CASE LAW Promotional claims
CASE LAW
Evaluating promotional claims as false or misleading David B. Brushwood, Caitlin A. Knox, Wei Liu, and Kevin A. Jenkins Am J Health-Syst Pharm. 2013; 70:1941-4
Case Law is intended to provide pharmacists with timely information about recent court decisions that may affect pharmacy practice. Each installment includes pertinent background information, excerpts from the opinion of the court, and brief commentary. The contributing editor for the section is David B. Brushwood, B.Pharm., J.D., Professor, Pharmaceutical Outcomes and Policy, College of Pharmacy, Health Sciences Center, University of Florida, Box 100496, Gainesville, FL 32610 ([email protected]).
I
t is well established that a clinician’s choice to use a Food and Drug Administration (FDA)approved medication outside what is described in the product labeling does not violate the Food, Drug, and Cosmetic Act (FDCA).1 Product labeling often fails to reflect the most up-to-date standard for patient care. Patients expect clinicians to use innovative practices when it is in the patient’s best interest to do so rather than adhering to a labeling document that often has not been modified for many years. Until recently, it has also been well established that a product manufacturer responsible for labeling a medication may not promote that medication for use in a way that has not been approved by FDA (i.e., offlabel use).2 A recent case from the U.S. Court of Appeals for the Second Circuit calls into question this traditional thinking.3 This case currently serves as precedent only within the states covered by that circuit (New York, Connecticut, and Vermont) but could be followed by other cir-
cuits. The court ruled that promotional statements for FDA-approved medications are subject only to the requirement that they not be false or misleading. Since there are rarely established facts within clinical science, an occupation that necessarily and successfully deals with both knowns and unknowns, the court’s novel perspective raises the question: “What level of evidence should lead to the conclusion that an assertion promoting the use of a medication is false or misleading?” At a theoretical level, this analysis begins with the foundational question: “What is truth?” At
David B. Brushwood, B.Pharm., J.D., is Professor, Department of Pharmaceutical Outcomes and Policy, College of Pharmacy; Caitlin A. Knox, M.P.H., is Ph.D. degree candidate, Department of Pharmaceutical Outcomes and Policy, College of Pharmacy; Wei Liu, M.D., M.Sc., is Ph.D. degree candidate, Department of Pharmaceutical Outcomes and Policy, College of Pharmacy; and Kevin A. Jenkins, M.A., is Ph.D. degree candidate, Department of Health Services Research, Management and Policy, College of Public Health, University of Florida, Gainesville.
a more operational level, the analysis will lead clinicians to ask: “How much evidence, and what quality of evidence, is sufficient to support a medication safety or efficacy claim as truthful and not misleading?” The issues raised in the recent case are as significant for pharmaceutical manufacturers and regulators as they are for clinicians. Manufacturers make many billions of dollars from the sale of products used for off-label purposes. The prosecution of manufacturers for off-label promotion also raises many billions of dollars for the government. If the legal test for impropriety in pharmaceutical product promotion shifts from the relatively straightforward “off-label” standard to the far more esoteric “false or misleading” standard, clinicians’ interpretation and application of this new standard have implications both for patient care and for regulatory compliance by manufacturers. Regulatory background It is a violation of the FDCA to introduce into interstate commerce a misbranded drug, to misbrand a drug while in interstate commerce, or to receive a misbranded drug that has been in interstate commerce. A
Address correspondence to Professor Brushwood at the Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, P.O. Box 100496, Gainesville, FL 32610-0496 (brushwood@ cop.ufl.edu). The authors have declared no potential conflicts of interest. Copyright © 2013, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/13/1101-1941$06.00. DOI 10.2146/ajhp130076
Am J Health-Syst Pharm—Vol 70 Nov 1, 2013
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CASE LAW Promotional claims
