Wither Off-Label?

  • by: |
  • 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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