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William A. McConagha, JD
Sidley Austin LLP

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• William A. McConagha “declare(s) no conflicts of interest, real or apparent, and no financial interests in any company, product, or service mentioned in this program, including grants, employment, gifts, stock holdings and honoraria.”
– The American College of Apothecaries is accredited by the Accreditation Council for
Pharmacy Education as a provider of continuing pharmacy education.

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At the conclusion of this educational session, the pharmacist and technician attendee will be able to:
• Discuss legal and policy issues associated with the promotion of prescription drugs.
• Explain how legal issues are evolving and impacting your pharmacy.
• Discuss how social media has impacted the promotion of prescription drugs.

• Promotional Labeling vs. Advertising
– Promotional Labeling: “Brochures, booklets, mailing pieces, detailing pieces, file cards, bulletins, calendars, price lists, catalogs, house organs, letters, motion picture films, film strips, lantern slides, sound recordings, exhibits, literature, and reprints and similar pieces of printed, audio, or visual matter descriptive of a drug . . . are hereby determined to be labeling . . . .
21 C.F.R. § 202.1(l)(2).
– Advertising: “Advertisements . . . include advertisements in published journals, magazines, other periodicals, and newspapers, and advertisements broadcast through media such as radio, television, and telephone communication systems.” 21 C.F.R. § 202.1(l)(1).

• Types of Promotion
– Product claim pieces
– Reminder pieces
– Disease awareness communications
• Within any of these categories, a piece can be either consumer- or professional-directed (e.g., a consumer-directed disease awareness communication is a “help-seeking” communication, or a pamphlet shared with a medical practitioner)

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• Authorities:
– § 502(a): Labeling must not be false or misleading in any particular
– § 502(f)(1): Labeling must include adequate directions for use
– § 502(n): Advertising must contain a “true statement” in “brief summary” relating to side effects, contraindications and effectiveness
• Advertising must not be false or misleading
• Advertising must be based on substantial evidence or substantial clinical experience
• Advertising must achieve “fair balance”
– Disclosure can be concise if accompanied by reference to complete risk information
– § 505(a): Labeling claims can trigger NDA requirement
– § 201(n): In considering whether advertising/labeling is false or misleading, material omissions matter

• Advertisements must include a “true statement” in “brief summary.”
– Interpreted in FDA regulations (21 CFR Part 202)
• advertisements are false, lacking in fair balance or misleading
– e.g., contains a drug comparison that represents or suggests that a drug is safer or more effective than another drug in some particular when it has not been demonstrated to be safer or more effective in such particular by substantial evidence or substantial clinical experience
• advertisement may be false, lacking in fair balance or misleading
– e.g., contains favorable information or conclusions from a study that is inadequate in design, scope, or conduct to furnish significant support for such information or conclusions

– Promotion of an off-label use is illegal.
– Exemplary regulations:
• Prescription drug advertising “shall not recommend or suggest any use that is not in the labeling.” 21 C.F.R. §
202.1(e)(4)(ii).
• An investigational drug may not be promoted for the uses for which it is under investigation. 21 C.F.R. § 312.7.

– “Scientific exchange” (21 C.F.R. § 312.7)
• Example: dissemination of scientific findings in scientific or lay media (properly executed press release announcing
Phase III data)
– “Position on the Concept of Solicited and Unsolicited
Requests” (Apr. 1982)
– Reprints
– CME

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• FDA Draft Guidance on “Good Reprint Practices” (Feb.
2008)
– September 2006 expiration of the FDAMA off-label reprints provision ( § 401) and corresponding FDA regulations (21
C.F.R. Part 99)
– Describes FDA’s current thinking regarding the distribution of medical journal articles and scientific or medical reference publications that discuss off-label uses of approved drugs; sets forth recommendations regarding:
• the types of reprints, articles, and publications to be disseminated
– peer-reviewed; not in the form of a special supplement; address adequate and well-controlled studies, etc.
• the manner of dissemination
– unabridged; not highlighted; accompanied by PI and comprehensive bibliography, etc.