drug is deemed to be misbranded if its labeling is “false or misleading in any particular.”4 The term labeling means all labels and other written, printed, or graphic matter placed on a product container or accompanying a product.5 A drug may be considered misbranded not only for what is included within the labeling but for what is not included. Under the FDCA, a drug is misbranded if its labeling fails to bear “adequate directions” for its intended use.6 It is the intent of the labeler that is critical, and under FDA regulations this intent may be demonstrated by “oral or written statements by such persons or their representatives.”7 Misbranding through commission occurs when labeling is false or misleading; misbranding through omission occurs when labeling does not include adequate directions for use. The choice between saying too little and saying too much is a fine line that labelers of pharmaceutical products must walk. The FDCA does not expressly prohibit the promotion of off-label uses of a drug. However, FDA has concluded that promoting a drug for an off-label use is misbranding because the labeling of the drug fails to contain adequate directions for that off-label use.8 The purpose of the FDCA is both to regulate the pharmaceutical industry and to protect the public health. Under the FDCA, FDA is charged with protecting those who use medications from false or misleading claims that could adversely affect outcomes from prescribed therapy. Patients and health care professionals rely on the agency to screen the information they receive about FDA-approved medications for scientific validity. The confidence currently placed in the agency could be undermined, to the detriment of the public health, should the agency choose not to develop a regulatory response to the recent case that relax1942
es the standard for scientific evidence supporting promotional claims. Case background According to the court, the manufacturer of sodium oxybate (Xyrem, Jazz Pharmaceuticals) received FDA approval to label the product with indications for narcolepsy with cataplexy and narcolepsy with excessive daytime sleepiness. The agency required a boxed warning stating that the drug’s safety and efficacy were not established in patients under 16 years of age and that there were limited data regarding its use in elderly patients. The case reported here is based on the activities of a sales representative who was hired by the manufacturer to promote sodium oxybate. The sales representative’s responsibility was to represent the company in his own capacity, and he also employed physicians as promotional speakers to answer questions about off-label use. The federal government launched an investigation of the sales representative and of a physician hired by the representative. The investigation focused on the promotion of off-label uses of sodium oxybate. Conversations were recorded between the sales representative, the physician hired as a promotional speaker, and another physician who was cooperating with the government. According to an excerpt from one conversation, the sales representative had indicated that sodium oxybate had various offlabel uses, including the treatment of insomnia, fibromyalgia, restless legs syndrome, daytime fatigue, and chronic pain. In addition, on separate occasions, the sales representative and the physician hired as a promotional speaker had told prospective prescribers that sodium oxybate could be used in patients under age 16 years. The sales representative was charged with conspiracy to introduce a misbranded drug into interstate
Am J Health-Syst Pharm—Vol 70 Nov 1, 2013
commerce. He was found guilty and sentenced to one year of probation, one hour of community service, and a $25 “special assessment.” He appealed this conviction. Ruling on appeal The sales representative argued on appeal that the First Amendment does not permit the government to prohibit and criminalize a pharmaceutical manufacturer’s truthful and nonmisleading promotion of an FDAapproved drug to physicians for offlabel use where such use is not itself illegal and others are permitted to engage in such speech.
The appellate court noted that the First Amendment protects against government regulation and suppression of speech on account of its content. When the government enforces a content-based regulation, it must show that the regulation is narrowly tailored to serve or promote a compelling government interest. The court reviewed precedent from a previous case from the U.S. Supreme Court, which had ruled on the constitutionality of the Vermont Prescription Confidentiality Law and held that the Vermont law unconstitutionally restricted speech.9 With this case as background, the court noted that the government cannot completely suppress information when narrower restrictions on expression would serve its interests just as well. The court specified that off-label promotion that is false or misleading is not entitled to First Amendment protection. A representative of a pharmaceutical manufacturer clearly may be prosecuted for making false or misleading statements about a drug. However, as off-label drug use itself is not prohibited, it does not follow that prohibiting truthful promotion of offlabel drug usage by a particular class
CASE LAW Promotional claims
of speakers would directly further the government goals of preserving the efficacy and integrity of the FDA’s drug approval process and reducing patient exposure to unsafe and ineffective drugs.
Justifying its decision, the court said Prohibiting off-label promotion by a pharmaceutical manufacturer while simultaneously allowing off-label use “paternalistically” interferes with the ability of physicians and patients to receive potentially relevant treatment information; such barriers to information about off-label use could inhibit, to the public’s detriment, informed and intelligent treatment decisions.
