own ends, possibly stealing from the research productivity planned by the data gatherers, or even use the data to try to disprove what the original investigators had posited. There is concern among some front-line researchers that the system will be taken over by what some researchers have characterized as “research parasites.”

Shaywitz writes he was delighted to see the editorial:

"Not because I agreed with it–my heart is truly with the data scientists–but because I was grateful that someone had the courage to articulate a perspective I’ve come to believe is shared by the vast majority of academic researchers, but publicly voiced by no one–until now.
The result: a classic case of stated preference vs. revealed preference, where every academic researcher dutifully claims to be interested in sharing their data widely and freely, but somehow, tend not to actually do this."

David is right.  But there is even more reason to ‘cheer’ the NEJM article.  It reveals that scientist think it is “their” data when in fact it is the patient’s data.  The researcher is entrusted with that data by us to use it to advance science and promote cures. 

And the self-interested way such data is used – or shared – often abrogates the social contract in many ways.

Let me focus on one in particular, from the research article in the NEJM -- CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer -- that was the subject of the editorial.  The researchers used data collected from cancer patients by the National Cancer Institute.  Drazen and Longo call this “symbiotic collaboration.”   I would call it another permutation of an approach that betrays patients. 

The article notes: “Given the exploratory and retrospective design of our study, these results will need to be further validated. We advocate for these findings to be confirmed within the framework of randomized, clinical trials, in conjunction with genomic DNA sequencing studies.”

In other words, the symbiotic collaboration first and foremost will be used to fund randomized trials and sequencing studies support by the same programs that were paid to put together the tissue bank.  As Stuart Kauffman, Colin Hill, Sui Huang and Lee Hood have noted: the methods used to generate so-called evidence-based medicine -- the basis for medical practice and reimbursement—randomized clinical trials (RCT) and comparative effectiveness research—are dangerously broken.

Data-sharing that respects the needs and hopes of patients is defined by how broadly data is shared and the degree to which researchers use data to tailor cancer treatment combinations to achieve the best outcomes possible.

So by definition, companies that use data from a variety of sources to establish biomarkers independent of the researcher who extracted tissue from patients in single person trials and based on powerful machine learning derived algorithms are supporting mutualistic relationships. 

Researchers that boldly push for the Drazen model are, in my opinion, the true data parasites.

I think lots of researchers become researchers because they want to change the world for the better.  You can check out the LabTV YouTube channel and see short videos of hundreds of researchers with such an ethos.   The Drazen model merely reinforces the control of a small elite that are both disdainful of people like Eric Topol who is paving the way for a consumer led data revolution and fearful that the transformation means they will be out of jobs.  Lee Hood’s P4 medicine vision is based on collecting and sharing data generated by patient activated social networks.  Would Drazen call Dr. Hood a parasite??


To those who say that sharing will reduce incentives for innovation, just the opposite is true.  Establishing the relationship between molecular insights and meaningful changes in disease progression depend heavily on collaborations that leverage the digitization of biology to its fullest. 

As Shaywitz points out, now that we know the true motives of researchers, we can define the parasite problem and tackle it head on.  Read More & Comment...