AUTH/3256/10/19 - Anonymous v Novartis

Promotion of Kisqali

  • Received
    08 October 2019
  • Case number
    AUTH/3256/10/19
  • Applicable Code year
    2019
  • Completed
    04 August 2020
  • No breach Clause(s)
  • Breach Clause(s)
  • Sanctions applied
    Undertaking received
  • Additional sanctions
  • Appeal
    Appeal by respondent

Case Summary

An anonymous individual, who described him/herself as a health professional, complained about a promotional leaflet (ref KIS19-CO25a) for Kisqali (ribociclib succinate) dated June 2019 issued by Novartis Pharmaceuticals UK Ltd. The complainant stated that the leaflet was provided at a conference for breast cancer.

Kisqali was indicated for the treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer in combination with an aromatase inhibitor or fulvestrant as initial endocrine-based therapy, or in women who had received prior endocrine therapy.

The complainant alleged that the leaflet was misleading, inaccurate and implied off-label use. The leaflet and campaign language was not responsible to patient care. In addition to the general comments, the complainant provided further information with regard to various parts of the leaflet which were considered as follows.

The detailed response from Novartis is given below.

1 Claim ‘First-line Kisqali. The difference for patients is survival’

The complainant noted that whilst Kisqali had an indication for initial endocrine-based therapy, the overall survival data referenced was only for first-line in combination with an aromatase inhibitor in endocrine-sensitive patients. There was a separate cohort of first-line advanced breast cancer patients who were endocrine resistant (ie recurred on adjuvant therapy) who would not receive aromatase inhibitor-based therapy but a fulvestrant-based therapy instead, which was not included in this data set. The complainant alleged that the claim was misleading in intent.

In the Panel’s view, first-line Kisqali, as referred to within the leaflet, could be seen as the use of Kisqali with either an aromatase inhibitor or fulvestrant as according to the Kisqali SPC each combination was indicated for initial endocrine-based therapy for the treatment of advanced breast cancer. The implication to readers might be that the overall survival data referred to within the leaflet applied to Kisqali in both combinations ie with either an aromatase inhibitor or fulvestrant which was not so.

The Panel noted that the leaflet at issue focussed on the results of a protocol-specified interim analysis of the key secondary endpoint of overall survival of the MONALEESA-7 trial data (Im et al). It noted Novartis’ submission about the patients enrolled in the MONALEESA-7 trial. Patients received Kisqali and endocrine therapy, (goserelin plus either tamoxifen or a non-steroidal aromatase inhibitor); no patient received fulvestrant as a combination partner.

The Panel noted that there was no clear statement in the leaflet that the data related only to the first-line combination of Kisqali and an aromatase inhibitor and not fulvestrant and considered that this was misleading and, in relation to fulvestrant, was not capable of substantiation. The Panel therefore ruled breaches of the Code.

2 Claim ‘Kisqali is the only CDK4/6 inhibitor to demonstrate significant overall survival benefit from a first-line phase III trial in a placebo-controlled trial of premenopausal women in combination with endocrine treatment as initial therapy’.

This claim appeared in a prominent orange band across the leaflet and the second half of the claim appeared in smaller type size than the first half. Below the band was a footnote ‘Kisqali is not recommended to be used in combination with tamoxifen’.

The complainant alleged that due to the explanation at Point 1 above, ‘the only’ was not true because another CDK4/6 inhibitor had overall survival data in first-line endocrine resistant patients (in combination with fulvestrant, rather than an aromatase inhibitor). The complainant alleged that the claim was not factually accurate.

The complainant added that ‘endocrine treatment’ implied either aromatase inhibitor or fulvestrant, as these were the only two endocrine treatments listed in the Kisqali marketing authorization. However, the study did not include the fulvestrant combination, and instead included aromatase inhibitor or tamoxifen. The tamoxifen combination was not within Kisqali’s marketing authorization. The complainant alleged that the claim was misleading and promoted off-licence use.

The Panel noted that the complainant did not identify the other CDK4/6 inhibitor or the study to which he/she referred to with regard to overall survival data in combination with fulvestrant. Novartis identified the CDK4/6 inhibitor with statistically significant overall survival data, as abemaciclib and the study as MONARCH 2 (Sledge et al 2019).

