OPDP’s One-Two Combo on Quantitative Efficacy Claims in DTC Ads

It has been a few weeks, but we thought it important to do a deeper dive on the two Office of Prescription Drug Promotion (OPDP) Untitled Letters published in November.  The letters, both issued on October 31, 2023 but published in early November, were to Otsuka and Evofem for misleading efficacy claims relating to overstating the efficacy of their respective products in direct-to-consumer (DTC) advertisements. Both letters addressed quantitative efficacy presentations—attacking the numbers as well as the underlying methodology for obtaining those numbers. The letters come on the heels of FDA finalizing its Guidance on Presenting Quantitative Efficacy and Risk Information in Direct-to-Consumer Promotional Labeling and Advertisements.

The Letters

In the letter to Otsuka, FDA called out a DTC television advertisement and web banner for misleadingly claiming that REXULTI® (brexpiprazole), an adjunctive treatment for major depressive disorder (MDD), was proven to “reduce depression symptoms 62% more,” and to provide “a 62% greater reduction in depression symptoms,” than with an antidepressant alone. Instead, OPDP calculated that the 2 mg tablet advertised reduced depression by 11.9%, and even less for other doses. To OPDP, the violative claim was even more concerning given the seriousness of MDD and Rexulti’s multiple serious, potentially life-threatening or irreversible risks. Rexulti carries a boxed warning for increased mortality in some elderly patients and an increased risk of suicidal thoughts and behaviors in young patients.

In the letter to Evofem, FDA focused on a DTC patient brochure claim that a “separate analysis” on PHEXXI® (lactic acid, citric acid, and potassium bitartrate), a contraceptive vaginal gel, showed that “99% of pregnancies were prevented per act of sex (101 pregnancies over 24,289 acts of sex).” FDA argued that the “per act of sex” efficacy claim is not validated. Because of the lack of validation, the claim that 99% of pregnancies were prevented overestimates the effect of Phexxi on pregnancy prevention.  The analysis treats each act of sex as equally likely to cause pregnancy, which is untrue given that conception depends on the timing of intercourse in relation to ovulation.

Digging into the Data

In Rexulti’s case, FDA used the results of Study 1, presented on Table 12 of the drug’s prescribing information (see below and here) to calculate efficacy. This is the placebo-subtracted difference in least-squares (LS) mean change from baseline (difference between 8.4 and 5.2 = 3.2) divided by the average baseline score of 27 to get 11.85%. Otsuka did not provide a citation for the 62% claim but may have used the placebo-subtracted difference in least-squares (LS) mean change from baseline (difference between 8.4 and 5.2 = 3.2) divided by the placebo LS mean change from baseline of 5.2 to get 61.5%. Even though Otsuka may have used the same underlying efficacy data as the FDA, the enforcement letter shows that the agency considered the company’s twist to be misleading to consumers.

OPDP calculated Phexxi’s efficacy using two alternative methods—a Kaplan-Meier life-table analysis, which provided an 86% cumulative pregnancy prevention rate, and the Pearl Index, a measure of pregnancies per 100 women with their first year of typical method use, which corresponded to a 72.5% cumulative pregnancy prevention rate. Both methods were included in Phexxi’s own prescribing information as well as in FDA’s draft 2019 guidance on establishing effectiveness for hormonal contraceptives (note: Phexxi is not a hormonal contraceptive). OPDP noted that both these methods analyzed cumulative failure rates over specific lengths of exposure rather than failure rates based on individual acts of intercourse.

OPDP noted that the “per act of sex” is not a validated measure to demonstrate the efficacy of contraceptive products and using it is misleading to consumers. While “per act of sex” measurements have been used to calculate breakage events for condoms, or the risk of HIV transmission in research, that measure has not traditionally been used to evaluate overall contraceptive rates.

Notably, Evofem provided considerable context around its 99% claim. The brochure (see screenshot below and here) presented the 86% figure from the prescribing information in bold font, albeit in smaller type. The company noted that the 99% claim was from a “separate analysis,” included “[s]ince Phexxi is an on-demand birth control.” Evofem also acknowledged that the data is “not found in the Product Information” and had “not undergone the same rigorous evaluation as other data from the study.” While OPDP noted the additional context around the analysis, it did not acknowledge the presentation of the 86% efficacy figure from the prescribing information and found that the context around the 99% number “[did] not mitigate the misleading overstatement of efficacy created by these claims.”

Some Additional Thoughts

Of the enforcement letters issued in 2023, all five have addressed misleading efficacy presentations with four out of the five letters prioritizing the efficacy presentations as misleading over any allegations regarding presentation of risk.  Earlier in the year, FDA finalized its guidance on Presenting Quantitative Efficacy and Risk Information in [DTC] Promotional Labeling and Advertisements (and updated it this month). In it, FDA explains that consumers are better at recalling and comprehending quantitative descriptions, which increases the importance of quantitative information being accurate and understandable.  This explains the focus in the last two letters on DTC materials with quantitative efficacy statements as well as the first Untitled Letter of the year to Xeris that focused on inaccurate quantitative representations of efficacy on a DTC website.

The August OPDP Warning Letter to AstraZeneca for making false or misleading efficacy claims serves as another  “wake up” call to industry as it grapples with what presentations may be considered “consistent” with FDA-Required labeling as well as the adequacy of underlying substantiation and sufficiency of disclaimers and additional context (see our post on that letter here).  The fact that the promotional piece, itself, was directed to healthcare professionals and not generally considered part of a wide-ranging promotional campaign, yet rose to the level of a Warning Letter, still has us scratching our heads.

In any case, the two new letters serve as yet another two reminders for pharmaceutical companies to ensure that their efficacy claims are adequately substantiated with appropriate data. And while the letters certainly call to mind the newly finalized Guidance on Quantitative Efficacy Presentations, the emphasis on efficacy presentations also signals to these bloggers that 2023 may be the year that FDA begins to dismantle the “shelter” that was once thought to be provided by the CFL guidance.