The court also said that “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.” The court offered advice on how FDA could enforce the FDCA more narrowly to further the interests served. For example, the court suggested that “if the government is concerned that off-label promotion may mislead physicians, it could guide physicians and patients in differentiating between misleading and false promotion, exaggerations and embellishments, and truthful or nonmisleading information.” Reversing the sales representative’s judgment of conviction, the court said “we construe the misbranding provisions of the FDCA as not prohibiting and criminalizing the truthful off-label promotion of FDAapproved prescription drugs.” Analysis The ruling of the U.S. Court of Appeals for the Second Circuit could lead pharmaceutical manufacturers to provide information to health care professionals beyond the
labeling-based information that is currently provided, subject only to the requirement that the information not be false or misleading. The health care professionals who receive the information will be left to determine, based on standards they adopt, whether the information is truthful and not misleading. The traditional level of evidence necessary to support a drug labeling claim has generally been considered to be what the FDCA refers to as “substantial evidence.” According to the FDCA, the term “substantial evidence” means evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof.10
But the Second Circuit Court has adopted an approach to the evaluation of evidence that is independent of product labeling, suggesting that a lesser level of evidence may suffice to meet the requirement that a promotional statement not be considered false or misleading. The recent legal ruling challenges the health care professions to develop an understanding of when a promotional statement is false, as well as when a true statement is misleading. The legal requirement is that a statement be neither false nor misleading. This requirement suggests a two-step process of evaluation. An assertion that is determined to be false would fail the test with no need to proceed further. An assertion that is initially determined to be true would then be subject to a second analysis of whether the assertion is misleading, the result
of which could be pass or fail. It can be expected that pharmacists, viewed in health care as the experts on drug use and drug information, will be called on to evaluate promotional claims that purport to be truthful and not misleading. It will be helpful to pharmacists if standards are developed for this validation. Pharmacists and other health care professionals understand that FDA usually requires at least two randomized, controlled clinical trials conducted independently by qualified investigators as support for the approval of a new drug and for the content of labeling that accompanies the drug. Health care professionals accept the responsibility for use of a drug as either consistent with the labeling or off-label. Both FDA and health care professionals view the assessment of drug safety and efficacy as an evolving process during the lifespan of a pharmaceutical product. The evidence that supported language in a product’s labeling at one time may not represent the current knowledge of the risks and benefits associated with the product. A systematic approach is needed to evaluate promotional claims that are not reflected in a product’s labeling. There is scant guidance in federal statutes on how someone might evaluate whether a promotional claim is true or false and how to determine whether a true claim is misleading. For example, regulations of the Federal Trade Commission state that No advertisement of a drug shall be deemed to be false if it is disseminated only to members of the medical profession, contains no false representation of a material fact, and includes, or is accompanied in each instance by truthful disclosure of, the formula showing quantitatively each ingredient of such drug.11
To use the tautology that a statement should be considered false only if it is false or not truthful is of little
Am J Health-Syst Pharm—Vol 70 Nov 1, 2013
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CASE LAW Promotional claims
help. Likewise, the FDA regulation that stipulates drug labeling shall be deemed to be misleading if it “fails to reveal material facts”12 does not provide sufficient specific guidance for a health professional to evaluate a promotional claim. FDA regulations concerning prescription drug advertising offer more-useful guidance. These regulations provide that a drug advertisement is false, lacking in fair balance, or otherwise misleading if it contains a representation or suggestion, not approved or permitted for use in the labeling, that a drug is better, more effective, useful in a broader range of conditions or patients (as used in this section patients means humans and in the case of veterinary drugs, other animals), safer, has fewer, or less incidence of, or less serious side effects or contraindications than has been demonstrated by substantial evidence or substantial clinical experience . . . whether or not such representations are made by comparison with other drugs or treatments, and whether or not such a representation or suggestion is made directly or through use of published or unpublished literature, quotations, or other references.13
This regulation describes the nature of an appropriate level of evidence needed to support an advertisement, which includes but is not limited to clinical studies with clinically significant and valid findings. The regulation specifies that advertisements are not to use the concept of “statistical significance” to support a claim if it does not have clinical validity or significance. Advertisements are false or misleading
1944