The Panel noted that like Kisqali, abemaciclib (Verzenios) was indicated for the treatment of women with hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative locally advanced or metastatic breast cancer in combination with an aromatase inhibitor or fulvestrant as initial endocrine-based therapy, or in women who had received prior endocrine therapy.

The Panel noted that MONARCH 2 (Sledge et al 2019) was a double-blind, placebo-controlled phase III study of abemaciclib plus fulvestrant vs placebo plus fulvestrant in women with HR-positive, ERBB2 (formerly HER2)-negative advanced breast cancer who progressed during prior endocrine therapy. This included women who progressed during neoadjuvant or adjuvant endocrine therapy, within 12 months after adjuvant endocrine therapy, or whilst receiving first-line endocrine therapy for advanced breast cancer. The latter did not appear to be the subject of a subgroup analysis.

The Panel noted Novartis’ submission with regard to the definition of primary and secondary endocrine resistance and what was meant by first-line and second-line treatment and that the MONARCH 2 population was a second-line population. It appeared to the Panel, however, that patients studied in MONARCH 2 were a mixture of first-line and second-line population in relation to advanced breast cancer. Outcome survival data for the first line patients did not appear to have been reported separately. MONARCH 2 was on pre-, peri- and post-menopausal women and again the first-line population data for pre- and peri-menopausal patients did not appear to have been reported separately.

The Panel did not consider that the complainant had provided evidence to show that the claim that Kisqali was the only CDK4/6 inhibitor to demonstrate significant overall survival benefit from a first-line phase III trial in a placebo-controlled trial of pre-menopausal women in combination with endocrine treatment as initial therapy was misleading or incapable of substantiation. The Panel therefore ruled no breaches of the Code.

The Panel noted that there was no clear statement in the leaflet that the claims referred to were only in relation to Kisqali in combination with an aromatase inhibitor and not in combination with tamoxifen. In the Panel’s view, there was, therefore, an implication that the data also referred to the combination with tamoxifen which was misleading and a breach of the Code was ruled.

Section 4.4 of the Kisqali SPC referred to QT interval prolongation results from MONALEESA-7 and included the statement that ‘Kisqali is not recommended to be used in combination with tamoxifen (see sections 4.8 and 5.1’. There was a similar reference in Section 4.5. This meant that some of the data in MONALEESA-7 would not be in line with the Kisqali summary of product characteristics. The SPC included details about MONALEESA-7 and its results in Section 5.1.

The Panel noted that there was a difference between using data from a study, which included licensed and unlicensed doses to substantiate a specific, within licence claim, and general use for promotional purposes of a study that used licensed and unlicensed doses. The Panel did not consider that the reference to the overall MONALEESA-7 data which included the use of a combination that was inconsistent with the particulars listed in the Kisqali SPC necessarily meant that there had been a breach of the Code. The data referred to in the leaflet was that covered by the indication for Kisqali. There were no specific claims for the results with tamoxifen and the leaflet clearly stated that Kisqali was not recommended to be used in combination with tamoxifen. Whilst noting its ruling above that the leaflet could have been clearer that the claims within it were only in relation to Kisqali in combination with an aromatase inhibitor, the Panel did not consider that, taking all the circumstances into account, the leaflet was inconsistent with the SPC and thus ruled no breach of the Code.

3 Claim ‘Kisqali is not recommended to be used in combination with tamoxifen’

The complainant noted that generally in the UK, ‘recommended’ was used to imply reimbursement (as the National Institute for health and Care Excellence (NICE) and the Scottish Medicines Consortium (SMC) used ‘recommended’ in technology appraisal documents to indicate a positive statement). The complainant noted, however, that not only did Kisqali not have reimbursement for use with tamoxifen, it did not have a marketing authorization to be used with tamoxifen. The complainant alleged that the claim was misleading and promoted off-licence use.

The Panel considered that the important point was that Kisqail was not recommended to be used with tamoxifen. It did not consider that the audience would interpret this statement in relation to reimbursement. The Panel did not consider that the statement, in itself, meant that the leaflet promoted Kisqali in a manner that was inconsistent with the SPC. No breach of the Code was ruled based on the narrow allegation.

4 Statement ‘[Overall survival] Data from MONALEESA – 2 and MONALEESA – 3 phase III trials in postmenopausal women with HR+/HER2 – advanced breast cancer are not available yet’

This statement appeared as a footnote to the claim considered at Point 2 above.