FDA Settles Amarin First Amendment Challenge

Amarin Pharma and the FDA recently announced a widely expected settlement of First Amendment litigation over restrictions on the company's promotion of its Vascepa product.

Readers may recall that this was one of several recent challenges to the FDA's attempt to restrict off-label promotion of prescription products, even if that speech is truthful and not misleading. Several trends have combined to undercut this overreach by FDA. A pharmaceutical representative's promotion of an FDA-approved drug's off-label use is speech. And “speech in aid of pharmaceutical marketing ... is a form of expression protected by the Free Speech Clause of the First Amendment.”  Sorrell v. IMS Health, Inc., 131 S.Ct. 2653, 2659 (2011).  Then, in United States v. Caronia, 703 F.3d 149 (2d Cir. 2012), the court vacated a conviction for conspiracy to sell a misbranded drug, recognizing that to criminalize the simple promotion of a drug's off-label use by pharmaceutical manufacturers would run afoul of the First Amendment.  Off-label drug usage is not unlawful, and the FDA's drug approval process generally contemplates that approved drugs will be used in off-label ways.  So, it does not follow that prohibiting the truthful promotion of off-label drug usage would directly further the government's stated goals of preserving the efficacy of FDA's drug approval process and reducing patient exposure to unsafe and ineffective drugs. This ruling was not limited to a subset of truthful promotional speech, such as statements responding to doctors’ queries or statements by non-sales personnel.
 

In Amarin Pharma, Inc. v. FDA, No. 1:15-cv-03588 (S.D.N.Y. Aug. 7, 2015), the issues surrounded proposed statements by the company concerning its Vascepa®, an omega-3 fatty acid, approved in 2012 as an adjunct to diet to reduce triglyceride levels in adults with severe hypertriglyceridemia. The FDA had entered into an SPA (Special Protocol Assessment) with the company for an expanded use. Amarin believed it had satisfied all of FDA’s requirements to obtain approval of Vascepa® for persistently high triglycerides pursuant to the SPA.  But FDA warned that any effort by Amarin to market Vascepa® for the proposed supplemental use could constitute misbranding under FDCA.

The company sued, arguing that the threat of prosecution for misbranding has a chilling effect on commercial speech protected by the First Amendment. It sought an injunction prohibiting the FDA from bringing a misbranding action for Amarin’s truthful and non-misleading statements regarding Vascepa® directly to healthcare professionals—not in direct-to-consumer advertising.  Specifically the company wanted to affirm its right to disseminate study results; report supportive but not conclusive research shows that their product may reduce the risk of coronary heart disease; and distribute reprints of peer-reviewed scientific publications relevant to the reduction of the risk of coronary heart disease.  The company was willing to do this along with “contemporaneous disclosures” to ensure that the messages Amarin communicated to doctors concerning the use of Vascepa® in patients with persistently high triglycerides was not misleading.  The FDA did not agree, and attempted to distinguish Caronia as fact-bound, turning on the particular jury instructions given in that trial.

Judge Paul A. Engelmayer rejected FDA’s interpretation of Caronia: the FDA may not bring such an action based on truthful promotional speech alone, consistent with the First Amendment.  Misbranding is not analogous to speech crimes of jury tampering, blackmail, or insider trading. “Where the speech at issue consists of truthful and non-misleading speech promoting the off-label use of an FDA-approved drug, such speech, under Caronia, cannot be the act upon which an action for misbranding is based.”  

The court then evaluated and ruled on each of Amarin’s proposed off-label statements concerning Vascepa® along with FDA’s responses.  The “agreed-upon statements and disclosures” (e.g., statements concerning the results of the key study; statements, along with the proposed contemporaneous disclosures) were “based on current information, truthful and non-misleading.”
The “contested disclosures” such as “not-approved for” language were handled through a court-crafted, revised disclosure. The proposed cardiovascular disease claim, as revised during litigation, given its qualified phrasing and its acceptance elsewhere by the FDA, was found by the court to be presently truthful and non-misleading.

The court did mention some caveats: A manufacturer that leaves its sales force at liberty to communicate unscripted with doctors about off-label use of an approved drug invites a misbranding action if false or misleading (e.g., one-sided or incomplete) representations result. Caronia leaves the FDA free to act against such lapses. The dynamic nature of science and medicine is that knowledge is ever-advancing. A statement that is fair and balanced today may become incomplete or otherwise misleading in the future as new studies are done and new data is acquired. So, said the court, Amarin bears the responsibility, going forward, of assuring that its communications to doctors regarding off-label use of Vascepa® remain truthful and non-misleading.

