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Comparative Claims: Learning from
FDA Warning and Untitled Letters
By Stefanie A. Doebler
Many promotional materials contain comparative statements that suggest one product
is superior to others on the market. These presentations often involve comparisons of
the products’ efficacy or safety profiles, but they may also compare indications, dosages,
patient preferences, price and so on.
Use of comparative claims is not without risk, however. In recent years, more than a
third of all Warning and Untitled Letters issued by the US Food and Drug Administration’s
(FDA) Office of Prescription Drug Promotion (OPDP) and its predecessor, the Division of Drug
Marketing and Communication (DDMAC), included allegations related to comparative claims.
Although the Federal Food, Drug, and Cosmetic Act (FD&C Act) and FDA regulations
provide some direction regarding the permissible bounds of comparative claims for prescription drugs, the bulk of FDA’s guidance on comparative claims can be gleaned only
from a careful review of the allegations set forth in Warning and Untitled Letters issued by
OPDP and DDMAC.
This article describes the requirements for making comparative promotional claims
under the FD&C Act and FDA regulations. It also reviews allegations regarding comparative claims set forth in Warning and Untitled Letters issued by OPDP and DDMAC between
January 2006 and July 2012.1
Based on this review, the article identifies the primary issues of concern cited by FDA
and provides guidance on how to best structure comparative claims in light of the current
enforcement landscape.
Applicable Law Provides Only Limited Guidance
Under the FD&C Act, a drug is misbranded if its labeling is “false or misleading in any particular.”2 FDA regulations identify specific types of statements that will be deemed “false,
lacking in fair balance, . . . misleading.”3
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One is 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.”4 Although this provision relates specifically to advertising, FDA applies the
same evidentiary standards to labeling.5
The requirement for “substantial evidence” in the context of comparative claims
comes from the provision of the FD&C Act governing proof of effectiveness for new drugs.6
That provision defines substantial evidence as “evidence consisting of adequate and wellcontrolled investigations, including clinical investigations.”7
FDA has not provided meaningful guidance regarding “substantial clinical experience”
or how this standard might differ in practice from the “substantial evidence” standard.
FDA enforcement letters use the two phrases interchangeably.
In practice, the agency typically requires that substantial evidence consist of at least
two adequate and well-controlled clinical trials.8 FDA has the authority, however, to determine that data from one adequate and well-controlled clinical investigation are sufficient
to establish effectiveness.9
Although many comparative claims in promotional materials are based on data from
only one study, FDA has on at least one occasion stated a comparison was not supported
by substantial evidence because the study was not replicated. In a 2007 Untitled Letter to
GlaxoSmithKline, DDMAC alleged that a detail aid misleadingly implied that Flonase was
superior to Nasonex in part because the claim was supported by only one reference.10
Comparative claims can be either express or implied. Unlike express claims (“Product
X is safer and more effective than Product Y”), implied comparative claims do not mention
a comparator product but instead offer vaguer superiority assertions, such as “preferable
side effect profile” or “best-in-class.” FDA applies the same standards to express and
implied comparative statements.
In a 2011 Untitled Letter, OPDP alleged a Pataday patient rebate offer with the
headline “Pay no more than $25 with this Most Relief Rebate” was unsupported by “substantial evidence or substantial clinical experience to support any suggestion that Pataday
demonstrates superior efficacy over other products approved for the same indication.”11
Enforcement Letters Shed Light on Key Issues
The remainder of this article examines OPDP and DDMAC enforcement letters that
address comparative claims and identifies FDA’s key allegations related to these claims.
To conduct this analysis, the author reviewed the 205 Warning and Untitled Letters issued
by OPDP and DDAMC between January 2006 and July 2012 (the review period).
Of these 205 letters, 75 (37%) alleged that the promotional materials at issue presented violative comparative claims, including superiority claims. Figure 1 shows the number
of letters issued by year. These letters include allegations that appeared under a heading of
“Unsubstantiated Superiority Claims,” “Misleading Comparative Claims” or a similar heading,
as well as those that did not appear under a heading specific to comparative or superiority
claims but where the claim at issue including an implicit or explicit comparison.
The majority of the 75 letters alleging violative comparative claims cited printed materials intended for healthcare professionals. Ten involved promotional materials aimed at
patients and eight involved claims on websites or in other forms of social media (whether
intended for patients, physicians or both). Four involved oral statements made by sales
representatives or other company personnel.
