AUTH/3215/6/19 and AUTH/3216/6/19 - GP v Pfizer and Bristol-Myers Squibb

Promotion of Eliquis

  • Received
    21 June 2019
  • Case number
    AUTH/3215/6/19 and AUTH/3216/6/19
  • Applicable Code year
    2019
  • Completed
    13 May 2020
  • Breach Clause(s)
  • Sanctions applied
    Undertaking received
  • Additional sanctions
    Advertisement
  • Appeal
    Appeal by respondents
  • Review
    To be published in the review

Case Summary

A general practitioner complained about a page of an Eliquis (apixaban) six-page, landscape, gatefold leavepiece (ref PP-ELI-GBR-4453) issued by Pfizer Limited and Bristol-Myers Squibb Pharmaceuticals Limited. Eliquis was a non-vitamin K antagonist oral anticoagulant (NOAC) indicated, inter alia, for the prevention of stroke and systemic embolism in certain adults with non-valvular atrial fibrillation (NVAF).

The complainant provided a page of the leavepiece headed ‘Eliquis is the only factor Xa inhibitor that does not require a dose adjustment in patients with NVAF who have mild or moderate renal impairment2*’. The page included a table which compared the dose adjustment required depending on degree of renal impairment when prescribing Eliquis vs rivaroxaban, edoxaban and dabigatran. The table showed that no dose adjustment was needed for Eliquis in patients with mild to moderate renal impairment or normal renal function. Low dose was required in severe renal impairment and Eliquis was not recommended in renal failure/dialysis. An asterisk appeared next to the headline and the ‘no dose adjustment’ statement for Eliquis within the table which took the reader to a footnote which read: ‘Dose reduction to Eliquis 2.5mg bd is recommended in patients with NVAF who meet two or more of the following criteria: ≥ 80 years, body weight ≤ 60kg, or serum creatinine ≥ 1.5 mg/dl (133µmol/l). Patients with exclusive criteria of severe renal impairment (CrCl 15-29ml/min) should also receive a lower dose of 2.5mg bd. Eliquis is not recommended for patients with CrCl<15ml/min’. The statement was referenced to the Eliquis summary of product characteristics (SPC).

The complainant alleged that the page was misleading and had potential to lead to patient harm if dose adjustments were not made to Eliquis according to its licence. The way the leavepiece was written might lead clinicians who did not notice the tiny asterisk to ignore dose adjustment that was necessary dependent on the patient’s creatinine clearance, age, creatinine level and weight.

In the complainant’s view, the leavepiece was designed to give unfair advantage over competitor medicines and he/she saw no reason for the companies to specifically highlight edoxaban (Lixiana, marketed by Daiichi-Sankyo) yet not highlight the need for dose adjustment with Eliquis. In the complainant’s view this was an example of aggressive and misleading marketing that could lead to inaccurate dosing with potential for either increased bleed risk or stroke in inappropriately dosed atrial fibrillation patients.

The detailed response from Pfizer and Bristol-Myers Squibb (the Alliance) is given below.

The Panel noted the Alliance’s submission about the layout and flow of the leavepiece and the way in which the pages of the gatefold leavepiece were likely to be read. There was no evidence before the Panel about the order in which recipients would read the leavepiece. Whilst context and flow of information was important the Panel noted that each page ought to stand alone with regards to the requirements of the Code – they could not rely on qualification necessary for Code compliance on either a separate page or a footnote.

The Panel noted the Alliance’s submission that the layout was designed to ensure that recipients viewed a page which included Eliquis data and licensed dosing requirements in the overarching NVAF patient population before viewing the dosage recommendations according to renal function which was presented in the context of the recommendations for the three other medicines in the NOAC class.

The Panel considered that although readers would likely see the bottom panel of view 2/outside back page when first opening the gatefold leavepiece, a reasonable number would read the detail of the inside triple page spread first, the last page of which included the detailed dosage recommendations in patients with NVAF according to renal function for the four NOACs in a tabular format which was the subject of complaint.