Rather than appeal, the government worked towards a settlement.  Under its terms, the FDA agrees to be bound by the court's conclusion that Amarin may engage in truthful and nonmisleading speech promoting the off-label use of the drug.  The company committed t ensure that it stays current on evolving science and updates its promotional statements accordingly.  The settlement agreement also provides for a procedure by which the FDA will give advance review to as many as two promotional communications annually for off-label uses of Vascepa, along with a timetable and process for resolving any concerns that the FDA may have about those new communications.

 

A copy of the settlement here.

 

 

Stay in Amarin Extended

The court recently extended its stay of the proceedings in Amarin Pharma Inc.'s suit against the FDA challenging threatened agency action concerning the alleged promotion of drugs for off-label uses See Amarin Pharma, Inc. v. FDA, No. 15-cv-3588 (S.D.N.Y.,  order 10/30/15).  The stay to December 17th is reportedly to give the parties more time to engage in settlement discussions. This one remains a case to watch for those in the pharma practice area.

First Amendment doctrine, and its relationship to the FDCA, has changed dramatically since the FDCA and many of its implementing regulations were adopted.  And one may question whether the FDA has kept up with these changes.

Earlier this Summer, the district court granted a motion for preliminary injunction in favor of Amarin, reaching the merits of Amarin’s First Amendment claims.  The case concerned Vascepa , an omega-3 fatty acid obtained from fish oil. Vascepa was approved to reduce triglyceride levels in adult patients with severe (≥ 500 mg/dL) hypertriglyceridemia. Amarin was seeking a new indication pursuant to a Special Protocol Assessment (“SPA”) agreement with FDA, for patients with “persistently high” triglycerides (≥ 200 and ≤ 500 mg/dL).  While Amarin believed it had satisfied all of FDA’s requirements to obtain the new approval, FDA disagreed and rescinded the SPA. FDA went further to warn Amarin that any effort by Amarin to market Vascepa for the proposed supplemental use could constitute "misbranding" under the Federal Food, Drug, and Cosmetic Act.

Amarin filed a civil complaint against FDA, claiming that this threat of prosecution for misbranding had a chilling effect on its commercial speech.  Amarin proposed to engage in truthful, non-misleading speech about Vascepa directly with healthcare professionals, such as disseminating study results and reprints of peer-reviewed scientific publications. The company also proposed to make "contemporaneous disclosures” to ensure that the messages were not at all misleading.

The court noted that in contrast to FDA’s long-standing position that off-label promotion of drug products can constitute criminal misbranding, off-label use is not illegal and may even be the standard of care in some circumstances.  The company relied on the Second Circuit's First Amendment decision in Caronia, but the FDA argued Caronia was a narrow, fact-bound decision, turning on particular jury instructions given at the sales rep's  trial. At the least, it ought to be construed in harmony with FDA regulations distingusihing between directed off-label speech and requests by the practicioner for information. The court rejected FDA’s interpretation, finding the FDA may not bring such an action based on truthful promotional speech alone. “Where the speech at issue consists of truthful and non-misleading speech promoting the off-label use of an FDA-approved drug, such speech, under Caronia, cannot be the act upon which an action for misbranding is based.”

With this rule in mind, the court evaluated and ruled on each of Amarin’s proposed off-label statements concerning Vascepa along with FDA’s responses.  This included the “agreed-upon statements and disclosures,” which were found to be “based on current information, truthful and non-misleading.”  And then the additional “contested disclosures” (such as “not-approved for” use language). The court eventually crafted a revised hybrid disclosure on that.  The court also said the proposed cardiovascular disease claim, as revised during litigation, given its qualified phrasing and its acceptance in other contexts by the FDA, was presently truthful and non-misleading.

 

The court offered a few important caveats: a manufacturer that leaves its sales force at liberty to converse unscripted with doctors about off-label use of an approved drug invites a misbranding action if false or misleading (e.g., one-sided or incomplete) representations result.

And the dynamic nature of science and medicine is such that knowledge is ever-advancing. A statement that is fair and balanced today may become incomplete in the future as new studies are done or new data is acquired.

Again, one to keep an eye on.
 

