Latest Drugwonks' Blog

There's been a lot of sub-textual cheering by The Wall Street Journal about the a court's ruling that Novartis can sell Zarxio, the biosimilar version of Amgen's Neupogen approved by the FDA a few months ago.  In particular, the PBMs have been saying that eventually as more biosimilars hit the market , the discounts to payors and PBMs will be 40-50 percent.  

Previously, the WSJ stated the approval was akin to " firing the starting gun on a new industry" that will reign in drug spending. 

More like shooting blanks.   

First, it is important to remember, as the FDA noted in it's approval, that " ZARXIO has not been determined to be interchangeable."  Which means: No switching. 

Second, a biosimilar requires a Phase III trial.   Prior to obtaining approval, Novartis-Sandoz had to conduct the PIONEER study (the official title is A Randomized, Double-blind, Parallel-group, Multi-center Phase III Study Comparing the Efficacy and Safety of EP2006 and Neupogen® in Breast Cancer Patients Treated With Myelosuppressive Chemotherapy)  The trial was initiated in 2011 and the results of the study were submitted in 2014.    Several studies estimate it takes 8-10 years and anywhere from $100 million to $250 million to produce one biosimilar. (That does not include the capital costs of failure, delay, etc. )  That timeline is no different than innovative drugs.  That fact should squash the conspiracy theorists like Public Citizen or Donald Light and Hagop Kantarjian who claim that's what a new biotech costs to develop since a biosimilar takes NO risk in investing in preclinical and early human studies. 

Third,  biosimilars will require the same post market surveillance expected of innovator products.  My colleague Peter Pitts has articulated the need for this -- and for monitoring marketing claims -- better than anyone.  

For these reasons, biosimilars have not been a profitable business.  That will change as more biotech products go off patent.  But don't expect deep discounts as long as the costs of development increase.  

Instead, it is possible that companies producing biosimilars will seek to increase profit margins by developing therapies that add value.  Turning an injectible into an oral treatment is one way.  Reformulations and drug combinations are others.  Companies will likely seek to create niches using diagnostics and finding additional uses for products. 

Which raises the possiblity of authorized generic versions.   Or not.   My guess is that Amgen will compete on price and seek additional indications for Neupogen.  
Biosimilars will not save the gazillions estimated by the media.    Rather, they will promote the kind of competition one sees in smartphones and tablets: similar functions, different consumer experiences as a result of incremental, but useful, changes in technology. 

That's innovation.  And that's good for patients. 

My article from the Louisville Courier-Journal on the ASCO Value Framework.  It can also be read as an analysis of Dr. Daniel Goldstein's effort to measure the value of a new medicine for people with stage IV squamous, non small cell lung cancer...

A group of cancer doctors has apparently decided to rewrite the Hippocratic Oath.

The ancient pledge charges physicians with applying “all measures that are required” for the benefit of the sick. The docs heading up the American Society of Clinical Oncology want to add a caveat — “unless those measures are too expensive. Then just let the patient die.”

The oncologists’ group has developed a “conceptual framework” that relies on cost-benefit analysis to determine the most “valuable” treatments for different patients.

Sounds innocent enough. But healthcare outcomes cannot be reduced to cost-benefit calculations. By focusing on the cost of a treatment — rather than the benefit it could deliver — the oncologists are allowing dollar signs to dictate whether a patient lives or dies.

Under ASCO’s framework, new treatments will be judged “based on clinical benefit, side effects and cost.” Those are the exact same measures health insurance companies use in limiting patient access to treatments. Indeed ASCO wants insurers to use its calculator to “evaluate the relative value of new treatments” as they develop “benefit structures, adjustment of insurance premiums, and implementation of clinical pathways and administrative controls.”

Such “controls” could include shifting drugs to the highest cost-sharing tier of an insurance plan or requiring patients to try older, cheaper drugs before gaining access to the most cutting-edge therapies.

Never mind that the Obama Administration has warned “placing most or all drugs that treat a specific condition on the highest cost tiers discourages enrollment by individuals based on age or based on health conditions” is discriminatory.

The oncologists are effectively asking insurers to discriminate against cancer patients — in direct contradiction of the Affordable Care Act’s intent.

ASCO’s framework openly ignores what really matters — benefit to patients.