if they contain results from secondary outcomes to support their claims or cite studies with inconsistent or poor statistical methodology. If an advertisement presents information implying that a study supports the safety or efficacy of a drug for a particular indication or in a population not included within the results of the study, the advertisement is false or misleading. Likewise, if an advertisement suggests that the drug dosage recommended is safe and effective for use in treatment of patients with specific diseases when data do not support this conclusion, the advertisement is false or misleading. From this definition it follows that all advertisements of off-label uses would require a minimum of one randomized controlled trial with a clinically significant finding to support the claims made. This regulation also supports the perspective that clinical opinions and case studies are not adequate evidence to support an advertisement of a prescription drug. Therefore, without a clinically significant and valid study to support each additional claim beyond those in the product labeling, a promotional statement would be considered false, lacking in fair balance, or otherwise misleading in accordance with FDA regulations. Summary In light of the “false or misleading” standard resulting from the recent legal ruling, it can be concluded that a true claim is one that is both factually and analytically true. Factual truth could be based on the accuracy of the information and the sufficiency of the information. Analytical truth could be based on the scientific foundation for the claim
Am J Health-Syst Pharm—Vol 70 Nov 1, 2013
and whether the information within the claim is presented in a balanced way. Regarding the assessment of whether a truthful claim is misleading, the evaluator could consider the relevance, consistency, and context of the information. Standards are important in medication use and medication regulation. Health care professionals who must decide whether a claim is truthful and not misleading will rely on guidance from FDA in determining how to evaluate promotional claims. As the court suggested in the case reviewed here, FDA could take the lead and provide guidance “in differentiating between misleading and false promotion, exaggerations and embellishments, and truthful or non-misleading information.” Existing FDA regulations provide a foundation for such guidance. The next step for the agency would be to expand existing guidance to specifically describe how an off-label claim can be identified as either false or misleading. References 1. Klasmeier C, Redish MH. Off-label prescription advertising, the FDA and the First Amendment: a study in the values of commercial speech protection. Am J Law Med. 2011; 37:315-57. 2. Boumil MM. Off-label marketing and the First Amendment. N Engl J Med. 2013; 368:103-5. 3. United States v. Caronia, 2012 U.S. App. LEXIS 24831 (2nd Cir. 2012 Dec 3). 4. 21 U.S.C. §352(f). 5. 21 U.S.C. §321(m). 6. 21 U.S.C. §352(f). 7. 21 C.F.R. §201.128. 8. 21 C.F.R. §201.5. 9. U.S. Supreme Court. Syllabus for Sorrell v. IMS Health Inc. www.supremecourt.gov/ opinions/10pdf/10-779.pdf (accessed 2013 Jul 2). 10. 21 U.S.C. §355(d). 11. 15 U.S.C. §55(a)(1). 12. 21 C.F.R. §121. 13. 21 C.F.R. §202.1(e)(6)(i).
Copyright of American Journal of Health-System Pharmacy is the property of American Society of Health System Pharmacists and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
CASE LAW
Evaluating promotional claims as false or misleading David B. Brushwood, Caitlin A. Knox, Wei Liu, and Kevin A. Jenkins Am J Health-Syst Pharm. 2013; 70:1941-4
Case Law is intended to provide pharmacists with timely information about recent court decisions that may affect pharmacy practice. Each installment includes pertinent background information, excerpts from the opinion of the court, and brief commentary. The contributing editor for the section is David B. Brushwood, B.Pharm., J.D., Professor, Pharmaceutical Outcomes and Policy, College of Pharmacy, Health Sciences Center, University of Florida, Box 100496, Gainesville, FL 32610 ([email protected]).
I
t is well established that a clinician’s choice to use a Food and Drug Administration (FDA)approved medication outside what is described in the product labeling does not violate the Food, Drug, and Cosmetic Act (FDCA).1 Product labeling often fails to reflect the most up-to-date standard for patient care. Patients expect clinicians to use innovative practices when it is in the patient’s best interest to do so rather than adhering to a labeling document that often has not been modified for many years. Until recently, it has also been well established that a product manufacturer responsible for labeling a medication may not promote that medication for use in a way that has not been approved by FDA (i.e., offlabel use).2 A recent case from the U.S. Court of Appeals for the Second Circuit calls into question this traditional thinking.3 This case currently serves as precedent only within the states covered by that circuit (New York, Connecticut, and Vermont) but could be followed by other cir-
cuits. The court ruled that promotional statements for FDA-approved medications are subject only to the requirement that they not be false or misleading. Since there are rarely established facts within clinical science, an occupation that necessarily and successfully deals with both knowns and unknowns, the court’s novel perspective raises the question: “What level of evidence should lead to the conclusion that an assertion promoting the use of a medication is false or misleading?” At a theoretical level, this analysis begins with the foundational question: “What is truth?” At
David B. Brushwood, B.Pharm., J.D., is Professor, Department of Pharmaceutical Outcomes and Policy, College of Pharmacy; Caitlin A. Knox, M.P.H., is Ph.D. degree candidate, Department of Pharmaceutical Outcomes and Policy, College of Pharmacy; Wei Liu, M.D., M.Sc., is Ph.D. degree candidate, Department of Pharmaceutical Outcomes and Policy, College of Pharmacy; and Kevin A. Jenkins, M.A., is Ph.D. degree candidate, Department of Health Services Research, Management and Policy, College of Public Health, University of Florida, Gainesville.