• Enforcement actions targeted educational activities that were also promotional in nature:
– “Educational activities that are balanced, that are not promotional in tone, content, or emphasis, and that are not false or misleading generally do not prompt a regulatory response, even if they include discussion of unapproved drugs or drug uses. The agency has, however, taken regulatory steps when it has found such activities to be misleading, unbalanced, or otherwise promotional with regard to the sponsor’s products.” David Kessler, Drug Promotion and
Scientific Exchange, 325 NEJM 201, 201 (1991
).
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• FDA emphasized that a program is considered promotional based in part on “the content of the information being conveyed—not necessarily on how it is delivered or by whom.” Carl Peck & Peter
Rheinstein, FDA Regulation of Prescription Drug Advertising, 264
JAMA 2424, 2424 (1990).
• In particular, FDA emphasized the degree to which an educational program is “independent” of a drug company’s influence, but using a third party to run a program “does not automatically ensure its safety from FDA scrutiny. What is more important is who controls the agenda, who selects the speakers and the audience, and what is said.” Kessler & Pines, supra, at 2411.
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• FDA proposed and ultimately finalized an “Industry-
Supported Scientific and Educational Activities” (ISSEA)
Guidance in several steps:
– Draft Concept Paper (Oct. 26, 1991)
– Draft Policy Statement, 57 Fed. Reg. 56412 (Nov. 27, 1992)
– Request for Comments, 59 Fed. Reg. 59820 (Nov. 18, 1994)
– Final Guidance on ISSEA, 62 Fed. Reg. 64074 (Dec. 3, 1997)
• The key touchstone is independence
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When Education Is Also Promotion:
FDA’s Factors for Evaluating Program Independence
Development of
Program
Identity of
Speaker and
Relationship with
Company
Context of
Program
Control of content
Existence of a written agreement regarding the speaker’s independence
Legal, business, or other relationships between the speaker and the company
Speaker involvement in company sales or marketing activities
Complaints or other history regarding the speaker’s lack of independence or the company’s attempts to influence programming
Audience selection
Opportunities for meaningful discussion
Proximity of ancillary promotional activities
Repetition of the program on multiple occasions
Dissemination of information from the program after its initial presentation
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• PhRMA Code on Interactions with Healthcare
Professionals
– Addresses interactions relating to pre-launch activities and product marketing (separate code for interactions relating to clinical research process and separate
“guiding principles” for DTC)
– Intended to be responsive to:
• Ethical standards
• Legal requirements
• Perceptions of patients and the public at large

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• Basic concepts
– Healthcare should be based, and should be perceived as being based, on a patient’s medical needs and a healthcare professional’s medical knowledge and experience
– Accordingly, nothing should be provided in a manner that would interfere with the independence of a healthcare professional’s prescribing practices

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• Interactions should:
– Inform healthcare professionals about products
– Provide scientific and educational information
– Support medical education and research
• Promotional materials should:
– Be accurate and not misleading
– Make only substantiated claims
– Reflect risk/benefit balance
– Be consistent with all applicable FDA requirements

• OPDP/APLB Operations
– Communication modes
• Advisory correspondence
• “Enforcement” correspondence
• Guidance
• Podium
– Regulations
– Federal Register Notices

• OPDP Review of Promotional Materials
– Sponsors must submit promotional labeling and advertising pieces at the time of initial dissemination of the labeling and initial publication of the advertisement.
21 C.F.R. § 314.81(b)(3)(i).
• Usually voluntary submission; pre-submission required for certain drugs
(e.g., subpart H “accelerated approval”)
– Routine surveillance of 2253 submissions
• Review the approved product labeling
• Assess the promotional piece for consistency with the labeling
– Provide advisory comments on draft promotional materials
• Product launches
• Professional promotional materials
• Direct-to-consumer
– Whistleblowers
– Attendance at Conferences
– Consumer or Competitor Complaints

