OFF LABEL MARKETING AND FREE SPEECH IN THE POST - PowerPoint Presentation

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OFF LABEL MARKETING AND FREE SPEECH IN THE POST CARONIA AND AMARIN WORLD

Habib Nasrullah, Esq.,

Partner

Wheeler Trigg O’Donnell, LLP

Stephen C. Matthews, Esq.,

Principal

Porzio, Bromberg & Newman, P.C.Slide2

TOPICS FOR TODAY

Background

of Off-Label Use and ProhibitionFirst Amendment Challenges to FDA Authority to Prohibit Off-Label PromotionNext Steps for Industry and FDA in Responding to the New Legal Landscape

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Background

FD&C Act

prohibits misleading labeling or labeling that fails to include adequate directions for useFDA has interpreted this prohibition against misleading labeling to allow FDA to prohibit drug and device manufacturers from engaging in “off-label promotion”-“Off Label promotion” simply means promotion of an indication that has not been specifically approved by FDAImportantly, there is no legal prohibition against actual off-label use. Indeed, the prescription and use of approved drugs and medical devices for purposes not set forth in their FDA-authorized labeling is legal3Slide4

Regulatory Authority

Drug Regulations

: A drug shall be deemed to be misbranded if its labeling is false or misleading in any particular. 21 U.S.C. § 352 (a)A drug shall be deemed to be misbranded unless its labeling contains adequate instructions for use. 21 USC § 352(f)(1)Device Regulations: A device must be adequately labeled with directions for use. 21 C.F.R. 801.5 If a manufacturer has notice that a device is used for conditions, purposes, uses or dosages other than those for which it is offered, the manufacturer is required to provide adequate labeling for the device in accordance with such other uses. 21 C.F.R. 801.4 A device may not be manufactured, packaged, stored, labeled, distributed or advertised in a manner that is inconsistent with any conditions to approval specified in the PMA approval order for the device. 21 C.F.R. 814.80

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FDA VIEWOff-Label Promotion Prohibited?

[T]he FD&C Act and FDA’s implementing regulations generally prohibit manufacturers of new drugs or medical devices from distributing products in interstate commerce for any intended use that FDA has not approved as safe and effective or cleared through a substantial equivalence determination. The Agency recognizes the value of having new indications and intended uses for products approved or cleared by FDA and encourages sponsors of medical products to seek such approvals or clearances. An approved new drug that is marketed for an unapproved use is an unapproved new drug with respect to that use. An approved drug that is marketed for an unapproved use (whether in labeling or not) is misbranded because the labeling of such drug does not include "adequate directions for use" Similarly, a medical device that is promoted for a use that has not been approved or cleared by FDA is adulterated and misbranded.

FDA Guidance, “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.” 74 Fed. Reg. 1694 (FDA Jan. 13, 2009).5Slide6

FDA VIEWTruthful Off-Label Promotion Allowed?:

FDA

does recognize, however, the important public health and policy justification supporting dissemination of truthful and non-misleading 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. Once a drug or medical device has been approved or cleared by FDA, generally, healthcare professionals may lawfully use or prescribe that product for uses or treatment regimens that are not included in the product's approved labeling (or, in the case of a medical device cleared under the 510(k) process, in the product's statement of intended uses). These off-label uses or treatment regimens may be important and may even constitute a 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 misleading6Slide7

First Amendment Challenge

2012

United States v. Caronia

, 703 F.3d 149 (2

nd

Cir. 2012)

Second Circuit overturned conviction of pharma salesman who was caught talking to physicians about unapproved uses for the narcolepsy drug Xyrem

Second Circuit

analyzed the promotional activity as commercial speech under

Central Hudson

Because physicians may prescribe and patients may use the drugs off-label, government’s prohibition of off-label

promotion

does not directly advance government interest in preventing off-label use

Held: “the government cannot criminally prosecute pharmaceutical manufacturers and their representatives under FDCA for

truthful, non-misleading speech

promoting the off-label uses of an FDA-approved drug”

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Caronia Extended in Civil Action

2015

Amarin Pharma, Inc. v. FDA

, 119 F.Supp.3d (2015)

Applying

Caronia in a civil case, SDNY grants preliminary injunction against FDA

Vascepa

approved to treat severe hypertricglyceridemia

Amarin sought, but FDA denied, approval to treat persistently high triglycerides

Amarin

pre-emptively sued FDA in SDNY, seeking to disseminate truthful promotion directly to HCPs relating to Vascepa use in patients with persistently high triglyerides,

along with contemporaneous disclosures to ensure it was not misleading

Held:

Caronia

forbids FDA from bringing a misbranding claim based on truthful and non-misleading

speech alone

March 8, 2016, FDA and Amarin settle, with FDA recognizing “that Amarin may engage in truthful

and non-misleading speech promoting off-label use” of its product and that “such speech may not form the basis of a prosecution for misbranding.”

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Pacira Pharmaceuticals, Inc. v. FDA

Pacira’s Exparel drug approved

as a “local anesthetic, indicated for administration into the surgical site to produce postsurgical analgesia.” Submitted clinical trial support was for removal of bunions and removal of hemorrhoids. FDA issued a warning letter against Pacira for promotional materials suggesting drug could be used in procedures other than bunion and hemorrhoid removal surgeryMonth after Amarin, Pacira brought a declaratory relief action in SDNY claiming FDA violated First Amendment rights by restricting truthful and non-misleading speechParties settled, with Pacira being able to promote beyond the listed clinical trialsFDA attempted to limit impact, stating “this resolution is specific to the parties involved in this matter

”

2011

2014

2015

2015

2015

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Caronia Holding Extended to Device Cases

2016

United States v. Vascular Solutions, Inc.