Consider how the framework attempts to dictate how long a person “should” live. It claims that patients “overestimate the benefits of treatments that sometimes extend life by only weeks or months.”

In other words, ASCO has concluded that a treatment that can keep patients alive for weeks or months has no real value.

The framework assigns zero value to any treatment that doesn’t increase survival by 20 percent. Right off the bat, numerous treatments for pancreatic, brain, lung, and stomach cancer today would be deemed worthless by the formula.

That 20 percent figure is completely arbitrary. Consider the case of someone with lung cancer who is alive today because of the accumulation of treatments that never made that arbitrary threshold. Cardiologists hailed a just approved drug that reduces the risk of death from heart failure by 20 percent as revolutionary.

Under ASCO’s framework, sorry — not good enough.

Between 1987 and 2000, various AIDS therapies increased patient life expectancy by less than 20 percent a year. Had ASCO’s framework been in force then, thousands of AIDS patients who benefited from those treatments would not be alive today.

ASCO defends its guidelines by claiming that expensive new treatments have sown “unrealistic patient and family expectations that lead clinicians to offer or recommend some of these services, despite the lack of supporting evidence of utility or benefit.” The American healthcare system can’t afford limitless spending on cancer treatments, the group says.

It’s true that spending on cancer drugs has risen. In 2014, it topped $100 billion. But that figure represents just 1 percent of U.S. healthcare spending.

What’s more, these medicines work — and are worth their price tags.

Successful drug therapies reduce overall medical costs by diminishing the need for future doctor visits and hospital stays. According to a study from the Center for Value and Risk in Health, specialty drugs often cost more than traditional drugs but “also tend to confer greater benefits and hence may still offer reasonable value for money.”

Successful treatment does more than just lower health costs and offer patients priceless extra time with loved ones. It also benefits the nation. According to one study, cancer survivors have contributed $4.7 trillion to the economy since 1990, simply by living and working longer.

Indeed, according to a Health Affairs study, “current technology assessments, which often determine access” to cancer therapies “may be missing an important source of value to patients and should either incorporate hope into the value of therapies.”

By valuing treatments based on what they cost insurance companies rather than the benefit they provide to patients and their families, the ASCO framework violates both the letter and spirit of the Hippocratic Oath. It should be scrapped before it puts patients in danger.

Today, the Critical Path Institute, founded by Ray Woosley, is celebrating it’s ten year anniversary.

Ray and C-Path has done more to advance personalized medicine than most.  C-Path – working closely with pharma and the FDA -- have led the development of tools and markers that are now routinely used in clinical trials to more quickly and accurately developed tools matchpatients to treatments that deliver the most benefit relative to risks.  

When C-Path was first launched it was difficult to bring together patients, researchers, private companies and regulators.  Under Ray’s stewardship and with the quiet but essential support of the FDA (especially Janet Woodcock) the collective intelligence C-Path brought together has been instrumental in transforming the clinical trial landscape around the world

And the best is yet to come: As current C-Path CEO Marsha Brumfield has written: “the boundaries are expanding with the growing realization of the substantial benefit that can result from new discoveries (such as biomarkers, modelling tools and clinical outcome assessments (COAs)). Even clinical data, traditionally considered proprietary, are contributed to pooled databases to help solve prespecified research questions.

The tools and methods created through sharing information precompetitively are changing the landscape of clinical trial design, enabling trials to be more optimally designed and executed. “

Peter and I are proud to have had Ray as a ‘rabbi’ and an ally in promoting personalized medicine.   We look forward to working with him and C-Path in the years ahead.

HRSA's 340B Fix

  • 08.28.2015

HHS's Health Resources and Services Administration (HRSA) has issued draft guidance on the 340B program that addresses some of industry's concerns with the program. Per BioCentury, the guidance includes a clearer definition of 340B-eligible patients.

The 340B program is intended to provide discounted outpatient drugs to hospitals that serve a disproportionate share of poor and uninsured patients. The 340B hospitals can then dispense the discounted drugs to their non-Medicaid outpatients and use the savings to pay for the care of indigent patients.
However, the number of 340B-eligible entities and discounted drugs sold to those entities has grown over the last several years, and industry has said some hospitals are not using the money to pay for charity care and are dispensing the discounted drugs to individuals who are not patients of the hospital.

