F.D.A. Deal Allows Amarin to Promote Drug for Off-Label Use

[garbon]

http://www.nytimes.com/2016/03/09/business/fda-deal-allows-amarin-to-promote-drug-for-off-label-use.html

In a deal that could change the way some companies market their drugs, the Food and Drug Administration has agreed to allow a pharmaceutical company to promote a drug for a use that the agency has not approved, the company said on Tuesday.

The agreement settles a legal case between the agency and the company, Amarin, a small drug maker that sued the F.D.A. last year for the right to promote its only product, Vascepa, to a broader range of patients. In August, a federal district judge in Manhattan ruled that the F.D.A. could not prohibit Amarin from using truthful information to promote its drug, even for unapproved uses, because doing so would violate the company's right to free speech.

The final settlement is still subject to approval by the court.

The agency on Tuesday downplayed the implications of the deal. In a statement, it said that the settlement applied only to the Amarin case and that its position on whether companies have a constitutional right to provide truthful information about off-label uses had not changed.

But some legal and drug-safety experts said the settlement could encourage other companies to seek similar arrangements and, ultimately, have profound implications for how drug makers sell their products.

"This really sends a signal to other companies that if you want to engage in off-label promotion, you can negotiate with the F.D.A.," said Dr. Michael Carome, director of health research at Public Citizen, a consumer advocacy group in Washington.

"Ultimately, that's taking us down a dangerous pathway."

While doctors may prescribe drugs in nearly any way they see fit, the F.D.A. has long argued that drug makers cannot promote their products for unapproved uses. Pharmaceutical companies have paid billions of dollars in fines in recent years after being accused of marketing drugs for off-label uses.

The pharmaceutical industry has held that it should have the right to share information about its products, provided that the information is not misleading.

In 2012, the agency permitted Amarin to begin selling Vascepa to people with extremely high levels of triglycerides, a kind of fat in the blood that has been linked to heart disease. After the ruling in August, Amarin said it would also begin promoting Vascepa, a prescription omega-3 fatty acid that is derived from fish, to people with slightly lower levels of triglycerides, a use the F.D.A. had previously denied.

The company has said that the F.D.A. denied its request because, even though a clinical trial showed Vascepa reduced triglycerides, the drug had not been proved to reduce the risk of heart disease. A clinical trial evaluating the impact of Vascepa on heart disease is underway.

Alan Bennett, a lawyer who represents the Medical Information Working Group, a coalition of drug and device companies that want the F.D.A. to expand their ability to talk about their products, said more companies may now approach the agency seeking similar deals.

"My guess is they don't want more of these cases, so my guess is they will be more flexible than they have in the past in permitting it," Mr. Bennett said.

Amarin said in a statement that truthful information ultimately served the public good. "This settlement serves the public interest by supporting informed medical decisions for tens of millions of patients with persistent high triglycerides," said John F. Thero, Amarin's president and chief executive.

Under the settlement, Amarin would have to submit proposed marketing materials to the agency, which could then object if it felt the information was untrue or misleading. If the two parties could not agree, a federal judge would sort it out.

Leaving such decisions to a judge, not the F.D.A., concerned Dr. Joshua M. Sharfstein, a former principal deputy commissioner at the F.D.A. who is now an associate dean at the Johns Hopkins Bloomberg School of Public Health.

"The courts are at the precipice of taking over a fundamental F.D.A. function of calling balls and strikes in the drug market about what's truthful and not misleading," Dr. Sharfstein said.

Mr. Bennett said he agreed that the F.D.A., not the judiciary, was best able to evaluate information about drugs. But he called on the agency to re-evaluate its position. "The F.D.A. has promised to take a look at these policies and try to bring them into alignment with the First Amendment," Mr. Bennett said.

[Capetan Mihali]

Good.  On-label/off-label is crap, since doctors can prescribe on or off as they see fit.  Klonopin's been used for anxiety for probably 30 years at least, and without looking it up, I don't know if it's currently on-label for anything except epilepsy and more recently panic disorder.

[garbon]

I don't know. It isn't as though knowledge about off-label uses is hard to come by with companies currently not being able to promote off-label indications.

[grumbler]

http://www.nytimes.com/2016/03/09/business/fda-deal-allows-amarin-to-promote-drug-for-off-label-use.html

In August, a federal district judge in Manhattan ruled that the F.D.A. could not prohibit Amarin from using truthful information to promote its drug, even for unapproved uses, because doing so would violate the company's right to free speech.