Lack of Substantial Evidence Is the Most Frequent Deficiency
By far, the agency’s most frequent allegation regarding comparative claims is they were
not supported by substantial evidence. This allegation was cited in 93% of letters discussing comparative claims (70 of the 75 letters). Whether substantial evidence exists to
support a claim can be a matter of debate, but the enforcement letters issued during the
review period suggest the following principles regarding the type of evidence necessary to
support comparative claims.
First, substantial evidence must be derived from clinical studies. In vitro, ex vivo and
animal studies are not substantial evidence. In seven of the letters issued during the
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review period, FDA alleged the comparative claims were not supported by substantial evidence because the underlying data were generated in in vitro studies. One letter involved
an ex vivo study and another involved an animal study.
For example, a sales aid for Abelcet stated, under the heading “Rapid Activity,” that
“[a]mphotericin B is released from the lipid more rapidly after administration of ABELCET®
than with AmBisome®.” The statement was followed by a bar graph comparing the percentage of amphotericin B released from the lipid after three hours.
In a 2007 Untitled Letter to the manufacturer, Enzon Pharmaceuticals Inc., DDAMC
noted the results were accurately presented on the bar graph, but it further stated “in vitro
data do not constitute substantial evidence to support a claim or implication of superior
clinical effectiveness.”12
Second, non-inferiority clinical studies are not sufficient to support superiority claims.
In five letters issued during the review period, FDA alleged claims were improperly supported by data from a non-inferiority study.
For example, a convention booth panel for Angiomax suggested it is more effective
than heparin for patients with acute coronary syndrome undergoing percutaneous coronary
intervention (and particularly for those with more-advanced disease). However, several of
the studies cited to support that claim were non-inferiority studies.
In an Untitled Letter to The Medicines Company, OPDP explained: “Non-inferiority trials
are not designed to demonstrate superiority over other agents. Rather, they are intended
to show that the effect of a new treatment is not worse than that of an active control by
more than a specified margin.”13
Third, data derived from post hoc analyses and meta-analyses do not constitute substantial evidence. In five letters, FDA alleged a comparison was not based on data from a
pre-specified analysis and therefore could not support the comparative claim. For example, a brochure for Lialda stated it was superior to Asacol and placebo with respect to the
percentage of patients who achieve “complete remission at week 8.”
But the reference cited to support the claim included a retrospective analysis not
set forth in the original study design. DDMAC alleged this exploratory analysis was not a
comparative, head-to-head study of Lialda and Asacol and, therefore, did not support the
superiority claims.14
Likewise, three letters involved allegations that comparative claims were based on
meta- or pooled analyses (i.e., use of statistical methods to combine the results of individual studies). For example, a slide presentation for Mephyton, an oral formulation of
phytonadione, suggested that it was as effective as intravenously administered phytonadione and superior to subcutaneously administered phytonadione.
In an Untitled Letter to Aton Pharma, DDMAC stated that the cited reference was “a
retrospective review of multiple clinical studies that were performed in diverse patient
populations, with different doses and dosage forms of phytonadione, and under varying
clinical protocols.”15
In addition, the enforcement letters issued during the review period cited the following
types of evidence as insufficient to support comparative claims:
• results of open-label studies (eight letters)
• review articles or literature reviews (six letters)
• studies in which the primary endpoint was not met (two letters)
Enforcement Letters Provide Additional Insight
In addition to establishing the standards for substantial evidence necessary to support a
comparative claim, the Warning and Untitled Letters issued by OPDP and DDMAC provide
further guidance regarding the permissible bounds of comparative claims. Perhaps most
importantly, comparative claims must compare apples to apples.
FDA has stated that comparative claims must relate to the approved uses of the products compared, although the comparative data themselves do not need to be included
in the products’ approved labeling.16 The products also must be approved for the same
indication and at the dosage regimens used in the comparison, provide an appropriate
basis for the comparison and be from the same part of the dosage range (for example, a
comparison of the maximum- or minimum-labeled doses).
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In four letters issued during the review period, FDA alleged promotional claims
included comparisons of indications or dosages that were not the same for the products
compared. For example, a sell sheet for Rozerem included a bar graph depicting the relative abuse liability of 19 sedatives and hypnotic drugs (with Rozerem shown to be the
only drug with both no likelihood of abuse and no detectable toxicity). DDMAC concluded
the chart was misleading because several of the drugs included in the graph were not
approved for the treatment of insomnia, the indication for which Rozerem is approved.17 In
fact, two of the drugs depicted in the graph were not approved for any use in US.