 In the draft, HRSA clarifies which patients would be eligible for 340B: those who receive care at the hospital and who have received a prescription from a provider directly affiliated with the hospital. The rule notes that a patient would be ineligible if the drug is dispensed while they are still an inpatient; if the only service provided by the hospital or provider is to dispense or infuse the drug to the patient; if the patient's physician has credentials or privileges at the hospital but who is not an employee of the hospital; or if the patient is an employee of the hospital but may get care elsewhere. 

Additionally, if patients of the covered entity choose to have their prescription filled at a pharmacy not affiliated with the hospital, the drug would be ineligible for the discount. 
The guidance also would allow manufacturers to audit covered entities if the manufacturer "has reasonable cause" to believe that the entity is providing duplicate discounts to Medicaid patients or diverting drugs to ineligible patients.

The draft guidance will be published in the Federal Register on Friday. Comments are due October 27th.

On Tuesday OMB completed its review of a proposed rule entitled "Designation of Official Names and Proper Names for Certain Biological Products."

It's as predicted ... and good news.

According to the Wizards of White Oak, “ Our current thinking is that shared nonproprietary names are not appropriate for all biological products. There is a need to clearly identify biological products to improve pharmacovigilance, and, for the purposes of safe use, to clearly differentiate among biological products that have not been determined to be interchangeable. Accordingly, for biological products, we intend to designate a nonproprietary name that includes a suffix composed of four lowercase letters. Each suffix will be incorporated in the nonproprietary name of the product.

This naming convention is applicable to biological products previously licensed and newly licensed under the PHS Act. The nonproprietary name designated for originator biological products, related biological products, and biosimilars will include a unique suffix. However, FDA is considering whether the nonproprietary name for an interchangeable product 2 should include a unique suffix, or should share the same suffix as its reference product. FDA invites comment on the draft guidance and solicits comments on ways to improve active pharmacovigilance systems for the purposes of monitoring the safety of biological products.

 The Proposed Rule says:

"The official names and proper names of these products would include distinguishing suffixes composed of four lowercase letters and would be designated as filgrastim-bflm (BLA 125553), filgrastim-jcwp (BLA 103353), filgrastim-vkzt (BLA 125294), pegfilgrastim-ljfd (BLA 125031), epoetin alfa-cgkn (BLA 103234), and infliximab-hjmt (BLA 103772). Although FDA is continuing to consider the appropriate naming convention for biological products, including how such a convention would be applied retrospectively to currently licensed products, FDA is proposing to take action with respect to these six products because of the need to encourage routine usage of designated suffixes in ordering, prescribing, dispensing, recordkeeping, and pharmacovigilance practices for the biological products subject to this rulemaking, and to avoid inaccurate perceptions of the safety and effectiveness of biological products based on their licensure pathway."

A win for sanity and patient safety.

Also, if you'd like more on the related biosimilar J-Code issue, see here.

Over at Forbes, the always thoughtful Matt Herper asks, “Remember when the FDA rejected drugs?”

Per Matt, “As recently as 2008, companies filing applications to sell never-before-marketed drugs, which are referred to by the FDA as “new molecular entities,” faced rejection 66% of the time. Yet so far this year the FDA has rejected only three uses for new chemical entities, and approved 25, an approval rate of 89%.”

(These numbers come from a new analysis commissioned by Forbes from BioMedTracker. The way BioMedTracker follows new molecular entities is slightly different from the way the FDA does. BioMedTracker users want to know about every use of a new medicine. That means that the 2015 rejection count includes rejections of Avycaz, a new antibiotic from Allergan, for hospital-acquired pneumonia, and selling Jardiance, a diabetes drug from Eli Lilly and Boehringer Ingelheim , in combination of metformin. But Avycaz was approved for two other uses and Jardiance is on the market by itself.)

Herper, “… it’s worth sticking to BioMedTracker’s definitions, because it allows us to compare this incredibly high approval rate with the past. And that tells a story of an agency that has been giving the green light more and more often.”

