AUTH/3227/7/19 - Ferring v Pharmasure

Promotion of Meriofert

  • Received
    19 July 2019
  • Case number
    AUTH/3227/7/19
  • Applicable Code year
    2019
  • Completed
    18 June 2020
  • No breach Clause(s)
  • Breach Clause(s)
  • Sanctions applied
    Undertaking received
  • Additional sanctions
  • Appeal
    No appeal

Case Summary

Ferring Pharmaceuticals Ltd complained about a Meriofert (menotrophin) detail aid issued by Pharmasure Limited. Meriofert was used to induce ovulation in women undergoing in vitro fertilization (IVF). Ferring marketed Menopur (menotrophin for injection) which was similarly used in fertility treatment.

Ferring’s concerns related to ‘urinary gonadotrophins’ which were essential in IVF treatment. Gonadotrophins were a class of hormones which included follicle stimulating hormone (FSH), luteinising hormone (LH) and human chorionic gonadotrophin (hCG). Gonadotrophins were manufactured either from the urine of postmenopausal or pregnant women or through recombinant technology and used for controlled ovarian stimulation, a technique used in IVF to stimulate the ovaries to produce multiple ovarian follicles. The goal was to harvest an optimal number of eggs from the woman's ovaries to maximize the chances that the eggs could be fertilized in vitro, and that an embryo could be implanted back into the uterus and develop into a healthy baby.

In a typical healthy pregnancy, hCG was secreted by cells from the placenta of the implanting conceptus from week 2, supporting the ovarian corpus luteum, which in turn supported the endometrial lining and therefore maintained pregnancy. In postmenopausal women, hCG was secreted from the pituitary gland. Whether secreted from the placenta or the pituitary gland, hCG was excreted in the urine.

Meriofert and Menopur were both urinary gonadotrophins (human menopausal gonadotrophin, hMG) containing menotrophin, which was extracted from the urine of postmenopausal women (for Menopur) and also from pregnant women (for Meriofert). Menotrophin consisted of FSH, LH and hCG components, providing FSH and LH hormone activity in a 1:1 ratio. The LH activity was provided by the hCG hormone component.

Menopur received a marketing authorization in 1999 and the marketing authorization for Meriofert was obtained in 2014 using its similarity to published Menopur data. The Public Assessment Report clearly stated ‘Overall, the Applicant has provided data to support that hMG-IBSA (Meriofert) is no different from the active comparator Menopur in any way that could lead to differences in efficacy between the two products’.

Ferring alleged that Pharmasure had attempted to differentiate its product Meriofert, on the grounds that it contained a high concentration of placental hCG, implying that this difference led to clinical differentiation in terms of better efficacy and efficiency. Ferring objected to Pharmasure’s claims that Meriofert was superior to Menopur substantiated by Lockwood et al (2017) and Alviggi et al (2013).

Lockwood et al was a non-inferiority study. The primary endpoint was to show the non-inferiority of Meriofert to Menopur in respect of the primary endpoint – total number of oocytes retrieved.

Ferring submitted that when there was one primary endpoint, findings of secondary outcomes were considered subsidiary and exploratory, rather than confirmatory, so no claims could be made on these secondary endpoints, unless the statistical analysis was predefined to proceed hierarchically or adjusted for multiplicity. No such plan was stated in Lockwood et al, although the promotional material at issue contained a number of claims based on secondary endpoints.

Alviggi et al was also a non-inferiority study, where the primary endpoint was the total number of oocytes retrieved. Again, for the secondary endpoints the statistical analysis was not predefined to proceed hierarchically or adjusted for multiplicity. It was thus misleading to imply statistically significant differences for secondary endpoints between the comparators based on this study. Ferring noted a number of limitations with regard to Alviggi et al which restricted the citation of the study for substantiation of promotional claims.

The detailed response from Pharmasure is given below.

1 Claim ‘Higher mature oocyte yield than Menopur’

The first claim on page 2 of the detail aid read, ‘The aim of ovarian stimulation in IVF is to produce an optimum number of mature oocytes and embryos available for transfer’, followed by the brand name (Meriofert) above two bullet points:

• Contains predominantly placental hCG
• Higher mature oocyte yield than Menopur.

Ferring alleged that the clear aim was to imply that Meriofert could produce a higher oocyte yield than Menopur, and therefore that Menopur was less effective than Meriofert. Ferring alleged that the claim was misleading and could not be substantiated.

Ferring noted that the claim in question was referenced to Lockwood et al. However, maturity of the oocytes was not a primary endpoint in that study. The primary endpoint was to show the non-inferiority of Meriofert to Menopur in respect of the total number of oocytes retrieved and the study was powered to demonstrate non-inferiority. Further, there was no indication of the amount of placental hCG present in Meriofert; and no indication of the amount of placental hCG that might be of clinical relevance in oocyte production.

Ferring further noted that Lockwood et al under-dosed Menopur compared with the UK licence and although the study design was included in small print beneath the bullet points, case precedent was clear that misleading claims could not be corrected by footnotes.