, CR No. 14-926 (W.D. Tex.)

Jury in District Court for the Western District of Texas found device manufacturer and its CEO not guilty on charges of illegal off-label marketing

VSI’s Vari-Lase product approved for the ablation of superficial veins

VSI also promoted Vari-Lase to treat perferator veins deeper in the leg

CEO, Howard Root, and company each charged with one count of conspiracy and eight counts of introducing adulterated and misbranded medical devices into interstate commerce

Court instructed jurors to find VSI and Root not guilty “if you find that VSI’s promotion speech to doctors was solely truthful and not misleading”

Jury acquitted on second day of deliberations

VSI issues scathing press release, calling for a review of “every current investigation of a medical device company concerning ‘off-label’ promotion”

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Press Release

The company and I are vindicated by today’s verdict, but outraged by the obscene legal process we were forced to endure.”“We are appalled by the malicious behavior and lack of substantive oversight of the government officials who pursued this matter – in particular Assistant U.S. Attorneys Bud Paulissen and Christina Playton of the Western District of Texas, Consumer Protection Branch Trial Attorneys Timothy Finley and Charles Biro, and FDA Special Agent George Scavdis. There simply is no excuse for abusive and dishonest conduct in any U.S. governmental agency, much less in the Department of Justice and our law enforcement agencies.” “if the U.S. Attorney in San Antonio still wants to prosecute someone for obstruction of justice in this case, in my opinion he wouldn’t even have to leave his own office to find the most suitable person to indict.”11Slide12

United States v. Facteau

United States v.

Facteau, No. 1:15-cr-10076-ABD (D. Mass, filed Apr. 8, 2015); federal court in Boston, two former device company executives are charged with various offenses related to alleged off-label promotion.12Slide13

United States v. FacteauLikely going to First Circuit – different outcome than Caronia

Could create a Circuit split – may end up in SCOTUS

Device case – Acclarent was manufacturer of 501(k) sinus spacer US alleged 14 felony fraud/conspiracy based on Acclarent’s promotion of device for steroid delivery (unapproved use) Prosecutors claimed that the steroid delivery was primary use – making premarketing notifications to FDA Government claimed that the sales force had only been trained on the off-label use Defense claimed that company never tried to hide use from FDA and had tried to get sinus use approved 13Slide14

United States v. FacteauAcquittal on all felony counts – but convictions on misbranding counts (misdemeanors)

Jury instructions were central in the convictions – instruction was that although promotional statements protected as free speech, they could be used as evidence of the elements of illicit marketing of “misbranded and adulterated’ device

“Truthful, non-misleading speech cannot be a criminal act in and of itself, but it can be evidence and therefore be used by you to determine whether the government has proved each element of each offense beyond a reasonable doubt, including the element of intent” 14Slide15

United States v. FacteauDOJ claims that off label speech is evidence of intent to distribute for an unauthorized use with premarket notification Contrary to Caronia – government cannot prosecute truthful, non-misleading off label promotion without violating the First Amendment

“Evidence of intent” is theory of appeal – coupled with Park Doctrine

Acquitted of fraud counts – manufacturers should be aware that even truthful off label promotion can be spun by DOJ as “evidence” of intent in misbranding prosecutions. 15Slide16

A Cautionary Note from the Court in Amarin

“A final observation: Although the FDA cannot require a manufacturer to choreograph its truthful promotional speech to conform to the agency’s specifications, there is practical wisdom to much of the FDA’s guidance, including that a manufacturer vet and script in advance its statements about a drug’s off-label use. 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 … A manufacturer may also conclude that it is prudent to consult with the FDA before promoting off-label use. Reasonable minds may differ over whether a given statement is misleading in context; and developments in science or medicine may make a once-benign statement misleading. Prior consultation with the FDA may prove a helpful prophylactic, and may avert misbranding charges where the FDA and the manufacturer would take different views of a statement.” - Amarin Opinion16Slide17

Next

Steps for Industry and FDA in Responding to

the New Legal LandscapeOn July 27, 2016 PhRMA and BIO release PRINCIPLES ON RESPONSIBLE SHARING OF TRUTHFUL AND NON-MISLEADING INFORMATION ABOUT MEDICINES WITH HEALTH CARE PROFESSIONALS AND PAYERSOn September 1, 2016 FDA announces a 2-day public hearing to obtain input on issues related to communications regarding FDA-regulated drugs and medical devices17Slide18

Key Concepts in the PhRma/Bio Responsible SharingCommitment to Science-based CommunicationsCommitment to Provide Appropriate Context about Data

Commitment to Accurate Representation of Data

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Issues to be addressed at FDA Public Hearing

FDA is “engaged in a comprehensive review of its regulations and policies governing firms communications about unapproved uses of approved/cleared medical products and the input from the meeting will inform FDA’s policy development in this area.

Specifically FDA is looking for information on eight brought categories/questionsHearings are scheduled for November 8-9, 201619