Interesting stuff – but what’s missing is a discussion of how the evolution of regulatory science has impacted the dynamic relationship between the FDA and the innovative pharmaceutical industry and has changed over the course of time (by design, and largely through the mechanism of PDUFA negotiations) the quality of NDAs reaching agency review.

More agency/sponsor meetings earlier in the process not only result in better submissions (more likely to be approved because of higher quality science and more sophisticated protocols), but fewer applications of questionable value . As one senior FDA official told me yesterday, “We’re seeing fewer dogs.”  

Another factor that’s important to consider is that failed NDAs are expensive. The following figures are illuminating.

  • A 10% improvement in predicting failure before clinical trials could save $100 million in development costs.
  • Shifting 5% of clinical failures from Phase III to Phase I reduces out-of-pocket costs by $15 to $20 million.
  • Shifting failures from Phase II to Phase I would reduce out-of-pocket costs by $12 to $21 million.
When he was asked why he was so successful, Thomas Edison replied, “Because I fail faster than everyone else.” One of the reasons the FDA is seeing fewer dogs is because they are helping innovators to recognize failure earlier in the process. And that also means more money that can be reinvested in new clinical programs. Furthermore, a high turndown rate is not a badge of honor--it is indicative of a dysfunctional system.

The good news is that more R&D time, talent, and treasure is being focused on personalized medicine using more sophisticated tools (i.e, biomarkers). Failure is being found sooner, targeted clinical success is easier to predict earlier – and can be expedited through the regulatory process through many new and exciting review pathways (i.e., Breakthrough Designation).

(PS/ Those who don’t think the FDA has “adaptive licensing” opportunities don’t understand what’s going on. And those who choose to blame the FDA for biotech investor anxiety had better find some new excuses.)

Those who wave their arms about the FDA “approving everything” don’t see (or choose not to see) the important success story behind the headline. That dog don’t hunt.

Lots of news about a survey by the Kaiser Family Foundation (KFF) showing that a majority of Americans (76 percent) strongly or somewhat support government price controls on prescription drugs.  

Let's set aside the survey's skewed approach to polling:  It singled out prescription drugs for such polling (i.e. there was no question asking people if they knew what they paid for drugs was already controlled -- by health plans -- and that prices were increasing though drugs remained a small share of insurer costs) and it undersampled Republicans and healthy, middle income people.   Indeed, the oversampling of Democrats and Independents and the focus on drug prices appears to be part of a broader effort to get drug price control referendum on the ballot in key primary and battleground states like Ohio and California.  

Let's instead ask what is the implication of the findings.

According to KFF CEO Drew Altman.. 

“Rightly or wrongly, drug companies are now the number one villain in the public’s eye when it comes to rising health-care costs,” said Foundation President Drew E. Altman, Ph.D. “People want to rein in the cost of prescription drugs, and just about anything we poll on with that aim gets public support.”

Altman did say that. But not about the recent poll.  He said it about a survey taken a decade ago. 

The same could be said about other surveys conducted by Kaiser or by their partner in polling, Harvard's Robert Blendon..

In 1984 seventy seven percent of Americans favored prices controls on all medical services.  In 1994 that figure was 72 percent.  

I bet if I surveyed people to see if they favored price controls on data plans or college tuition or food, I'd get the same number. 

All of which proves what polling pioneer Daniel Yankelovich concluded after looking through mounds of Gallup polling data:

The factual ignorance and fickleness reflected in surveys like the KFF tracking polls are often counterbalanced by a remarkable sureness of judgement in applying basic values... 

These polls generate headlines and help groups supporting such referendum to raise money.  They don't shape policy.  In fact, with one or two exceptions that were disastrous (Truman and Nixon's wage and price controls) the American electorate has shied away from outright price controls or laws that would limit the choice of medicines to what is cheapest such as mandatory generic substitution.  

As a result, American has since the 1960s, outpaced the world in the development of important treatments for HIV, cancer, Hepatitis C and heart disease that -- since 1990 -- have reduced death and disability as well as made treating people with these illnesses much less expensive (and more effective) compared to older therapies. 

So perhaps in addition to polls and ballot initiatives promoting price controls, stakeholders and patient groups should commission surveys and propose referendum about how health plans limit access to new medicines by hiking drug prices and saying no to new medicines.  