In addition, even if factually correct, comparisons must not minimize the risks
associated with the product at issue or be otherwise misleading. Eight letters included
allegations the claim downplayed the product’s risks.
In one case, a white paper included a number of claims suggesting Abraxane is safer
than other forms of paclitaxel because it contains the naturally occurring protein albumin. The white paper also suggested Abraxane is safer than other chemotherapeutic
agents used to treat metastatic breast cancer because it does not contain solvents that
can cause serious toxicities. OPDP noted that not only were the claims unsupported by
substantial evidence, but also they minimized the potentially serious risks of Abraxane,
including bone marrow suppression, possible teratogenic effects and sensory neuropathy.18
Similarly, an online banner issued by GlaxoSmithKline stated, “Treximet ™ is superior
at relieving migraine pain to the active ingredient in Imitrex.” While technically correct, the
banner did not prominently disclose that Treximet is a combination of the active ingredient
in Imitrex and naproxen sodium. DDMAC concluded the banner “misleadingly fail[ed] to
appropriately convey the most material information related to this claim.”19
Comparative claims often include statements about a product’s mechanism of action,
but FDA’s enforcement letters establishing these comparisons cannot be used to suggest clinical superiority absent substantial evidence to that effect. Twelve letters included
allegations that discussion of a product’s mechanism of action or delivery system misleadingly suggested the product was superior to a competitor.
A television advertisement for Lunesta stated, “Lunesta is different. It keys into receptors
that support sleep, setting your sleep process in motion.” DDMAC alleged this comparative
statement was unsupported because Lunesta’s precise mechanism of action is unknown.20
But FDA has also said these claims can be misleading even when the mechanism
of action is well understood. For example, DDMAC alleged in a 2011 Untitled Letter that
a sales representative misleadingly stated Savella is a better analgesic than Cymbalta
because Savella has a 3:1 affinity for norepinephrine reuptake inhibition.21 DDMAC
acknowledged Savella inhibits norepinephrine uptake with approximately three times more
potency in vitro than serotonin, but it concluded the statement implied Savella is more
effective than Cymbalta due to its increased affinity for norepinephrine reuptake inhibition
when there is no clinical evidence to support such a claim.
The letters also establish that comparisons of intrinsic product properties cannot
suggest clinical superiority. FDA generally has not required head-to-head study data to
support a comparison of the intrinsic properties of drug products (e.g., stating that one
product is dosed once a day while another product with the same indication requires multiple doses). However, the agency has issued enforcement letters related to comparisons
of intrinsic properties when the comparison suggested a clinical benefit or was otherwise
false and misleading.
For example, a flashcard for Tracleer included a chart comparing Tracleer and sildenafil in several respects, including, “Indicated to reduce the risk of clinical worsening?”
and “Over 2 years of follow-up data in PAH [pulmonary arterial hypertension] clinical trials?” Each question was followed by the word “Yes” for Traceleer and “No” for sildenafil.
DDMAC alleged that, although the answers were true, “[t]he overall presentation suggests
that Tracleer is a better treatment option than sildenafil when physicians are initiating PAH
therapy for a patient,” particularly because the flashcard did not include any comparison
of the risks of the two products.22
Finally, the letters make clear that promotional claims cannot imply a brand drug is
superior to its generic counterpart. FDA has stated comparisons of the safety or efficacy
of therapeutically equivalent drugs are false or misleading because the claims directly
conflict with FDA’s determination the products are therapeutically equivalent.
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A professional mailer for Peridex contained the statement, “What if you ordered a
Cadillac but they delivered a Yugo? That’s like prescribing PERIDEX, and the pharmacist
substituting a generic.” The mailed further stated Peridex is “the acknowledged gold
standard in chlorhexidine rinses.” In a Warning Letter, DDMAC explained FDA “considers
the products therapeutically equivalent; one can be substituted for the other with the full
expectation that the substituted product will produce the same clinical effect and safety
profile as the prescribed product.”23 It concluded that “any promotion suggesting a lack of
equivalence between Peridex and products deemed to be its therapeutic equivalent are
considered false or misleading.”
A significant theme in many letters is that promotional material cannot disclaim a
violative comparison. OPDP’s (and, previously, DDMAC’s) letters clearly establish a manufacturer cannot circumvent an unsupported (or otherwise problematic) comparison by
acknowledging the lack of substantial evidence to support the comparison or by disclosing
any other deficiency.