Citizen's United: the fuck that keeps on fucking.  I can think of many reasons why the company should be allowed to use truthful information to promote its drug, but the rationale that legal fictions have real human rights is not one of them.  Can Amarin kill, in self-defense, a shareholder who wants to dismantle and "kill" the company?

[Capetan Mihali]

Amarin or Amarout, coach?  That's the real question.

[Malthus]

The point is that it is very difficult to determine what is "true" when it comes to drug claims.

The current system is very expensive and time-consuming: typically double-blinded clinical trials, reviewed by an allegedly impartial agency.

For "small" drugs, the cost of establishing "truth" on that basis is prohibitive. Since docs can prescribe a drug for whatever they want, off-label sales for new indications are their only choice. This allows docs to determine what is "true".

However, if the manufacturer can promote for off-label claims, they then have no incentive to run the expense of actual clinical trials, which is considered a key safeguard for truth in drug claims.

[The Minsky Moment]

Citizen's United: the fuck that keeps on fucking.  I can think of many reasons why the company should be allowed to use truthful information to promote its drug, but the rationale that legal fictions have real human rights is not one of them. 

While I agree with this statement, in substance and in sentiment, in this case it is more a problem with the reporting and not with the judge's decision.  The decision in this was based on an earlier appeals court opinion from 2012 (Caronia) - which concerned an attempted prosecution of a pharma rep for giving truthful off-label info about a drug.  Neither this case nor Caronia either rely on or even cited to Citizen's United.  They both relied on the Supreme Court's old Central Gas case that set forth the standards for evaluating commercial speech.  The rights that are at stake are the speech rights for speech made by company representatives on behalf of the company.  There is no need to import legal fictions like "corporate speech rights" to decide the case; that was just imprecise reporting from the NYT.

[The Minsky Moment]

The point is that it is very difficult to determine what is "true" when it comes to drug claims.

One thing to keep in mind is that the Federal drug laws provide for criminal penalties for off-label statements.  Indeed, not only were such statements prosecuted, they were rare instances of strict liability crimes where theories of vicarious liability were accepted - so that pharma execs could be prosecuted criminally for truthful off label statements by reps even if they had no knowledge those statement were made.

It's with that legal backdrop that the appeals court decided in Caronia that the first amendment barred the prosecution of a rep.

[Malthus]

The point is that it is very difficult to determine what is "true" when it comes to drug claims.

One thing to keep in mind is that the Federal drug laws provided for criminal penalties for off-label statements.  Indeed, not only were such statements prosecuted, they were rare instances of strict liability crimes where theories of vicarious liability were accepted - so that pharma execs could be prosecuted criminally for truthful off label statements by reps even if they had no knowledge those statement were made.

It's with that legal backdrop that the appeals court decided in Caronia that the first amendment barred the prosecution of a rep.

The penalties for off-label promotion are in theory draconian in Canada, as well. Though due diligence is a defense against execs being charged for a rogue rep.

But what happens in reality, is that either Health Canada sends a chiding letter to the company, or it is resolved through trade complaints at an "independent" industry agency: either the "Pharmaceutical Advertising Advisory Board ("PAAB") or "Innovative Medicines Canada" ("IMD" - used to be Rx&D).

Actual prosecutions, while an available option, are vanishingly rare. I don't think there has even been one, for off-label promotion itself. 

The difficulty though is similar: if you allow "off label" promotion, you reduce the incentive to spend a bajillion dollars scientifically establishing "on label" claims. Particularly here in Canada, where direct to consumer promotion of Prescription-only drugs is in any case prohibited - what is on the actual label, thus what has actually been proven to the requisite standards of evidence, will become much less relevant.

[garbon]

However, if the manufacturer can promote for off-label claims, they then have no incentive to run the expense of actual clinical trials, which is considered a key safeguard for truth in drug claims.

I don't know enough about the specifics here but from the article it read that they ran the trial (and submitted data) showing efficacy in wider range of patients but that FDA said we don't dispute that but no, we want you to have data from clinical trial showing that it lowers risk of heart disease before we widen your label from just those with severely high levels of triglycerides. So typical sort of thing FDA might ask.

Sounds like they then said, screw that, you don't disagree that we are lower levels so why can't we make a true claim on that already even if you want us to hit a different clinical endpoint.

So it seems like, unless all went crazy, that companies would still need to run a clinical trial because how else could they prove that yes their off-label claim was not misleading. A poorly designed trial (or non-existent one) seems like those would be easy things to run roughshod over and company would ultimately be fined heavily for not true claims.