In the immortal words of Don Draper, “If you don't like what is being said, then change the conversation. And nowhere is that more true than in our national dialogue over opioid pain medications.

Senior leadership at the FDA has returned again and again to the role the agency must play in facilitating physician and patient education -- and not only through labeling language. Former FDA Commissioner Hamburg specifically mentioned CME and working to develop (with a broad constituency) validated tools for physicians to use in determining which patients may be more prone to slide into abuse so they can choose their therapeutic recommendations more precisely.

“It all comes back to provider education,” she said. Amen.

Education – the Hamburg Manifesto.

That’s not regulatory mission creep; it’s the appropriate application of the agency’s Safe Use of Drugs initiative. The way you make a drug “safer” is to ensure that it is used by the right patient in the proper manner.

In keeping with that philosophy, an important announcement from Purdue Pharma:

Purdue Pharma L.P. Launches

New Resource Aimed at Educating About Opioid Analgesics with Abuse-Deterrent Properties and Team Efforts to Deter Abuse of Prescription Medicines

 STAMFORD, Conn., August 17, 2015 – Purdue Pharma L.P. proudly introduces Team Against Opioid Abuse, a new website designed to help healthcare professionals and laypeople alike learn about different abuse-deterrent technologies and how they can help in the reduction of misuse and abuse of opioids. Combating misuse and intentional abuse of prescription pain relievers involves more than just the person holding the prescription pad. It is a team effort, including pharmacists, nurses, counselors, caregivers, patients, and payers, both public- and private-sector. Public health experts have stated that Opioids with Abuse-Deterrent Properties (OADP) are an essential component of a comprehensive, evidence-based strategy to reduce opioid abuse that requires coordinated and sustained efforts from the healthcare team along with multiple other players, such as manufacturers, policymakers, regulators, educators, and law enforcement.

“Education about the proper use of opioid analgesics is a top priority at Purdue Pharma. Everyone on the team should understand their role and responsibilities, so they can do their part in combating abuse of opioids, while ensuring their availability for appropriate purposes,” said J. David Haddox, DDS, MD, Vice President, Health Policy, Purdue Pharma L.P. “Opioids with Abuse-Deterrent Properties are one tool to help the team in their efforts in fighting drug abuse. We developed this website to inform everyone who influences how drugs are prescribed, taken, stored, and destroyed, when no longer needed.”

Opioid abuse is a critical problem in America and one that healthcare professionals, payers, law enforcement, policymakers and drug makers are all working to combat. The 2013 National Survey on Drug Use and Health reported that, among persons age 12 or older in 2012 to 2013, approximately 68 percent of people who used prescription pain relievers for nonmedical purposes said they got the medicines from a friend or relative, for free, by purchase, or by theft.[1] In 2011, the White House identified prescription drug abuse and misuse as a major public health and public safety crisis.[2]

Using clear graphics and easy to understand language, the website features sections about why it’s critical to deter abuse and how all the members on the healthcare team can make a difference. It also outlines the 2015 Food & Drug Administration’s Guidance on Abuse-Deterrent Opioids — Evaluation and Labeling, which informs drug developers about FDA’s current thinking on what kinds of testing potentially abuse-deterrent opioids should undergo. Because FDA states that having information about an opioid’s abuse deterrence available for healthcare professionals and patients, the website also reviews how Section 9.2 of a drug product’s Full Prescribing Information is the key to identifying opioid formulations with FDA-approved abuse-deterrent properties.[3]

The Team Against Opioid Abuse website can be can be accessed at

 [1] Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality. Results from the 2013 National Survey on Drug Use and Health: Summary of National Findings. NSDUH Series H-48, HHS Publication No. (SMA) 14-4863. Accessed August 8, 2015.

2 White House Office of National Drug Control Policy. Epidemic: Responding to America’s Prescription Drug Abuse Crisis. 2011. Accessed August 8, 2015.

3 Food and Drug Administration, Center for Drug Evaluation and Research (CDER), US Department of Health and Human Services. Abuse-Deterrent Opioids — Evaluation and Labeling: Guidance for Industry. Accessed August 8, 2015.

 Well done Team Purdue.

Dear President Carter:

I was sorry to learn that you are fighting an advanced form of cancer that has spread to your liver and other parts of the body.   There is good news, sort of.

