Aleve Challenge, New Study Catch Up To Advil 'Works Longer' Claim In NAD Review

Although 1993 studies to make Aleve available OTC didn't support claiming the naproxen oral analgesic lasted longer than ibuprofen-containing Advil, 2018 study Bayer submitted for National Advertising Division review shows Advil's efficacy doesn't exceed Aleve's. Report also says while Pfizer criticized inpatient methodology of Bayer's study, inpatient is industry standard method for pain medication trials.

Evidence that supports making a drug available OTC in the US isn't the final word on marketing claims for the ingredient, a Council of Better Bureaus' industry self-regulation arm concluded in a review of Aleve marketer Bayer AG's challenge to Pfizer Inc.'s advertising for Advil.

A report published 10 September by the National Advertising Division of the council's BBB National Programs Inc. also states that while Pfizer criticized the inpatient methodology of the study Bayer submitted to support its challenge, inpatient is the industry standard for pain medication trials.

Bayer challenged the ad claim “Nothing works longer than Advil” used in marketing since 2007. Pfizer based the claim on three studies conducted by the firm that owned Aleve when it was switched in 1994, finding no statistically significant differences in the duration of pain relief provided by the two non-steroidal anti-inflammatory drugs, according the NAD report.

Although 1993 studies presented to the Food and Drug Administration in a new drug application to make Aleve available OTC didn't support claiming that the naproxen oral analgesic lasted longer than ibuprofen-containing Advil, a 2018 study Bayer submitted for the review shows that Advil's efficacy does not exceed Aleve's, say NAD attorneys. They recommended discontinuing the claim.

Although 1993 studies presented to FDA to make Aleve available OTC didn't support claiming the naproxen oral analgesic lasted longer than ibuprofen-containing Advil, a 2018 study by Bayer shows Advil's efficacy doesn't exceed Aleve's, say NAD attorneys.

"FDA’s OTC approval does not and should not arrest all scientific study and development regarding drugs on the market. It does not prevent Aleve from later proving that durational superiority or from contradicting Advil’s claim of durational parity in the future," the attorneys wrote.

Records of the FDA's evaluation of the Aleve switch NDA show it concluded that Aleve could not be labeled or advertised with claims that it was longer lasting than Advil. Additionally, during agency officials' discussions with the switch sponsors, "a consensus was reached that labeling and promotional materials could not claim that Aleve lasts longer than Advil due to the lack of evidence to support the claim," according to the NAD review.

Bayer has owned the Aleve brand outright since acquiring Roche's OTC drug business in 2004, after it already was marketing the line in the US under license from the Swiss firm, which had acquired full ownership of the brand from Procter & Gamble Co. in 1996.

Advil became available OTC in 1984 on a proposal by the brand's then-owner, American Home Products Corp., which became Wyeth in 2002. Pfizer gained the Advil brand when it acquired Wyeth in 2009; it moved all its consumer health brands into a joint venture launched earlier in 2019 that GlaxoSmithKline PLC is operating as the majority partner. (Also see "Pfizer Consumer Health True To Form Pending Move To JV With GSK" - HBW Insight, 30 Jan, 2019.)

Brands' Earlier Litigation Not A Stop Sign

While Bayer challenged Pfizer's advertising, Pfizer argued in its response to NAD that a 1995 court decision in litigation between the former owners of the two NSAID brands precludes an additional review of the ad claims by the CBBB arm.

In a complaint for preliminary injunction American Home Products filed against P&G, a judge in US District Court for the District of New Jersey found that the studies in the record – the same studies Pfizer provided for NAD's review – didn't demonstrate Aleve’s statistically significant durational superiority to Advil. (Also see "Aleve data vs. Advil shows "trend" toward longer action, court says in rejecting AHP suit." - HBW Insight, 2 Jan, 1995.)

Pfizer asserted that the court also relied upon the FDA's meeting minutes that detailed why Aleve could not claim durational superiority over Advil.

It contended "an important tenet" of NAD review is to “avoid multiple and potentially conflicting findings from more than one tribunal,” which “could be unduly burdensome for advertisers and create confusion for consumers," according to the report.

Dosing Duration Differences On Labels

NAD attorneys noted that differences in dosing instructions on Aleve and Advil labels cast doubt on claims that Advil lasts as long as Aleve.

Aleve labeling includes:

• “Do not take more than directed. The smallest effective dose should be used … Take 1 tablet every 8 to 12 hours while symptoms last. For the first dose you may take 2 tablets within the first hour. Do not exceed 2 tables in any 8- to 12-hour period. Do not exceed 3 tablets in a 24-hour period.”

While the same section on Advil labeling states:

• “Do not take more than directed. The smallest effective dose should be used … take 1 tablet every 4 to 6 hours while symptoms persist. If pain or fever does bit respond to 1 tablet, 2 tablets may be used. Do not exceed 6 tablets in 24 hours, unless directed by a doctor.”

NAD, the attorneys explained in the report, has declined to review advertising even where challenged claims were not exactly the same as those examined by a court and "where decades separated the two matters or even where the parties were different."

However, American Home Products complaint against P&G didn't target claims for Advil Bayer challenged in the NAD review. Instead, the court ruling addressed claims about the product now marketed by Bayer filed by a previous marketer of Advil.