For example, a sales aid for Xibrom contained two charts under the heading:
“XIBROM: Greater Potency with Sustained Ocular Bioavailability.” The following statement
was printed in small type under both charts: “In vitro study, the clinical significance is
unknown.” In a Warning Letter, DDMAC stated that the disclaimer “[did] not mitigate the
overwhelming misleading impression created by the claims and chart that Xibrom is superior to other drugs in its class.”24 Similarly, the Lialda brochure, described above, included
the following two statements: “Asacol 2.4 g/d was included in this study as a reference
arm only” and “The study was not designed as a comparative head-to-head trial of Lialda
versus Asacol.” The subsequent Untitled Letter explained “these statements do not mitigate the misleading overall implication that Lialda is better than Asacol.”25
Pharmacoeconomic Claims May be Supported by Competent and Reliable
Evidence
FDA’s substantial evidence standard for promotional claims presents challenges for drug
companies seeking to make claims of comparative effectiveness or pharmacoeconomic
claims. Most comparative effectiveness studies tend to be in the form of meta-analyses,
epidemiological studies and observational studies. These studies are not “clinical investigations” and, therefore, generally do not constitute substantial evidence to support
comparative claims.26
When such claims are provided to formulary committees, however, they may be supported by “competent and reliable” evidence, rather than by substantial evidence.27 FDA
has not defined this standard, but legislative history suggests that it was intended to be a
somewhat less rigorous standard than “substantial evidence.”28
Although four letters issued during the review period included claims related to price
or cost effectiveness, none of the allegations related to statements made to formulary
committees. One letter, however, related to pharmacoeconomic claims included in a professional sales aid for Acetadote. The presentation compared treatment time and resulting
treatment costs in an intensive care unit and hospital ward for Acetadote, which is administered intraveneously, and oral n-acetylcysteine (NAC). DDMAC alleged the reference cited
to support the pharmacoeconomic modeling was not adequately designed to support the
presentation because it assumes adequate effectiveness between the two products, which
has not been demonstrated by substantial evidence.29 According to DDMAC: “[T]he implication conveyed by the above presentation (i.e., that Acetadote and oral NAC are comparable
in terms of efficacy, and Acetadote offers the added benefit of a reduction in treatment
costs compared to oral NAC due to reduced treatment time) is misleading.”
Another letter addressed claims in a journal advertisement that the addition of
sodium ferric gluconate to treatment with erythropoiesis-stimulating agents (ESAs) would
result in significant cost savings as compared to ESA therapy alone. In an Untitled Letter
to Watson Pharmaceuticals Inc., OPDP took the position that the economic analyses
used to support this claim did not constitute substantial evidence.30 One such study was
an open-label study and the second was an observational extension study. Each study
was conducted for six weeks, but the journal advertisement suggested the cost savings
were observed over a 12-week period. OPDP also noted the presentation “describes an
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economic model that only evaluated drug acquisition costs and costs associated with
hospitalizations due to serious adverse events, and does not account for other aspects of
treatment costs such as treatment of mild to moderate adverse events, laboratory monitoring, drug administration, etc.”
Patient Preference, Quality-of-Life Claims Subject to Same Requirements
Although the ultimate prescribing decision is made by a patient’s physician based on
discussions with the patient, promotional pieces often include claims regarding patient
preference. FDA applies the same substantial evidence to claims of patient preference as
to other comparative claims.
Moreover, FDA has noted “patient preference” is a broad concept that encompasses
multiple aspects of patient experiences, such as convenience, ease of use, dosing, dosage form, multiple aspects of efficacy and adverse events. Studies must be designed to
fully evaluate patient preference, or claims must clearly delineate which aspects of patient
preference are being compared.
In the review period, five letters included allegations regarding patient preferences.
One involved patient preference claims made in a sales aid for Testopel. The claims
included the following statement on the front cover: “92% of men choose to continue with
Testopel® rather than switch back to their prior testosterone therapy.” Inside, the sales
aid said, “9 of 10 men prefer testosterone pellet therapy over their previous form of treatment.” In a Warning Letter to Slate Pharmaceuticals, DDMAC noted the references cited
to support the claims “do not describe adequate and well-controlled head-to-head studies
that evaluate patient preference for patients on Testopel compared to their previous treatments.”31 DDMAC further stated the studies were not designed to evaluate the full range
of patient preference.