 

PhRMA Responds to FDA Letter in First Amendment Dispute

The Pharmaceutical Research and Manufacturers of America last week submitted an amicus brief relating to the FDA's response to a drug company's suit challenging limits on truthful communications about off-label uses of a drug. See Amarin Pharma, Inc. v. FDA,  No. 15-cv-03588 (S.D.N.Y)(amicus brief filed 6/11/15).

Readers will recall that the case involves FDA interpretations that potentially make a drug manufacturer criminally and civilly liable for providing truthful and non-misleading scientific and medical information to well-trained health care professionals regarding unapproved uses of FDA-approved drugs or data that are not contained in the FDA approved labeling for such medicines. (Our friends over at the Drug and Device Law Blog have covered this issue extensively.)

PhRMA said in the amicus brief filed June 11th in the U.S. District Court for the Southern District of New York that FDA's recent maneuver -- a regulatory letter to the plaintiff, Amarin Pharma  --did not “cure the constitutional defects in FDA's content-based restrictions on protected speech.” In the letter, the FDA said it now all of a sudden doesn't object to many of the "off-label statements" the company might consider making about its cholesterol treatment drug.  So, the agency wouldn't necessarily consider the dissemination of some of that information to be false or misleading.

Because doctors routinely lawfully prescribe FDA-approved drugs for unapproved uses, informed patient care relies upon doctors having access to accurate, comprehensive, and current information about such uses. Biopharmaceutical manufacturers are an important source of this knowledge, said the brief. Amarin has a First Amendment right to provide such truthful and non-misleading  information. Doctors have a First Amendment right to receive it. And patients have a strong health-related interest in an affirmation of those rights. 

FDA’s recent made-for-litigation “regulatory letter” to Amarin does not cure the constitutional defects in FDA’s content-based restrictions on protected speech. The brief argued that instead FDA exacerbates and reinforces them in a footnote which reiterates in broad strokes the Agency’s 
longstanding position that the FDCA and FDA’s implementing regulations prohibit manufacturers from speaking to healthcare professionals about unapproved uses. Beyond that, the letter purports to be an exercise of enforcement discretion, relies on “draft” guidance documents that FDA itself contends do not bind the Agency, and contains significant caveats that preserve the Government’s option to pursue criminal and civil enforcement based on manufacturers’ protected speech.

For example, “under these circumstances,” FDA stated in the letter, it does not intend to object to the proposed communications “if made in the manner and to the extent described below.” FDA thus seeks to create a one-off discretionary exception, applicable to this case and nowhere else -- precisely the type of case-by-case determination regarding the legality of speech that the First Amendment forbids. Moreover, the letter relies exclusively on guidance documents that FDA itself contends are non-binding. Even if they would be deemed binding, many of the guidance documents cited in FDA’s letter remain in “draft” form.  PhRMA and others have submitted comments to FDA objecting to many aspects of these draft guidance documents, because, among other things, they continue to censor and burden protected speech based on both its content and the identity of the speaker.

The brief points out that FDA’s letter is not the first instance of a discretionary modification of ostensibly nonbinding guidance infringing on First Amendment rights. When manufacturers have
challenged FDA’s approach to speech about unapproved uses in Court, FDA has previously made ad hoc statements backing off of certain of those policies as a matter of enforcement discretion and with carefully vague caveats. FDA should not be permitted, argued the amicus, to avoid judicial scrutiny of its published regulations restricting protected speech on the basis of such non-final and potentially nonbinding “guidance” and such revocable assertions of enforcement discretion. 

Certainly one to watch.

Summary Judgment for Drug Company in Pain Pump Case

A federal court has granted defendant summary judgment in a case which alleged that cartilage damage sustained by the plaintiff, a former high school athlete, was caused by the post-surgery use of the drug company’s pain medication in an automated pump device. Jensen Meharg, et al. v. I-Flow Corp., et al., No. 1:08-cv-00184 (S.D. Ind. 3/1/10).

The former high school athlete underwent shoulder surgery, after which a pain pump was utilized. The pain pump in question was manufactured and sold by I-Flow Corporation; the local anesthetic–bupivacaine Hcl – was manufactured and sold by defendant AstraZeneca.  AstraZeneca did not in any way promote the use of bupivacaine with pain pumps, and that use was not mentioned in the instructions and warnings provided with the drug -- an off-label use. Several months later, plaintiff began to experience shoulder pain again. An MRI allegedly revealed that plaintiff had developed chondrolysis in her shoulder, which she alleged was caused by the post-surgery administration of the bupivacaine with the pain pump.