NAD attorneys acknowledged that their review and the 1995 court ruling addressed comparative duration of analgesia claims between Aleve and Advil. However, their analysis of supporting evidence submitted by Bayer and by Pfizer "is unlikely to create conflicting guidance for industry – especially considering the differing burdens at NAD and Federal court and the different bodies of evidence at issue."

Moreover, the litigation "occurred over a decade ago and there is new scientific evidence that has been submitted for consideration," they said.

Aleve Studies Support Advil Claim?

Although Bayer challenged Pfizer's advertising for Advil, as evidence to support its claims Pfizer submitted the three studies that American Home Products provided for the Aleve switch NDA comparing durations of analgesia for naproxen sodium and ibuprofen.

Pfizer argued that the results of those studies, all from 1993 and all conducted with subjects using the products and recording their input in their homes, supported claiming superiority of Advil over Aleve. It asserted that the studies have and continue to serve as a reasonable basis for its durational parity claim because they are the most reliable and consistent studies in the record.

One study found no statistically significant difference, using lower doses of the two drugs, between the median time to rescue, which was the primary metric for determining the duration of efficacy measuring times during 12-hours periods until patients re-dosed due to pain. A 220-mg dose of naproxen resulted in a median time to rescue of 9.4 hours, while a 200-mg dose of ibuprofen resulted in a median time to rescue of 8 hours.

The second study found a median time to rescue of 7 hours for subjects taking 440 mg naproxen, and 6 hours for those taking a 400 mg ibuprofen. The third study used the same doses and found no significant difference between the drugs, though it showed durational superiority for ibuprofen at 7.3 hours median time to rescue while the naproxen group's median time was 6.2 hours.

The 2018 study Bayer submitted was a 24-hour single center, randomized, double-blind, placebo-controlled trial of nearly 400 subjects experiencing moderate to severe pain following extraction of their third molar, or wisdom tooth. They received a single dose of naproxen sodium, ibuprofen or a placebo following the procedure and were assessed regularly, with time to rescue medication as the primary measure.

Using inpatient methodology to ensure pain assessments and data were reliable, the subjects could rest where they underwent extractions, drink clear liquids prior to and eat soft foods after dosing. Pain assessments were conducted by trained staff at set intervals. Subjects not achieving adequate pain relief after initial dosing were permitted, after being encouraged to wait 90 minutes, to take rescue medication and were required to rate their pain intensity immediately after.

Bayer said the median time to rescue medication was "significantly longer" in the Aleve group compared to the Advil group and to placebo –on both a statistical and user-perceptible basis. In the Advil group, 83% of the subjects took rescue medication within the 24-hour period, 25% at around 8 hours and 50% at around 10.5 hours; in the Aleve group, 35% took rescue medication within the 24-hour period and 25% re-dosed at around 11 hours.

The German firm also that the three studies Pfizer submitted were designed to focus on multiple efficacy parameters, not only duration, and didn't use large enough samples sizes to detect statistically significant differences in duration of efficacy.

Pfizer, however, contended Bayer's study was an outlier and did not show better evidence than the 1993 studies on the relative duration of analgesia from the two NSAIDs. The New York-based pharma contended these problems rendered Bayer's study less reliable:

• it sequestered subjects at a clinical facility for the 24-hour test period, making it less relevant to consumers and less reflective of their real-world experience with the drugs;

• as the only single-dose, 24-hour inpatient study for relevant analgesic products, the length of the study artificially extended the median time to analgesia because after 12 hours subjects may forgo rescue medication because their pain is naturally receding, not because the medication is still effective;

• the baseline pain distribution of the study population did not reflect the types of consumers who use OTC pain medication, with too high a percentage experiencing “severe” pain.

Bayer, though, responded that it currently is standard to conduct this type of trial as an inpatient study because it creates more reliable data as outpatient studies can produce sloppy, patient-reported data and poor compliance. Additional, Bayer pointed out that "Pfizer also now conducts pain studies using an inpatient method," according to the NAD report.

Pfizer 'Did Not Rebut' Inpatient Trials As Industry Standard

The 24-hour, inpatient design of Bayer's study weighed heavily in NAD attorneys' decision to agree with its argument. While "both methods are reasonable, given the conflicting values at hand," Bayer "asserted (and [Pfizer]did not rebut) that an inpatient method is standard and used by both parties in pain studies."

With median time to rescue medication following a single-dose administration of a drug the industry standard metric for measuring relative duration of analgesia, Aleve's labeling approved by the FDA indicates that consumers should expect a longer period before re-dosing, the attorneys said. Based on Aleve's "FDA-approved dosing schedule," trials such as the three Pfizer submitted that are limited to 12 hours will not record data for subjects re-dosing after that period, lowering the median duration of the drug's efficacy.

"By excluding subjects who experienced pain relief beyond 12 hours, [the 1993] studies may have failed to detect a real difference in duration that may have existed between to drugs – a difference that shows up in the data of the 2018 Bayer study," NAD attorneys stated.

The longer study period, they said, is appropriate for measuring the relative duration of analgesia for the studied drugs as it may detect differences in duration that were not observed in pain studies of shorter duration.

Pfizer stated in the report that it "may disagree with NAD’s basis underlying its recommendation," but it agrees to comply with the recommendation to discontinue the durational parity claim.