The Panel noted that according to its SPC the recommended dose of Eliquis for the prevention of stroke and systemic embolism in patients with NVAF was 5mg taken orally twice daily. A dose reduction of 2.5mg taken orally twice daily was recommended in patients with NVAF who had at least two of the following characteristics: age ≥ 80 years, body weight ≤ 60kg, or serum creatinine ≥ 1.5mg/dL (133 micromole/L).

Section 4.2 of the Eliquis SPC ‘Renal impairment’ stated: ‘In patients with mild or moderate renal impairment, the following recommendations apply: for the prevention of stroke and systemic embolism in patients with NVAF and serum creatinine ≥1.5 mg/dL (133 micromole/L) associated with age ≥80 years or body weight ≤60 kg, a dose reduction is necessary and described above. In the absence of other criteria for dose reduction (age, body weight), no dose adjustment is necessary (see section 5.2)’.

In the Panel’s view, the table at issue which stated that no dosage adjustment for Eliquis was required in NVAF patients with normal renal function or mild or moderate renal impairment would be read in conjunction with the prominent headline claim ‘Eliquis is the only factor Xa inhibitor that does not require a dose adjustment in patients with NVAF who have mild or moderate renal impairment’ and implied that no dosage adjustment for Eliquis was needed in all NVAF patients with mild to moderate renal impairment which was not so.

The Panel considered the immediate impression of the table to a busy health professional was misleading. The footnote in very small font at the very bottom of the page in question, and the data and licensed dosing requirements for Eliquis in the overarching NVAF patient population on a separate page of the leavepiece were wholly insufficient to qualify the misleading impression given about Eliquis dosing in NVAF patients with normal renal function and mild or moderate renal impairment. A breach of the Code was ruled.

The Panel considered that the dosing information within the table and associated headline claim did not accurately reflect the dosage recommendations in the Eliquis SPC for NVAF patients with normal renal function or mild and moderate renal impairment. A breach of the Code was ruled.

With regard to the allegation that the page in question was designed to give an unfair advantage over competitor medicines, the Panel noted that the table at issue stated that no dose adjustment was required in NVAF patients with normal renal function or mild renal impairment for any of the four NOACs.

The Panel noted that for moderate renal impairment low dose was recommended for rivaroxaban and edoxaban. No dose adjustment was stated for Eliquis which was highlighted green, whereas no dose adjustment for dabigatran was highlighted orange and further stated below ‘(Consider 100mg BD in patients with high bleeding risk)’.

The Panel noted that rivaroxaban was the only NOAC that did not have an asterisk next to the no dosage adjustment statement within the table. It considered the explanations for the various asterisks.

The Panel noted that other than for rivaroxaban, each reference to no dose adjustment within the table was similarly misleadingly qualified by a footnote. The Panel noted, however, that the table and headline misleadingly implied that Eliquis was the only NOAC for which no dose adjustment was required in NVAF patients with moderate renal impairment, which was not so; a dosage reduction for Eliquis was recommended in certain NVAF patients with moderate renal impairment as noted above. Noting its comments above the Panel considered that the comparison was misleading, and a breach of the Code was ruled.

The Panel considered that the Alliance had failed to maintain high standards and a breach of the Code was ruled. Upon appeal by the Alliance, the Appeal Board noted that some busy health professionals might read the page at issue without necessarily reading the leavepiece as intended by the Alliance. When viewed in isolation the table and page at issue were insufficient for a health professional to make an appropriate prescribing decision. The Appeal Board considered that there had been a failure to maintain high standards and it upheld the Panel’s ruling.

The Panel noted the complainant’s concern about the potential for increased bleeding risk or stroke in inappropriately dosed patients. The Panel considered that patient safety was of the utmost importance and the Alliance’s failure in this regard brought discredit upon, and reduced confidence in, the pharmaceutical industry. A breach of Clause 2 was ruled which was upheld on appeal by the Alliance.