a more operational level, the analysis will lead clinicians to ask: “How much evidence, and what quality of evidence, is sufficient to support a medication safety or efficacy claim as truthful and not misleading?” The issues raised in the recent case are as significant for pharmaceutical manufacturers and regulators as they are for clinicians. Manufacturers make many billions of dollars from the sale of products used for off-label purposes. The prosecution of manufacturers for off-label promotion also raises many billions of dollars for the government. If the legal test for impropriety in pharmaceutical product promotion shifts from the relatively straightforward “off-label” standard to the far more esoteric “false or misleading” standard, clinicians’ interpretation and application of this new standard have implications both for patient care and for regulatory compliance by manufacturers. Regulatory background It is a violation of the FDCA to introduce into interstate commerce a misbranded drug, to misbrand a drug while in interstate commerce, or to receive a misbranded drug that has been in interstate commerce. A
Address correspondence to Professor Brushwood at the Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, P.O. Box 100496, Gainesville, FL 32610-0496 (brushwood@ cop.ufl.edu). The authors have declared no potential conflicts of interest. Copyright © 2013, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/13/1101-1941$06.00. DOI 10.2146/ajhp130076
Am J Health-Syst Pharm—Vol 70 Nov 1, 2013
1941
CASE LAW Promotional claims
drug is deemed to be misbranded if its labeling is “false or misleading in any particular.”4 The term labeling means all labels and other written, printed, or graphic matter placed on a product container or accompanying a product.5 A drug may be considered misbranded not only for what is included within the labeling but for what is not included. Under the FDCA, a drug is misbranded if its labeling fails to bear “adequate directions” for its intended use.6 It is the intent of the labeler that is critical, and under FDA regulations this intent may be demonstrated by “oral or written statements by such persons or their representatives.”7 Misbranding through commission occurs when labeling is false or misleading; misbranding through omission occurs when labeling does not include adequate directions for use. The choice between saying too little and saying too much is a fine line that labelers of pharmaceutical products must walk. The FDCA does not expressly prohibit the promotion of off-label uses of a drug. However, FDA has concluded that promoting a drug for an off-label use is misbranding because the labeling of the drug fails to contain adequate directions for that off-label use.8 The purpose of the FDCA is both to regulate the pharmaceutical industry and to protect the public health. Under the FDCA, FDA is charged with protecting those who use medications from false or misleading claims that could adversely affect outcomes from prescribed therapy. Patients and health care professionals rely on the agency to screen the information they receive about FDA-approved medications for scientific validity. The confidence currently placed in the agency could be undermined, to the detriment of the public health, should the agency choose not to develop a regulatory response to the recent case that relax1942
es the standard for scientific evidence supporting promotional claims. Case background According to the court, the manufacturer of sodium oxybate (Xyrem, Jazz Pharmaceuticals) received FDA approval to label the product with indications for narcolepsy with cataplexy and narcolepsy with excessive daytime sleepiness. The agency required a boxed warning stating that the drug’s safety and efficacy were not established in patients under 16 years of age and that there were limited data regarding its use in elderly patients. The case reported here is based on the activities of a sales representative who was hired by the manufacturer to promote sodium oxybate. The sales representative’s responsibility was to represent the company in his own capacity, and he also employed physicians as promotional speakers to answer questions about off-label use. The federal government launched an investigation of the sales representative and of a physician hired by the representative. The investigation focused on the promotion of off-label uses of sodium oxybate. Conversations were recorded between the sales representative, the physician hired as a promotional speaker, and another physician who was cooperating with the government. According to an excerpt from one conversation, the sales representative had indicated that sodium oxybate had various offlabel uses, including the treatment of insomnia, fibromyalgia, restless legs syndrome, daytime fatigue, and chronic pain. In addition, on separate occasions, the sales representative and the physician hired as a promotional speaker had told prospective prescribers that sodium oxybate could be used in patients under age 16 years. The sales representative was charged with conspiracy to introduce a misbranded drug into interstate
Am J Health-Syst Pharm—Vol 70 Nov 1, 2013
commerce. He was found guilty and sentenced to one year of probation, one hour of community service, and a $25 “special assessment.” He appealed this conviction. Ruling on appeal The sales representative argued on appeal that the First Amendment does not permit the government to prohibit and criminalize a pharmaceutical manufacturer’s truthful and nonmisleading promotion of an FDAapproved drug to physicians for offlabel use where such use is not itself illegal and others are permitted to engage in such speech.