• Longstanding: Judicial Remedies
– Seizure
– Injunction
– Criminal penalties (fines/imprisonment)
– Responsible Corporate Officer (Park; Dotterweich)
• New: Civil Monetary Penalties (CMPs)
– Government may collect CMPs through administrative proceedings.
– The Food and Drug Administration Amendments Act of 2007 (FDAAA) gave FDA CMP authority for false/misleading DTC ads.
• NDA/BLA products only
• Both print and broadcast
• Up to $250,000 for the first violation in a three-year period; $500,000 for each subsequent violation in any three-year period

• FDA is a concern, but it is no longer the only concern
– Department of Justice/U.S. Attorneys Offices
– Office of the Inspector General
– State Attorneys General
– Federal Trade Commission
• Laws of concern:
– Federal Food, Drug, and Cosmetic Act (FDCA)
– Federal False Claims Act
– Anti-Kickback Law
– State Laws and Enforcement Actions
– Federal Trade Commission Act
– Other Liability Issues

• Representative Pharmaceutical Industry Cases
– TAP $885 million
– Serono $704 million
– Purdue Pharma $600 million
• Purdue executives $34 million
– Abbott $600 million
– Bristol-Myers Squibb $515 million
– Bristol-Myers Squibb $499 million
– Cephalon $444 million
– Schering-Plough $435 million
– Pfizer $430 million
– AstraZeneca $355 million

• Pfizer/Warner-Lambert (2004):
– Government asserted that the company sponsored purportedly
“independent” medical education events regarding off-label
NEURONTIN uses, but had extensive input regarding topics, speakers, content, and participants.
– Government also asserted that the company “misled the medical community beforehand about the content, as well as the lack of independence from the company’s influence, of many of these educational events. In at least one instance, when unfavorable remarks were proposed by a speaker, Warner-Lambert offset the negative impact by ‘planting’ people in the audience to ask questions highlighting the benefits of the drug.” See DOJ Press Release, http://www.usdoj.gov/opa/pr/2004/May/04_civ_322.htm
.
– $430 million settlement
– Corporate Integrity Agreement (CIA)
( http://oig.hhs.gov/fraud/cia/agreements/pfizer_5_11_2004.pdf
)
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• Harkonen: Convicted of wire fraud in 2009 for issuing a press release describing clinical trial results about Actimmune
– Government alleged the press release overstated the results
– Sentenced to 3 years probation, 6 months home detention, community service, and a $20,000 fine
– Ninth Circuit affirmed conviction
• Coronia: Convicted of conspiracy to introduce a misbranded drug into interstate commerce in 2008 for promoting unapproved uses of Xyrem
– Sentenced to one year probation, 100 hours of community service, $25 special assessment

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• US v. Coronia, 1703 F.3d 149 (2d Cir. 2012) –
– Conviction vacated by second circuit on First Amendment grounds
• FDCA’s misbranding provisions do not prohibit the truthful off-label promotion of FDA-approved prescription drugs
• Thompson v. Western States Medical Center,
535 U.S. 357 (2002)
– Illustrates the scrutiny applied to government efforts to curtail speech for legal products
– Supreme Court agreed with 9 th Circuit Court of Appeals: The solicitation and advertising provisions in 503A violate the First Amendment

• FDA has not articulated a “formal” policy
• FDA’s Principal Position: Internet communications are subject to the same statutory and regulatory provisions as traditional advertising and promotional labeling formats
– 2009 draft guidance regarding the presentation of risk information in promotion provides principles that apply
“regardless of the medium used”
– Evaluated on a “case-by-case” basis
– Sponsors generally apply the rules governing promotional labeling, although some regard paid placements in new media contexts as “advertising” under the FDCA and FDA regulations

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• Meta-tags, sponsored links, and search engine optimization
– Spring of 2009, DDMAC sent Untitled Letters to 14 drug companies objecting to sponsored links appearing in response to search queries
– Allegedly violative because mentioned a drug and contained efficacy claims, but did not include risk information
– Links to the drug’s PI were not sufficient to balance efficacy claims – Death of “one-click rule”
• New media and user generated content
– Sponsor could be held responsible for:
• Inadequate risk information or lack of fair balance
• Off-label discussion
• Adverse event information
• Criticism of competitor’s product

