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FDA's Opioid Manifesto

  • 02.05.2016
  • 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.

From today's edition of Morning Consult:

Tricky Road Ahead For Safe Approval of Biosimilars

On February 9th, 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.


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. 

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." 


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.

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. 

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.  

Compound Fracture

  • 02.01.2016

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

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.


More information can be found here.

FDA finds Indian drug maker Wockhardt hid failed tests


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.

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.

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.


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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