1. The Limits of FDA-Approved Labeling and the Evolving Informational Needs of a Changing Healthcare System
Coleen Klasmeier
June 16, 2017

2. Summary
Manufacturer communications regarding new uses, or other departures from FDA-approved labeling, are a constituent part of medical and surgical practice.
FDA policy is explicitly one of “delicate balance” between facilitating rational deviations from approved labeling and robustly enforcing the FDCA.
Far from limiting manufacturer communications to those directly taken from approved labeling, FDA has devised a complex system of regulatory rules and safe harbors that give manufacturers broad latitude to provide information, including promotional information.
The current debate over “off-label promotion” focuses on the need for clear a priori rules within the existing framework and does not necessarily present an existential threat to the long-standing regulatory scheme.
The research-based medical products industry supports the continued central role of FDA in adjudicating claims of drug and device effect in advance, based on the existing “gold standard” of scientific evidence.
Regulatory reform opponents who set constitutional limitations in opposition to public health protection ignore both the public health need served by scientific exchange and the federal government’s own established policy of encouraging a certain amount of appropriate “out-of-labeling” communication by manufacturers.
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3. The False Dichotomy
“Judges should refrain from using the First Amendment to undermine core regulatory functions.”
Sharfstein JM, Charo A. The Promotion of Medical Products in the 21st CenturyOff-label Marketing and First Amendment Concerns. JAMA. 2015;314(17): .
“[T]he moment you start to drift off into an ideological First Amendment kind of discussion, in theory, you lose your moorings from what’s important for public health.”
Sharfstein J. Nov. 10, 2016, Part 15 Hearing,
Manufacturer Communications Regarding Unapproved Uses of Approved or Cleared Medical Products
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4. Policy Considerations Favor A Modulated Regulatory Approach
A nuanced approach to manufacturer communication issues is demanded by:
The limits of FDA-approved labeling; and
The rapidly evolving informational needs of the health care delivery system.
“The Commissioner clearly recognizes that the labeling of a marketed drug does not always contain all the most current information available to physicians relating to the proper use of the drug in good medical practice. Advances in medical knowledge and practice inevitably precede labeling revision by the manufacturer and formal labeling approval by the Food and Drug Administration.”
40 Fed. Reg (April 7, 1975).
“[R]egulatory barriers that inhibit progress toward paying for drugs based on value need to be removed Looking ahead, we need to ensure that health plans and manufacturers have the flexibility to experiment with new value-based arrangements, ensure consumer safety, and have robust evaluations to assess the real-world benefits to patients and consumers.”
AHIP CEO Marilyn Tavenner, quoted in the Wall Street Journal, April 10, 2016
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5. “Delicate Balance”
FDA policy is to seek a “delicate balance” between allowing manufacturer communication of reliable scientific information regarding off-label uses and limiting off-label “promotion.”
FDA policies should “strike the proper balance between the need for an exchange of reliable scientific data and information within the health care community, and the statutory requirements that prohibit companies from promoting products for unapproved uses.”
The public health rationale supporting this relatively permissive approach has been clearly and repeatedly articulated by FDA:
Because off-label use is important to patient care and to scientific discovery, clinicians must have access to information beyond FDA-approved labeling, and that information can and should be provided by manufacturers, subject to reasonable limitations.
Sources: 61 Fed. Reg. 52,800, 52,800 (Oct. 8, 1996); 59 Fed. Reg. 59,820, 59,823 (Nov. 18, 1994); 57 Fed. Reg. 56,412, 56,412 (1992).
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6. How is FDA’s current approach “relatively permissive”?
Although built on the “substantial evidence” gold standard, it applies that standard flexibly and selectively
The statutory definition (21 U.S.C. § 355(d)) refers to whether “experts qualified by scientific training and experience” could fairly and responsibly conclude that the drug will have the effect it purports to have under the labeled conditions of use
Substantial evidence, as a matter of law, is premised on the interpretations of experts
Any characteristic of an adequate and well-controlled clinical investigation, as defined in 21 C.F.R. § , may be waived by CDER
The sponsor’s petition must explain why the criteria are not reasonably applicable to the particular clinical investigation, must identify the alternative procedures, and must state “why the clinical investigations so conducted will yield, or have yielded, substantial evidence . . .”