As a recent article in the Boston Herald noted:

Former President Jimmy Carter revealed yesterday that he will undergo treatment for cancer that has spread to various parts of his body — and doctors say that despite his advanced age, the 90-year-old may fare well thanks to recent advances in personalized medicine.

“With cancer cells, there are many different mechanisms that make them grow, and a lot of the science has been dissecting genes and proteins that cause it,” said Dr. Andrew M. Evens, director of Tufts Cancer Center. “There’s work around identifying treatment for the patient’s individual cancer and doing it at a genetic level.”

Not so fast Mr. President.

Even as a former President, you will be faced with what is called “step therapy” or “quality pathways” that determine what treatments you get.   You have to fail first on the first step of therapy before getting to up to five other ‘approved’ treatments before getting to the ‘advances in personalized medicine.’ 

You were a plain spoken president, so I probably don’t have to tell you that for people with advanced form of cancer,  ‘fail first’ is code for getting sicker and closer to death.

Health insurers claim these pathways don’t affect outcomes.  But they refuse to cover the advances that have a very good chance of keeping you alive and well.
Neither the tests for the genetic makeup of your cancer cells to identify where it started, and guide treatment are not at the end of any of these pathways.  Under the Affordable Care Act, anything not on a pathway has to be paid for in full by you.

You might think that your doctor will fight to get you the treatments that could save your life.

Sorry to disappoint you.

The leading cancer doctor group -- The American Society For Clinical Oncology (ASCO) – has developed a calculator of value that treats all patients as the same; ignoring the genetic variation in patient response that allows doctors to personalize care.

Indeed, ASCO wants insurers to use their calculator to “evaluate the relative value of new treatments” as they develop “benefit structures, adjustment of insurance premiums, and implementation of clinical pathways and administrative controls.” 

That’s not good news either.   I’ll give you a couple of examples.   I read that you have a family history of pancreatic cancer.   So I used the ASCO calculator to come up with a value score (the highest score is 130).  The most common treatment for advanced pancreatic cancer that has spread everywhere adds, on average, about 2.5 months of life.  That’s worth a whole 32 points.  But then 20 points are deducted because of side effects, leaving you with 12 points of “net health benefit” out of 130 which the app helpfully notes will cost $5000 a month.  Other treatments that provide less survival and are cheaper are given a higher score.  Guess which treatments you have to use before getting to the most effective treatment covered?

The news is even worse if you have advanced colorectal cancer.  The newest drugs add more survival for this deadly disease.  But ASCO doesn’t think it’s worth more than 16 points.  Deduct 20 points because ASCO doesn’t like the side effects (rashes, nausea, fatigue) and you’re in negative territory. According to ASCO, that treatment has no clinical value at all.  And the advances Dr. Evens mentioned aren’t even measured.  And they won’t until randomized trials that take years to organize and complete are published.

It’s sad and ironic.   You lead a 30-year effort to eradicate guinea worm disease around the world.  The disease is not fatal but extremely painful and debilitating.  In 1986, there were an estimated 3.5 million cases in 21 countries in Africa and Asia. Your effort was criticized as not cost-effective from the start.  You ignored the bean counting because it only focused on 2-3 measures of value.   (Sound familiar?)

Today, that number has been reduced by more than 99.99 percent, with the vast majority of cases remaining in South Sudan.

It’s a good thing it was you – not the alliance of insurers and ASCO – tackling that challenge.   Unfortunately they are putting a price tag on whether you live or die.  Maybe you can change that.  A grateful nation is pulling for you to win one more campaign.

Wither Off-Label?

  • 08.14.2015

The debate over off-label communications doesn’t begin or end with the Caronia or Amarin decisions. It’s a continuing dialogue between manufacturers and the FDA, between doctors and patients, between doctors and academics, between lawyers and judges, and between advocates on all sides.

And the red thread that ties these conversations together is responsible off-label communications. Not sales strategies. Not DTC tactics. Not managed market negotiations – the responsible sharing of truthful and accurate information.

It’s important to say early in the conversation that almost no one is against sharing valuable information about FDA-approved medicines. The discussion – the heated discussion – is over how (or if) that conversation should be regulated by the FDA.