The strict liability claim was for alleged failure to warn; a warning defect claim requires that defendant had a duty to warn.  Duty is generally a legal issue.  In the context of a prescription drug manufacturer, the duty to warn does not arise until the manufacturer knows or should know of the risk.  In cases that involve an off-label use of a prescription drug that is not promoted by the manufacturer, the requisite knowledge of the risk, at a minimum, includes that the manufacturer must know (or be charged with knowledge of) both that the off-label use is occurring and that the off-label use carries with it the risk of the harm at issue – in this case, damage to cartilage.

The court found as a matter of law that the information allegedly possessed by defendant was insufficient to trigger AstraZeneca’s duty to warn of the risk of cartilage damage from continuous infusion of bupivacaine into a patient’s joint. Simply put, the plaintiff failed to point to sufficient evidence that demonstrated that at the time of plaintiff’s surgery AstraZeneca knew of that risk or that it should have known of the risk because experts in the relevant field had such knowledge.

More interesting was plaintiff's other theory. Plaintiff's expert also opined that prior to plaintiff’s surgery the defendant supposedly knew that bupivacaine was being used in pain pumps, and that this knowledge triggered an alleged duty to “investigate the nature of that use, determine whether the drug was being promoted in accordance with approved indications, conduct or sponsor those studies necessary to ensure that the promoted use was safe, and to warn physicians that long-term risks to the joint had not been scientifically established but that the risks should be weighed seriously, given that the anticipated use was for elective post-operative pain therapy for which multiple alternatives existed.”  The court noted that such a  “duty” does not exist under relevant (Indiana) law.  The duty to warn does not arise until the manufacturer knows or should know of the risk.  The alleged far broader duty  – a  duty, in essence, to warn physicians that there might be a risk, although we don’t know yet because neither we or the scientific community at large has studied it yet -- doesn't exist.

Such a duty would cause physicians to be inundated with such pseudo-warnings and quasi-risk information distracting them from heeding real warnings of actual risk; and it would add very little to the fact that physicians already know, i.e., that if a use is omitted from a prescription drug’s label, that use has not been tested sufficiently to demonstrate to the FDA that it is safe and effective.

State Supreme Court To Address Government Use Of Contingency Fee Private Counsel

Next month the Supreme Court of Pennsylvania will hear argument in a pharmaceutical case that has implication for all readers of MassTortDefense, regardless of what industry they may represent. See Commonwealth of Pennsylvania, C/O Office of General Counsel v. Janssen Pharmaceutica, Inc., No. 24 Eap 2009 (S.Ct. Pa.).  This case presents not only significant constitutional and statutory issues, but also impacts policies affecting the public interest in open government, health care policy, and the regulation of the practice of law in the context of governmental litigation.

In the underlying case, the Commonwealth seeks damages for asserted financial harm allegedly caused by Janssen’s supposed deceptive marketing practices in promoting its anti-psychotic drug, Risperdal, for off-label uses. This action was originally filed in the Court of Common Pleas of Philadelphia County in February 2007. In June 2008, Janssen filed a Motion to Disqualify Plaintiff’s Counsel, the private Texas-based plaintiff personal injury firm of Bailey Perrin & Bailey, which had been hired by the state on a contingency fee basis.   Public records indicate that during the precise time period that the fee contract was negotiated and executed, one of Bailey Perrin’s founding partners made repeated and significant contributions, totaling more than $100,000, to Pennsylvania Governor Rendell’s re-election campaign and to the Democratic Governors Association, according to defendant.

The Commonwealth opposed the Motion; the trial court denied the Motion on December 8, 2008. Janssen thereafter sought extraordinary appellate relief in the state Supreme Court, which was granted.

The Commonwealth’s retention of contingent fee private counsel in this matter raises significant issues including whether and when state law authorizes the Office of General Counsel to enter into a contingent fee contract with outside counsel; whether the Commonwealth’s hiring of outside litigation counsel on a contingent fee basis violates the state constitution, including the separation-of-powers mandate of the Pennsylvania Constitution; and whether the Commonwealth’s hiring of outside litigation counsel on a contingent fee basis violates the due process rights of the defendant company.

In many contexts, the legal policy of the Commonwealth -- like many states -- strongly favors open, competitive bidding for contracts involving state funds. Such requirements, included in the state Constitution and various statutes, are designed to prevent fraud, eliminate bias and favoritism, and thus protect vital public interests.