The appellate court noted that the First Amendment protects against government regulation and suppression of speech on account of its content. When the government enforces a content-based regulation, it must show that the regulation is narrowly tailored to serve or promote a compelling government interest. The court reviewed precedent from a previous case from the U.S. Supreme Court, which had ruled on the constitutionality of the Vermont Prescription Confidentiality Law and held that the Vermont law unconstitutionally restricted speech.9 With this case as background, the court noted that the government cannot completely suppress information when narrower restrictions on expression would serve its interests just as well. The court specified that off-label promotion that is false or misleading is not entitled to First Amendment protection. A representative of a pharmaceutical manufacturer clearly may be prosecuted for making false or misleading statements about a drug. However, as off-label drug use itself is not prohibited, it does not follow that prohibiting truthful promotion of offlabel drug usage by a particular class
CASE LAW Promotional claims
of speakers would directly further the government goals of preserving the efficacy and integrity of the FDA’s drug approval process and reducing patient exposure to unsafe and ineffective drugs.
Justifying its decision, the court said Prohibiting off-label promotion by a pharmaceutical manufacturer while simultaneously allowing off-label use “paternalistically” interferes with the ability of physicians and patients to receive potentially relevant treatment information; such barriers to information about off-label use could inhibit, to the public’s detriment, informed and intelligent treatment decisions.
The court also said that “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.” The court offered advice on how FDA could enforce the FDCA more narrowly to further the interests served. For example, the court suggested that “if the government is concerned that off-label promotion may mislead physicians, it could guide physicians and patients in differentiating between misleading and false promotion, exaggerations and embellishments, and truthful or nonmisleading information.” Reversing the sales representative’s judgment of conviction, the court said “we construe the misbranding provisions of the FDCA as not prohibiting and criminalizing the truthful off-label promotion of FDAapproved prescription drugs.” Analysis The ruling of the U.S. Court of Appeals for the Second Circuit could lead pharmaceutical manufacturers to provide information to health care professionals beyond the
labeling-based information that is currently provided, subject only to the requirement that the information not be false or misleading. The health care professionals who receive the information will be left to determine, based on standards they adopt, whether the information is truthful and not misleading. The traditional level of evidence necessary to support a drug labeling claim has generally been considered to be what the FDCA refers to as “substantial evidence.” According to the FDCA, the term “substantial evidence” means evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof.10
But the Second Circuit Court has adopted an approach to the evaluation of evidence that is independent of product labeling, suggesting that a lesser level of evidence may suffice to meet the requirement that a promotional statement not be considered false or misleading. The recent legal ruling challenges the health care professions to develop an understanding of when a promotional statement is false, as well as when a true statement is misleading. The legal requirement is that a statement be neither false nor misleading. This requirement suggests a two-step process of evaluation. An assertion that is determined to be false would fail the test with no need to proceed further. An assertion that is initially determined to be true would then be subject to a second analysis of whether the assertion is misleading, the result
of which could be pass or fail. It can be expected that pharmacists, viewed in health care as the experts on drug use and drug information, will be called on to evaluate promotional claims that purport to be truthful and not misleading. It will be helpful to pharmacists if standards are developed for this validation. Pharmacists and other health care professionals understand that FDA usually requires at least two randomized, controlled clinical trials conducted independently by qualified investigators as support for the approval of a new drug and for the content of labeling that accompanies the drug. Health care professionals accept the responsibility for use of a drug as either consistent with the labeling or off-label. Both FDA and health care professionals view the assessment of drug safety and efficacy as an evolving process during the lifespan of a pharmaceutical product. The evidence that supported language in a product’s labeling at one time may not represent the current knowledge of the risks and benefits associated with the product. A systematic approach is needed to evaluate promotional claims that are not reflected in a product’s labeling. There is scant guidance in federal statutes on how someone might evaluate whether a promotional claim is true or false and how to determine whether a true claim is misleading. For example, regulations of the Federal Trade Commission state that No advertisement of a drug shall be deemed to be false if it is disseminated only to members of the medical profession, contains no false representation of a material fact, and includes, or is accompanied in each instance by truthful disclosure of, the formula showing quantitatively each ingredient of such drug.11