[DGuller]

I think there is room for middle ground here, but this is just my lay opinion.  If there is some low-risk drug that can be taken for quality of life issues, be open with "take at your own risk" policy.  "We didn't test it in medical trials, but if you think it helps, go ahead, it won't kill you".

[LaCroix]

thank god for citizen's united

[Capetan Mihali]

thank god for citizen's united

majority opinion by c.j. bell hooks.

[Malthus]

However, if the manufacturer can promote for off-label claims, they then have no incentive to run the expense of actual clinical trials, which is considered a key safeguard for truth in drug claims.

I don't know enough about the specifics here but from the article it read that they ran the trial (and submitted data) showing efficacy in wider range of patients but that FDA said we don't dispute that but no, we want you to have data from clinical trial showing that it lowers risk of heart disease before we widen your label from just those with severely high levels of triglycerides. So typical sort of thing FDA might ask.

Sounds like they then said, screw that, you don't disagree that we are lower levels so why can't we make a true claim on that already even if you want us to hit a different clinical endpoint.

So it seems like, unless all went crazy, that companies would still need to run a clinical trial because how else could they prove that yes their off-label claim was not misleading. A poorly designed trial (or non-existent one) seems like those would be easy things to run roughshod over and company would ultimately be fined heavily for not true claims.

Apparently they are actually running the trial, it just hasn't been concluded yet.

The company has said that the F.D.A. denied its request because, even though a clinical trial showed Vascepa reduced triglycerides, the drug had not been proved to reduce the risk of heart disease. A clinical trial evaluating the impact of Vascepa on heart disease is underway.

The issue is though that allowing what hasn't yet been approved by the FDA opens the door. The FDA process is the one that was, prior to this, used to establish "truth". Now, some lesser subset of that process, as overseen by a court, will be.

There is all sorts of evidence out there at varying levels of reliability about the safety and effectiveness of drugs - if the FDA's process isn't the standard, it is hard to say what is (other than "whatever won't get you convicted").

It may not be the case that a court is better positioned than the FDA to determine these issues.

[garbon]

However, if the manufacturer can promote for off-label claims, they then have no incentive to run the expense of actual clinical trials, which is considered a key safeguard for truth in drug claims.

I don't know enough about the specifics here but from the article it read that they ran the trial (and submitted data) showing efficacy in wider range of patients but that FDA said we don't dispute that but no, we want you to have data from clinical trial showing that it lowers risk of heart disease before we widen your label from just those with severely high levels of triglycerides. So typical sort of thing FDA might ask.

Sounds like they then said, screw that, you don't disagree that we are lower levels so why can't we make a true claim on that already even if you want us to hit a different clinical endpoint.

So it seems like, unless all went crazy, that companies would still need to run a clinical trial because how else could they prove that yes their off-label claim was not misleading. A poorly designed trial (or non-existent one) seems like those would be easy things to run roughshod over and company would ultimately be fined heavily for not true claims.

Apparently they are actually running the trial, it just hasn't been concluded yet.

The company has said that the F.D.A. denied its request because, even though a clinical trial showed Vascepa reduced triglycerides, the drug had not been proved to reduce the risk of heart disease. A clinical trial evaluating the impact of Vascepa on heart disease is underway.

The issue is though that allowing what hasn't yet been approved by the FDA opens the door. The FDA process is the one that was, prior to this, used to establish "truth". Now, some lesser subset of that process, as overseen by a court, will be.

There is all sorts of evidence out there at varying levels of reliability about the safety and effectiveness of drugs - if the FDA's process isn't the standard, it is hard to say what is (other than "whatever won't get you convicted").

It may not be the case that a court is better positioned than the FDA to determine these issues.

As far as I can tell though, they aren't promoting that it can reduce risk of heart disease, no? I thought they just wanted to promote it as a way to reduce triglycerides in other patient types which they have shown but FDA didn't want to get approval until they had established that their drug is reducing risk of heart disease. Which is sort of fair enough because if it is reducing triglycerides but that isn't linked to reducing risk of heart disease, why is that drug needed for people who don't have severly high levels of triglycerides.

It seems like Amarin was willing to setup trial for the risk of heart disease but said that even before that happens, they should still be able to promote to people with lower elevated levels of triglycerides that their product reduces triglycerides. The dispute then being FDA saying even though that's true we haven't given you label for that so you can't say it. Amarin and court saying, no actually they can as all have agreed they actually do that.

Could be misreading something but that's the gist I'd got from articles that I'd read.