“Substantial evidence” is not just data from adequate and well-controlled clinical trials
FDA has interpreted the law broadly where “data on a particular drug were convincing”
“[T]here has been substantial progress in the science of drug development resulting in higher quality clinical trial data.”
FDA, Guidance for Industry
Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products (May 1998)
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7. How is FDA’s current approach “relatively permissive”?
Under FDA’s interpretation, many information sources that routinely inform health care decision making are treated as inherently suspect:
It might make sense to have the same substantiation standard for both initial and “successive” efficacy claims, but:
The level of substantiation required should not be unduly demanding
The types of claims for which a lower standard is appropriate should be clearly identified
FDA’s own practices and policies in this area are complex:
Many drugs remain on the market without “substantial evidence”
Non-drug products are subject to lower evidentiary standards for clinical claims
Many alternative approaches are used to meet the “substantial evidence” standard, apart from data from two adequate and well-controlled clinical trials (e.g., FDAMA § 115, animal efficacy rule)
Other regulatory bodies accept efficacy claims based on different standards
- Open-label studies
- Post hoc subgroup analyses
- Meta-analyses
- Comparative studies
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8. How is FDA’s current approach “relatively permissive”?
To what does “substantial evidence” apply, in FDA’s view?
“Claims of treatment benefit” with respect to drugs that have been through the post NDA process
The effect of treatment on how a patient “survives, feels, or functions” in daily life (“clinical benefit”)
What alternative standards does FDA recognize?
“Substantial Clinical Experience”
21 C.F.R. § 202.1(e)(4)(ii)(c)
Non-NDA drugs
“Competent and Reliable Scientific Evidence”
FDAMA § 114
FTC definition
Standards Applicable to Other Claims
No suggestion of treatment benefit; vary by claim
“Convenience, ease of use, drug utilization, etc.”
Standards Applicable to Non-Claims Communications
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9. How is FDA’s current approach “relatively permissive”?
FDA frequently refers to the distinction between “promotional” versus “non- promotional” communication
This dichotomy is used as “shorthand” to describe the distinctions established by the FDCA between statements that are permitted and those that are not
In litigation and other contexts, FDA has said that “promotion” encompasses communications that “prescribe, recommend, or suggest” a particular use of a product
FDA has construed this mean communications that include a "claim," i.e., a representation or suggestion that "a particular use is safe or effective." See, e.g. Government Briefs in Allergan v. United States, No. 09-cv (D.D.C. filed Oct. 1, 2009)
"These types of statements invite healthcare professionals to rely on the conclusions drawn by the manufacturer instead of inviting them to analyze and interpret the data using their own professional judgment.” See Declaration of Janet Woodcock in Amarin Pharma Inc. v. FDA, No (S.D.N.Y. June 23, 2015).
FDA has not otherwise issued clear, overarching guidance on the distinction between “promotional” and “non-promotional” communication
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10. Safe Harbors
Communications Not Required to Comply With FDA Promotion Rules
Communications Protected by the First Amendment
Communications Not Within FDA’s Statutory Authority
Communications Covered by a “Safe Harbor”
Responses to Unsolicited Requests
Industry-Supported Scientific and Educational Activities
Reprints, Reference Texts, Clinical Practice Guidelines
Scientific Exchange
Because the legal lines are unclear, it is possible that safe-harbored communications are not subject to FDA rules for any of these reasons.
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11. FDA & The First Amendment
For decades after the first federal food and drug laws were enacted, courts considered the First Amendment largely irrelevant.
In early cases, the First Amendment was not mentioned at all.
See, e.g., United States v. Ninety-Five Barrels . . . Alleged Apple Cider Vinegar, 265 U.S (1924).
In the few cases in which First Amendment arguments were made, they were summarily rejected.
“Freedom of Speech does not include the freedom to violate the labeling provisions of the Federal Food, Drug and Cosmetic Act.”
United States v. Articles of Food . . . Clover Club Potato Chips, 67 F.R.D. 419, 424 (D. Idaho 1975).