To use the tautology that a statement should be considered false only if it is false or not truthful is of little
Am J Health-Syst Pharm—Vol 70 Nov 1, 2013
1943
CASE LAW Promotional claims
help. Likewise, the FDA regulation that stipulates drug labeling shall be deemed to be misleading if it “fails to reveal material facts”12 does not provide sufficient specific guidance for a health professional to evaluate a promotional claim. FDA regulations concerning prescription drug advertising offer more-useful guidance. These regulations provide that a drug advertisement is false, lacking in fair balance, or otherwise misleading if it contains a representation or suggestion, not approved or permitted for use in the labeling, that a drug is better, more effective, useful in a broader range of conditions or patients (as used in this section patients means humans and in the case of veterinary drugs, other animals), safer, has fewer, or less incidence of, or less serious side effects or contraindications than has been demonstrated by substantial evidence or substantial clinical experience . . . whether or not such representations are made by comparison with other drugs or treatments, and whether or not such a representation or suggestion is made directly or through use of published or unpublished literature, quotations, or other references.13
This regulation describes the nature of an appropriate level of evidence needed to support an advertisement, which includes but is not limited to clinical studies with clinically significant and valid findings. The regulation specifies that advertisements are not to use the concept of “statistical significance” to support a claim if it does not have clinical validity or significance. Advertisements are false or misleading
1944
if they contain results from secondary outcomes to support their claims or cite studies with inconsistent or poor statistical methodology. If an advertisement presents information implying that a study supports the safety or efficacy of a drug for a particular indication or in a population not included within the results of the study, the advertisement is false or misleading. Likewise, if an advertisement suggests that the drug dosage recommended is safe and effective for use in treatment of patients with specific diseases when data do not support this conclusion, the advertisement is false or misleading. From this definition it follows that all advertisements of off-label uses would require a minimum of one randomized controlled trial with a clinically significant finding to support the claims made. This regulation also supports the perspective that clinical opinions and case studies are not adequate evidence to support an advertisement of a prescription drug. Therefore, without a clinically significant and valid study to support each additional claim beyond those in the product labeling, a promotional statement would be considered false, lacking in fair balance, or otherwise misleading in accordance with FDA regulations. Summary In light of the “false or misleading” standard resulting from the recent legal ruling, it can be concluded that a true claim is one that is both factually and analytically true. Factual truth could be based on the accuracy of the information and the sufficiency of the information. Analytical truth could be based on the scientific foundation for the claim
Am J Health-Syst Pharm—Vol 70 Nov 1, 2013
and whether the information within the claim is presented in a balanced way. Regarding the assessment of whether a truthful claim is misleading, the evaluator could consider the relevance, consistency, and context of the information. Standards are important in medication use and medication regulation. Health care professionals who must decide whether a claim is truthful and not misleading will rely on guidance from FDA in determining how to evaluate promotional claims. As the court suggested in the case reviewed here, FDA could take the lead and provide guidance “in differentiating between misleading and false promotion, exaggerations and embellishments, and truthful or non-misleading information.” Existing FDA regulations provide a foundation for such guidance. The next step for the agency would be to expand existing guidance to specifically describe how an off-label claim can be identified as either false or misleading. References 1. Klasmeier C, Redish MH. Off-label prescription advertising, the FDA and the First Amendment: a study in the values of commercial speech protection. Am J Law Med. 2011; 37:315-57. 2. Boumil MM. Off-label marketing and the First Amendment. N Engl J Med. 2013; 368:103-5. 3. United States v. Caronia, 2012 U.S. App. LEXIS 24831 (2nd Cir. 2012 Dec 3). 4. 21 U.S.C. §352(f). 5. 21 U.S.C. §321(m). 6. 21 U.S.C. §352(f). 7. 21 C.F.R. §201.128. 8. 21 C.F.R. §201.5. 9. U.S. Supreme Court. Syllabus for Sorrell v. IMS Health Inc. www.supremecourt.gov/ opinions/10pdf/10-779.pdf (accessed 2013 Jul 2). 10. 21 U.S.C. §355(d). 11. 15 U.S.C. §55(a)(1). 12. 21 C.F.R. §121. 13. 21 C.F.R. §202.1(e)(6)(i).
Copyright of American Journal of Health-System Pharmacy is the property of American Society of Health System Pharmacists and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