Those same goals of open and good government reside in the requirement that state officials give their undivided loyalty to the people of the Commonwealth. The antithesis of these goals and policies is “pay-to-play,” the award of government contracts to major campaign contributors. This case threatens to expand the scope of pay-to-play in unprecedented fashion. The very sovereignty of the Commonwealth itself – its legal enforcement authority and parens patriae powers – should not be subject to sale. Public records reveal hundreds of thousands of dollars of contributions to the benefit of the state governor in close proximity to the issuance of a no-bid, contingency fee contract to one of the contributors, according to defendant.  The media has widely and correctly assailed the appearance of impropriety thus created.


Aside from its questionable origins, the contingent fee contract violates the core principle that attorneys pursuing actions on behalf of the Commonwealth represent a sovereign whose obligation to govern impartially is essential to its right to govern. Government attorneys must exercise independent judgment as a ministers of justice and not act simply as advocates. The impartiality required of government lawyers cannot be met here, where the private pecuniary interest inherent in the contingent fee is the primary motive force behind the bringing of this very action. By turning over sovereign prosecutorial power to contingency counsel, the Governor effectively created a new branch of government – motivated by the prospect of private gain rather than the pursuit of justice or the public welfare.

This subversion of neutrality does more than implicate the due process rights of those confronting such tainted prosecutions. Direction of state prosecutions by financially interested surrogates also damages the very public interest that such litigation is supposed to advance. Here, it is already clear that Pennsylvania’s in-force health care policies concerning the use of atypical anti-psychotic medications dramatically conflict with the reckless allegations of contingent fee counsel’s complaint. Those (typical plaintiff) allegations broadly equate all “off-label” use of prescription drugs with “medically unnecessary” use, and blindly assert that all such “medically unnecessary” use is “illegal.” The law, however, recognizes off-label use as generally accepted by the medical community and the FDA, and as perfectly legal, and does not consider prescription drugs unsuitable for use merely due to lack of FDA approval. The allegations of the complaint – crafted more for the pecuniary goals of counsel than for the needs of the patients served by the affected state programs – risk the public health by threatening to deprive some of our neediest citizens of a medicine that the Commonwealth’s own unbiased administrators consider “preferred” for the same off-label indications that the complaint brands “illegal.”

It will be interesting to see how the Supreme Court approaches these significant issues int he coming weeks.

[Your faithful blogger was able to contribute to the amicus brief of the Washington Legal Foundation , the public interest law and policy center, in this matter.]

FDA Issues Guidance On Distribution Of Medical And Scientific Articles Regarding Off-Label Usage

The FDA has finalized guidelines for how manufacturers can distribute information to doctors about unapproved uses for drugs or medical devices. The ‘‘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’’
allows for the limited dissemination of medical journal articles describing off-label uses. The FDA proposed the guidelines in February, 2008 and took public comments before finalizing them.
 

Allegations of off-label promotion are common in mass tort litigation involving drugs and medical devices. Off-label promotion is illegal, but many critics of the industry and plaintiff lawyers seem to forget that doctors can prescribe drugs for any use they see as medically appropriate. The FDA in its guidelines confirms that the public health can be served when health-care professionals receive truthful and non-misleading scientific and medical information on unapproved uses. It will likely help practitioners to receive timely and accurate medical information in an environment where off-label use is common. The FDA's guidance will help assure that medical professionals receive timely and accurate medical information prior to the lengthy process of securing FDA approval for wider use. Such off-label use can save lives, especially in practice areas where there are few effective treatments. These off-label uses or treatment regimens thus may be quite important and may even constitute the medically recognized standard of care. Accordingly, the public health may be advanced by healthcare professionals' receipt of medical journal articles and medical or scientific reference publications on unapproved new uses of approved or cleared medical products that are truthful and not misleading.

This guidance is being issued consistent with FDA’s good guidance practices regulation (21 CFR 10.115), and suggest that the distribution be in the form of an unabridged reprint, copy of an article, or reference publication;  not be marked, highlighted, summarized, or characterized by the manufacturer in any way (except to provide the accompanying disclosures discussed in the guidance), and be accompanied by the approved labeling for the drug or medical device.

The guidance represents the agency’s current thinking on the dissemination of medical journal articles and medical or scientific reference publications on unapproved uses of approved drugs and approved or cleared medical devices to healthcare professionals and healthcare entities.