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12. FDA & The First Amendment
No special rule allows greater speech regulation in areas of heavy product regulation
Rubin v. Coors Brewing Co., 514 U.S. 476 (1995) (declining to adopt more speech-restrictive standard of First Amendment review for regulation of commercial speech concerning alcohol).
The First Amendment “directs us to be especially skeptical of regulations that seek to keep people in the dark for what the government perceives to be their own good.” 44 Liquormart, Inc. v. Rhode Island, 517 U.S. 484, 503 (1996).
FDA’s core argument that it is regulating conduct, not speech, has been rejected
Washington Legal Found. v. Friedman,13 F. Supp. 2d 51, 66 (D.D.C. 1998): The "proper inquiry is not whether the speech violates a law or regulation, but rather whether the conduct that the speech promotes violates the law."
U.S. v. Caputo, 288 F. Supp. 2d 912, 920 (N.D. Ill. 2003): “The FDA argued that the speech concerned unlawful activity because it was a prohibited act: misbranding. The court properly rejected this argument ”
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13. FDA & The First Amendment
There are limits on the extent to which FDA can invoke the sanctity of premarket review to defend even commercial speech restrictions
Thompson v. Western States (535 U.S. 357, 376 (2002)): The government’s “interest could be satisfied by the far less restrictive alternative of requiring each compounded drug to be labeled with a warning that the drug had not undergone FDA testing and that its risks were unknown.”
Washington Legal Found. v. Friedman (13 F. Supp. 2d 51, 67 (D.D.C. 1998)): “In asserting that any and all scientific claims are presumptively untruthful or misleading until the FDA has had the opportunity to evaluate them, FDA exaggerates its overall place in the universe.”
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14. FDA & The First Amendment
“The FD&C Act, its implementing regulations, and FDA policies must protect the public health – the fundamental interest underlying FDA’s mission and the statutory framework – while harmonizing this goal with First Amendment interests in the dissemination of truthful, accurate, and non-misleading information regarding medical products We are granting your request These tasks are part of FDA’s more comprehensive review of its regulations and guidance documents in an effort to harmonize the goal of protecting the public health with First Amendment interests.”
FDA Response to MIWG Citizen Petitions at 6, 8
(Jun. 6, 2014)
“FDA recognizes that there can be in certain instances a tension between the substantial public health interests underlying the premarket review process and other important interests such as furthering scientific research and supporting healthcare provider and patient decision-making for individual patient treatment. Rather than adopt an approach that favors one set of interests at expense of other interests, FDA takes into account all of the varied interests, including First Amendment interests.”
Woodcock Decl., Amarin (Jun 23, 2015)
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15. Endgame?
Stakeholder proposals have included suggested clarifications to existing safe harbors and regulatory provisions governing manufacturer speech, along with an administrative mechanism for manufacturers to obtain FDA advice on proposed activities
Some advocacy has emphasized “truthful and non-misleading” as the touchstone, with attendant questions:
Who adjudicates?
What is the standard?
If you assume courts will continue to reject speech restrictions, at what point does the regulatory scheme become unsustainable?
Is a defense of the status quo an adequate response to these changes in the external environment?
Even if a restrictive approach could be defended against First Amendment attack, what are the public health consequences of resisting reform?
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16. Summary
Manufacturer communications regarding new uses, or other departures from FDA-approved labeling, are a recognized incident to medical and surgical practice.
FDA policy is explicitly one of “delicate balance” between facilitating rational deviations from approved labeling and robustly enforcing the FDCA.
Far from limiting manufacturer communications to those directly taken from approved labeling, FDA has devised a complex system of regulatory rules and safe harbors that give manufacturers broad latitude to provide information, including promotional information.
The current debate over “off-label promotion” focuses on the need for clear a priori rules within the existing framework and does not necessarily present an existential threat to the long-standing regulatory scheme.
The research-based medical products industry supports the continued central role of FDA in adjudicating claims of drug and device effect in advance, based on the existing “gold standard” of scientific evidence.
Regulatory reform opponents who set constitutional limitations in opposition to public health protection ignore both the public health need served by scientific exchange and the federal government’s own established policy of encouraging a certain amount of appropriate “out-of-labeling” communication by manufacturers.
SIDLEY AUSTIN LLP