Physicians are permitted to prescribe drugs off-label. By off-label, I really mean “silent label.” Silent label implies the manufacturer has not received FA approval to market the drug as safe and effective for treating the off-label condition.
An example: some antibiotics have been approved for those 18 or older. The label granted by the FDA likely reflects the submission. The manufacturer might have wanted to keep costs down and only test adults. Most manufacturers know that if a drug is approved for adults, some physicians will prescribe the medication for younger patients. And the law generally allows physicians to do precisely that. (We are aware of only a narrow class of restrictions where the federal government dictates the uses for which a drug can be prescribed – anabolic steroids and human growth hormone). Eventually, the literature will accumulate data about the safety and efficacy of the antibiotic’s use in minors.
So doctors have had significant latitude to prescribe medications off-label.
But, pharmaceutical manufacturers have had their hands tied. They are allowed to market the drugs only for the indications which have been approved by the FDA. So, in the example above, a pharmaceutical rep was not legally entitled to say that the antibiotic can safely be prescribed in children – even if the literature supports that conclusion.
Pharma had several safe harbors. They could send some medical literature about a drug’s off-label use. This was “codified” in 2009 with the inviting title: “Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices.” That draft guidance focused on what types of literature may be distributed to health care providers as well as the conditions under which such literature may be provided.
Here are a few of the conditions:
The article must be: 1) unabridged; 2) not marked, summarized or characterized by the manufacturer in any way; 3) accompanied by the product’s approved labeling; 4) accompanied by a comprehensive bibliography; 5) accompanied by a representative opposing article that reaches a different conclusion (if one exists); and 6) separate from information that is promotional in nature.
And there are more.
Which brings us to 2012. And USA v. Caronia. Caronia was a pharmaceutical representative who promoted the drug Xyrem for off-label use. Xyrem contains gamma-hydroxy-butyrate (“GHB”) and was indicated for some types of narcolepsy. (GHB has also been implicated in date rape – clearly not an “indicated use.”) In 2009, a federal court found Caronia guilty of criminal conspiracy to introduce a misbranded drug into interstate commerce. He allegedly told a doctor (the conversation was taped) Xyem could be used for “daytime fatigue and excessive sleepiness.” And so on.
The penalty included potential jail sentence – although the judge sentenced him to one year probation, 100 hours of community service, and a $25 special assessment.
A federal appeals court just reversed the conviction. And now a lot has changed.
The appellate court concluded the FDA cannot prevent a pharmaceutical representative from speaking the truth about off-label indications. The court noted that the outcome – physicians prescribing off-label – is allowed. But, speaking about that outcome – a representative’s promotion of off-label – is not allowed. The court believed this did not make sense.
The court acknowledged the FDA has a substantial interest in securing the drug approval process in supporting safety and efficacy of drugs. But,
if the government is concerned that off-label promotion may mislead physicians, it could guide physicians and patients in differentiating between misleading and false promotion, exaggerations and embellishments, and truthful or non misleading information. The government could develop its warning or disclaimer systems, or develop safety tiers within the off-label market, to distinguish between drugs. The government could require pharmaceutical manufacturers to list all applicable or intended indications when they first apply for FDA approval, enabling physicians, the government, and patients to track a drug’s development. To minimize off-label use, or manufacturer evasion of the approval process for such use, the government could create other limits, including ceilings or caps on off-label prescriptions. The FDA could further remind physicians and manufacturers of, and even perhaps further regulate, the legal liability surrounding off-label promotion and treatment decisions. Finally, where off-label drug use is exceptionally concerning, the government could prohibit the off-label use altogether. The possibilities are numerous indeed.
The court continued:
prohibiting off-label promotion by a pharmaceutical manufacturer while simultaneously allowing off-label use “paternalistically” interferes with the ability of physicians and patients to receive potentially relevant treatment information; such barriers to information about off-label use could inhibit, to the public’s detriment, informed and intelligent treatment decisions.
In sum, the court concluded “the government cannot prosecute pharmaceutical manufacturers and their representatives under the [Federal Food, Drug, and Cosmetic Act] for speech promoting the lawful, off-label use of an FDA-approved drug.
I guess there will be much more to discuss next time a pharmaceutical representative brings lunch.
They still would have to overturn Friedman v. the Washington Legal Foundation, to do away with off-label prescribing by doctors. To do so would eliminate over 90% of oncology prescribing and more than 50% of pediatric prescribing, and the list goes on.
–SN
Dr. Nelson:
The ruling makes it more likely off-label prescribing is allowed – not less. More specifically, it allows pharmaceutical companies to engage in truthful dissemination of information about their compounds for indications not approved by FDA.
When it comes to Government supervision of physicians, the best supervision is usually the least supervision. I have had patients who were airline pilots for major carriers. This what they tell me: “Your certification as a pilot who flies hundred-million dollar aircraft suggests that your employer has enough confidence in you to allow you to make the best choices for the circumstances without micromanagement.”
No matter how hard Government tries to regulate prescribing, “perfection” is impossible. More regulations will constrain your actions to the point where you might do more harm than good, as well as completely miss the opportunity to make the best decision for your patient.
Michael M. Rosenblatt, DPM
Sir:
Your blog states “The appellate court concluded the FDA cannot prevent a pharmaceutical representative from speaking the truth about off-label indications.”
Caronia, the drug rep in question, spoke un-truths to the doctor to whom he was promoting his drug, Xyrem.
The Court ruled in favor of Caronia. Falsehood became truth.
Kafka, anyone?
sincerely,
Dr Eric Cohen
re: Dr. Cohen’s comments, I don’t quite get it. If Caronia said that the drug did what the website says it did, I don’t see where any of this makes sense. What does “misbranded” mean? The Xyrem website claims that the drug is used to treat narcolepsy and daytime fatigue.
A minor matter.
The FDA’s charter is basically to protect the safety of the American public from drugs and devices (and also foods and cosmetics, but we’ll spot them this one for the moment). Note–it’s to protect us from bad drugs and devices, and it specifically does ~not~ require them to approve the use of things that might be life-saving.
So, on to a modest proposal. I propose that the FDA’s charter be changed from a proscriptive one to an advisory role. At this pont in time, a pharmaceutical company can research the living daylights out of a drug and the FDA can, at its whim, decide against approving it. In the device industry, I am personally aware of several instances in which thy’ve done this, and in some cases, it has led to the death of the company along with denying patients the products that they made–and that worked.
How about allowing the FDA to decide whether it ~would~ have approved a drug or device, and require a manufacturer to declare whether it has FDA approval to market it. The company could decide on its own whether it agrees with the FDA’s approval status, but it has to show the doctor, hospital, clinic, and most importantly, the patient the actual status. If everyone agrees to go along with using the drug or device, it gets used. If lawsuits arise later, say because a company misrepresented the results of its testing–which have to be legally available to any and all who want to see them–then it goes to court. But the patient(s) get the benefit of the drug or device.
It seems to me that this would be a win-win(-win-win) scenario:
1) Patients and doctors get to use what they think is in their best interests;
2) Drugs and devices will invariably become less expensive since manufacturers would have to spend FAR less on research, which the FDA overkills like there’s no tomorrow;
3) Manufacturers also have longer to recoup the cost of R&D since the device or drug would get to market more quickly, so have a longer time under patent protection; and finally
4) Plaintiff’s lawyers would have a field day suing everyone under the sun when the occasional drug or device is actually misrepresented.
Or am I missing something here?
JH