Steve Jobs said, “Innovation distinguishes between a leader and a follower. And make no mistake, off-label communications is about innovation. Innovation in the safe and effective use of medicines. Off-label communications is about getting the right medicine to the right patient in the right dose at the right time – even though the right medicine or the right dose may not correspond precisely to the FDA label.

But who is the leader and who is the follower? Or perhaps a better question to ask is, why can’t we all be leaders?

Off-label communications, properly done, advances precision medicine, delivering speedier positive patient outcomes, and reducing costs to our healthcare system. Off-label communications provides patients with more options for effective medicines.

Those who think that the argument over off-label is just about marketing and sales are looking at this issue through very narrow blinders.

What is the role of the FDA is off-label communications. Well, first let’s stipulate that the FDA doesn’t regulate the practice of medicine. Then let’s discuss the fact that the agency can (and indeed must) help to facilitate the free and fair dissemination of timely, truthful, and trustworthy scientific knowledge.

Also, initial licensing approval is not based on data for every possible indication. Initial approval is based on a “best foot forward” approach. But that doesn’t mean there isn’t robust scientific evidence to support broader therapeutic uses. In fact, initial approvals, based on a narrow, randomized population, only provide a window into future clinical possibilities.

According to the House Energy & Commerce Committee’s 21st Century Cures Initiative initial white paper:

Communication about how certain treatments are working in certain patients is happening through a multitude of media around the globe. These conversations between and among doctors, patients, researchers, and scientists in academia and industry should be facilitated. This includes the free flow of data, research, and results related to what a therapy or combination of therapies does or does not do well and in what types of patients.

 Off-label communications is about recognizing that the speed of scientific discourse impacts clinical practice years before it drives official label changes.

You don’t have to look much further than oncology and many orphan diseases to see that off-label use is regularly considered first line therapy. And payers in the US and elsewhere reimburse off-label prescribing. Why? Because it enhances outcomes.

How do physicians learn about off-label usage? Medical meeting presentations, professional journal articles, discussions with their peers, and through materials from manufacturers. Please note that I haven’t listed DTC. There is a difference between off-label communications and off-label marketing – and it is a distinction with a difference.

So, what do academics and physicians, payers and patients know about off-label communications that the FDA does not? Asked in a more progressive way, how can the FDA be an accelerator rather than a sea anchor when it comes to facilitating off-label communications?

In a word, the answer is clarity. Alas, regulators love ambiguity because it gives them unlimited options. And nowhere is this more evident than when it comes to issues concerning communication. It would be generous to call the FDA’s views on the dissemination of off-label information ad hoc. With the important exception of the agency’s guidance on Good Reprint Practices. According to the March 2014 revised guidance, reprints that discuss off-label use mustn’t:

  • Be false or otherwise misleading;
  • Recommend or suggest use of the product in such a way that the product is dangerous to health when used in the manner suggested; nor
  • Be marked, highlighted, summarized, or characterized by the manufacturer, in writing or orally, to emphasize or promote an unapproved use.

Those are pretty broad guideposts. More interesting and germane to current events are those related to Clinical Practice Guidelines (CPG):

Any CPG that includes information on unapproved or uncleared uses must meet Institute of Medicine (IOM) standards for whether it is a “trustworthy” guideline.  According to IOM, a guideline is “trustworthy” if it:

  • Is based on a systematic review of the existing evidence;
  • Is developed by experts in the subject area;
  • Considers important patient subgroups and patient preferences;
  • Is transparently developed and funded such that biases are minimized;
  • Provides logical relationships between treatment recommendations, health outcomes, and includes the quality and strength of the underlying evidence; and
  • Is reconsidered and revised as new information becomes available.

Beyond this, what will the FDA do next? More importantly, will it lead or follow, or follow and then lead? And this brings us to the recent court decisions in the Caronia and Amarin cases.

The Caronia decision, a 2012 decision from the Second Circuit Court of Appeals, overturned the conviction of Alfred Caronia, a sales representative for Orphan Medical, which was later acquired by Jazz Pharmaceuticals. After Caronia was caught talking to physicians about various off-label uses of the narcolepsy drug Xyrem, the court said the First Amendment protected truthful and non-misleading off-label speech. Key words, “truthful and non-misleading.”