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• Untitled Letter to Warner Chilcott re Atelvia (May
2011)
– Video created by and featured a sales representative for Atelvia, and was posted by the sales representative on YouTube under the direction of a Warner Chilcott District Manager
– Cited for failure to include risk information, failure to include material dosing information and failure to submit the video under cover of
Form FDA-2253
• Untitled Letter to Novartis re Tasigna (July 2010)
– Facebook share social media widget that generates Novartiscreated information on Tasigna that can be shared with Facebook users
– Cited for failure to communicate any risk information, inadequately communicating the drug’s FDA-approved indication, implying superiority over other products, and failure to submit the content under cover of Form FDA-2253

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• FDASIA Section 1121 mandates that FDA issue guidance on internet and social media promotion by
July 9, 2014
• FDA unlikely to issue a internet- or social mediaspecific guidance
– Instead, FDA will most likely address the internet and social media in the context of other regulatory issues
– E.g., FDA’s Draft Guidance on Unsolicited Requests (Dec. 2011)
• “is the first of multiple draft guidances the Agency plans to publish that address questions and issues related to emerging electronic media”

1. All compounded drug products are illegal under federal law and FDA regulates through the exercise of enforcement discretion (CPG 460.200)
2. Federal Statue Authorizes Compounding
– 503A
– New legislation in Congress (e.g., S. 959)

• Under CPG 460.200, FDA regulates by exercise of enforcement discretion
• FDA has discretion to limit promotion as it deems appropriate
• First Amendment rights limited because products are technically illegal

• FDA silent to date on this issue
• But expect FDA to frown upon promotional claims made for compounded drugs, especially as they relate to safety or efficacy
• Multiple Reasons for FDA to take strict view:
– Absence of substantial evidence in support of safety or effectiveness claims
– Undermines incentives to adhere to new drug approval pathway
– Traditional “triad” relationship is grounded in idea that pharmacists compound drugs at the request of a physician, not generate the physician’s interest in the use of a new drug

• Under 503A and S. 959 compounded drugs are legal under federal law in certain instances
• Speech about legal products enjoys a level of First
Amendment protection that does not apply to speech about illegal products.
• Commercial speech doctrine applies
– Central Hudson Test
• Western States:
– The solicitation and advertising prohibitions in 503A violate the
First Amendment

• So what more, if anything, can be said in the promotion of compounded drugs.
• Very Complicated Issue:
– 503A and S. 959 exempt certain compounded drugs from:
• 505(a) and 502(f)(1)
– These two provisions are legal cornerstones of FDA’s promotion policy.
– Is the scope of the exemption limited?
– Did Congress really intend compounded drugs to be exempt from these provisions regardless of how they were promoted?

• Regardless, 502(a) and 502(n) still apply
• In fact, S. 959 explicitly clarifies application of 502(a)
• The government retains clear authority to challenge false or misleading labeling
• And to challenge false or misleading advertising
• Oral statements present a greater difficulty for FDA
– 502(f) is the charge most commonly associated with creating a new, non-sanctioned intended use through oral representations
(see 21 CFR 201.128)
– Will/can the government assert that oral statements are advertising?
– Can the establishment of a new intended use render a drug’s label false or misleading under 502(a)? (consider application of 201(n)).
– Does lack of substantial evidence give rise to a 502(a) charge?

• If new federal legislation clarifies the legal status of the compounded products under federal law, it should also address promotional issues to the extent possible
• Are the exemptions from 505(a) and 502(f)(1) limited in scope?
• Will Congress venture into speech issues after Western
States?
• Is it ever appropriate to promote a drug in the absence of substantiating clinical evidence?
• Will failure to clarify in the legislation lead to abuses?
• Where should the line be drawn?