FDA takes a similar view of quality of life claims. A sales aid for Pentasa stated it
improves patients’ quality of life in seven respects (sexual relationship, work, social activities, hobbies, outdoor activities, sleep and indoor activities), with percentage improvements
cited for each activity. In an Untitled Letter to Shire Development Inc., DDMAC alleged the
quality-of-life claims were not supported by substantial evidence because questions about
single parameters cannot provide a complete understanding of a patient’s overall quality of
life.32 Other important considerations, such as emotional functioning and financial stability,
which also contribute to quality of life, were not measured. Moreover, a single parameter
such as outdoor activities does not capture all facets of a particular activity.
Conclusion
As described above, FDA has provided relatively little direct guidance regarding comparative claims in promotional materials.
Instead, Warning and Untitled Letters issued for allegedly violative claims provide the
best insight into the agency’s current views on the data necessary to support comparative
claims and the manner in which such claims may be presented. Promotional materials
that include comparative claims should be carefully reviewed against the backdrop of
these enforcement letters.
References
1. This article merely summarizes the allegations contained in FDA’s letters. It does not contain any analysis, opinions or characterizations of the letters.
2. FD&C Act § 502(a); 21 U.S.C. § 352(a).
3. 21 CFR § 202.1(e)(6).
4. Ibid. § 202.1(e)(6)(ii).
5. DDMAC Warning Letter to Pedinol Pharmacal Inc. 20 August 2009.
6. FD&C Act § 505(d); 21 USC § 355(d).
7.Ibid.
8. US Food and Drug Administration. Guidance for Industry—Providing Clinical Evidence of Effectiveness for Human Drugs and
Biological Products 4. May 1998.
9. FD&C Act § 505(d); 21 USC § 355(d).
10. DDMAC Warning Letter to GlaxoSmithKline. 7 May 2007.
11. OPDP Untitled Letter to Alcon Research Ltd. 14 October 2011.
12. DDMAC Untitled Letter to Enzon Pharmaceuticals Inc. 21 May 2007.
13. OPDP Untitled Letter to The Medicines Company. 13 April 2012.
14. DDMAC Untitled Letter to Shire Development Inc. 27 April 2010.
15. DDMAC Untitled Letter to Aton Pharma 2 August 2011.
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16. 63 Fed. Reg. 64555. 20 November 1998.
17. DDMAC Untitled Letter to Takeda Pharmaceuticals North America Inc. 28 January 2010.
18. OPDP Untitled Letter to Celgene Corporation. 23 December 2011.
19. DDMAC Untitled Letter to GlaxoSmithKline. 9 March 2009.
20. DDMAC Untitled Letter to Sepracor Inc. 9 June 2010.
21. DDMAC Untitled Letter to Forest Laboratories Inc. 28 April 2011.
22. DDMAC Warning Letter to Actelion. 24 November 2008.
23. DDMAC Warning Letter to Zila Pharmaceuticals Inc. 18 April 2008.
24. DDMAC Warning Letter to ISTA Pharmaceuticals. 10 March 2010.
25. Shire Untitled Letter.
26. Former FDA Commissioner Mark McClellan and others have noted “[t]here is widespread agreement . . . that current methods for primary CER often fail to provide sufficient credible, relevant, and timely evidence.” Tunis SR, Benner J, McClellan
M. Comparative Effectiveness Research: Policy Context, Methods Development and Research Infrastructure. Statistics in
Medicine. 2010: 29: 1963-1976.
27. FD&C Act § 502(a); 21 USC § 352(a).
28. See S. Rep. No. 105-43, at 42 (1997). HR Rep. No. 105-110, at 65 (1997).
29. DDMAC Untitled Letter to Cumberland Pharmaceuticals. 14 June 2010.
30. DDMAC Untitled Letter to Watson Pharmaceuticals Inc. 7 June 2012.
31. DDMAC Warning Letter to Slate Pharmaceuticals. 24 March 2010.
32. DDMAC Untitled Letter to Shire Development Inc. 27 April 2010.
Author
Stefanie Doebler is special counsel at Covington & Burling LLP. Her practice focuses on health care compliance matters for pharmaceutical and medical device companies. She regularly provides advice related to advertising and promotion, fraud and abuse,
aggregate spend, and state marketing laws. © 2012 by the Regulatory Affairs Professionals Society. All rights reserved.
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