That’s a good off-label equation: Truthful + Non-Misleading = Trustworthy.

Although the agency said that the decision wouldn’t impact it’s views and practices concerning the regulatory oversight of off-label communications, the decision, combined with increased pressure from industry, forced the FDA to put the issue of off-label communications on the front burner.

Unfortunately, it was put on the front burner on a low flame.

Between Caronia and Amarin, the FDA issued some very valuable draft language on the issue. Under the proposal, FDA would not “object to the distribution of new risk information that rebuts, mitigates, or refines risk information in the approved labeling.” The studies must be “well-designed” and “at least as informative as the data sources” that the FDA used in generating the official warning.”

The new FDA draft guidance opens the door for companies to share truthful, scientifically accurate, and data-driven information with healthcare professionals to inform treatment decisions. For example:

—  Observational data and “real world evidence”

¡ Information on the safety and effectiveness of medicines taken from medical records based on actual use of approved medicines.

—  Sub-population data

¡ Information on the safety and effectiveness of medicines in sub-populations including gender and race. Such information can help healthcare professionals tailor their treatment to meet the needs of individual patients.

—  Observational and comparative data

¡ Information from the use of a medicine outside of randomized clinical trials, especially comparisons between two or more therapies.

—  Pharmaco-economic information

¡ Healthcare economic data and information on the economic value of medicines can improve the efficiency of patient care.

—  Information on medically accepted alternative uses of medicines

¡ Information on new uses of approved medicines that are listed in major compendia and/or routinely reimbursed by the federal government and major payers.

Things seemed to be moving ahead and the FDA seemed to be driving the conversation – and then came Amarin and it’s drug Vascepta – approved by the FDA for treatment of patients with “Very High” triglycerides.

In April, the FDA rejected Amarin’s claim for “Persistently High” triglycerides and also decided Amarin couldn't include clinical trial data in Vascepa labeling about the extent to which the pill may effectively treat people with slightly lower levels of triglycerides.

In May Amarin filed a lawsuit in Federal Court claiming it “finds itself in a bind,” since it “may not freely communicate truthful and non-misleading information about Vascepa to health-care professionals…without fear of criminal prosecution and civil liability.” In its lawsuit, Amarin included a list of medical journal articles it would like to distribute to physicians.

In June, the FDA sent a letter to Amarin saying the types of materials the drug maker would like to distribute to doctors actually would not be a problem and “would not consider the dissemination of most of that information to be false or misleading.” Then the FDA suggested that Amarin might have known this if the drug maker had discussed the issue before filing its lawsuit, “as other pharmaceutical companies sometimes do.”

 Earlier this month the court agreed Amarin materials are truthful and took the government to task for essentially arguing that speech alone can be the basis for liability and that the agency’s action is at odds with the Caronia holding and the First Amendment.

Post-Caronia and pre-Amarin, hoping to maintain its ability to apply “regulatory discretion, “the FDA signaled it was going to loosen the reins on off-label communications. And, in fact, this was part of the government’s argument in the Vascepta case. The Judge asked when the FDA would be issuing further guidance on off-label communication, asking if it would be in 2015 or afterwards, or before Labor Day. The government’s attorney said she had “no idea” when the agency would act or if more speech will be permitted when it does. Bad answer.

 So what happens now?

I predict that the FDA will continue to develop its new thinking on off-label (informed and influenced by both the Caronia and Amarin decisions). It will then issue a more complete draft guidance and collect feedback via a Federal Register docket. That’s the way the system works and rules must be follows.

I further predict, barring overly ambiguous and wimpy language from the agency, that most pharmaceutical companies will declare victory and follow the FDA’s lead. That being said, the agency will need to carefully monitor i’s off-label oversight – and his means a lot more than the usual and customary OPDP review. It means senior management attention to how the agency views “trustworthy” and a very careful eye on any actions it considers taking.

All this to say that off-label communications is now on the agency’s front burner and the flame is on high. As Everett Dirksen used to say, “When I feel the heat, I see the light.”

Can the FDA recapture a leadership role in the off-label conversation? I believe it can – and will. But it will require the agency to trade ambiguity for predictability because, when it comes to trustworthy off-label communications, predictability is power in pursuit of the public health.

Stay tuned.


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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