The Panel noted that the first claim on page 2 ‘The aim of ovarian stimulation in IVF is to produce an optimum number of mature oocytes and embryos available for transfer’ and the second bullet point below this (the claim in question) were both referenced to Lockwood et al. The Panel noted that Lockwood et al was powered as a non-inferiority study, to confirm the non-inferiority of Meriofert compared with Menopur with regard to clinical outcome (the primary end point being the total number of oocytes retrieved).

The Panel noted that in general terms non-inferiority trials demonstrated that a test product was no worse than a comparator by more than a pre-specified, small amount.

It was unclear to the Panel whether the secondary end points had been clearly pre-specified within Lockwood et al in the study design section, however, it appeared from the results and discussion section that the study authors considered the secondary endpoints were powered to show significance; the authors did not mention any limitations to the contrary.

The Panel considered that the presentation of positive secondary endpoint data (without reference to the primary endpoint) in a non-inferiority trial was not necessarily unacceptable so long as such references complied with the Code and were not otherwise misleading. In the Panel’s view, page 2 of the leavepiece implied that Meriofert was more efficacious than Menopur, it referred to the inclusion of predominantly placental hCG and a higher mature oocyte yield thereby satisfying the aim of ovarian stimulation as described in the statement which introduced the page ‘The aim of ovarian stimulation in IVF is to produce an optimum number of mature oocytes and embryos available for transfer’. The Panel was concerned that the impression of clinical superiority given by the page was inconsistent with Lockwood et al which concluded that Meriofert was non-inferior to Menopur in terms of its primary endpoint, the total number of oocytes retrieved. The Panel further noted that Lockwood et al found that no statistically significant differences between Meriofert and Menopur were reported for most of the clinically significant end-points including embryo quality, fertilization rate, implementation rate, ongoing pregnancy rate and live birth rate and noted the author’s views that IVF efficacy corelated with the number of fertilized oocytes obtained.

The Panel further noted that according to the companies Lockwood et al was designed in such a way that Menopur treatment was stopped earlier than recommended in its SPC. According to both companies the Menopur SPC recommended that there should be at least 3 follicles greater than 17mm in diameter with 17 beta-oestradiol levels of at least 3500pmol/L (920 picograms/ml); Human chorionic gonadotrophin should not be administered if these criteria have not been met, whereas Lockwood et al was designed in a way that daily gonadotrophin administration was continued until at least two follicles had a mean diameter greater than 16mm, serum oestradiol levels greater than 400pg/ml (or 1500pmol/l), or both.

The Panel queried whether the number of oocytes or MII (mature) oocytes retrieved for Menopur would have been different had the recommendation as referred to by both companies been followed. The Panel noted that although it was stated in small font in a footnote at the bottom of the page that the study was a non-inferiority study designed in such a way that it was not in line with the recommendation in the Menopur SPC, it noted the advice contained in the supplementary information to the Code that claims should be able to stand alone and in general should not be qualified by footnotes and the like.

The Panel noted its comments above and considered that given the unambiguous nature of the comparative claim in question ‘Higher mature oocyte yield than Menopur’ within the context of the page and its overall implication of clinical superiority, the reader was not provided with sufficient information to properly assess the claim and form his/her own opinion of the therapeutic value of Meriofert vs Menopur. The Panel noted its comments above and considered that the claim in question within the overall implication of the page in question was misleading and not capable of substantiation; breaches of the Code were ruled.

2 Claim ‘Contains predominantly placental hCG’

This claim appeared as a bullet point on page 2 of the detail aid as described above.

In Ferring’s view, the secondary aim of page 2 was to imply that the type of hCG within Meriofert had a direct impact on the production of oocytes and embryos available for transfer. Ferring alleged that the claim that Meriofert ‘Contains predominantly placental hCG’ was misleading as it implied some special merit to placental hCG and also that Menopur was therefore somehow inferior to Meriofert.

Ferring stated that there was no indication of the amount of placental hCG present in Meriofert; and no indication of the amount of placental hCG that might be of clinical relevance in oocyte production. The layout of the page meant that the claim ‘Contains predominantly placental hCG’ implied that placental hCG had an impact on oocyte production. Ferring alleged that this could not be substantiated. The Panel noted that the claim ‘Contains predominantly placental hCG’ was referenced to the Meriofert SPC, IBSA data on file (hCG content) and Birken et al.

The Panel disagreed with Pharmasure’s submission that it had not claimed or implied any clinical benefit regarding the difference in the type of hCG present in Meriofert or that the type of hCG had a direct impact on the production of oocytes and embryos available for transfer. Pharmasure stated that it had summarised the two key differences on page 2 but had not linked them. The Panel noted that the claim in question was the first bullet point below the more prominent and first claim on the page ‘The aim of ovarian stimulation in IVF is to produce an optimum number of mature oocytes and embryos available for transfer’ and above the second bullet point which read ‘Higher mature oocyte yield than Menopur’. In the Panel’s view, the claim in question would be read in light of what the Panel considered to be the headline claim and the claim below and thus would be considered to result in a clinical benefit in relation the production of mature oocytes and embryos available for transfer. In the Panel’s view, readers would assume that there was a clinical benefit unless clearly told otherwise.

In the Panel’s view, the reader was not provided with sufficient information to properly assess the claim ‘Contains predominantly placental hCG’ and form his/her own opinion of its therapeutic impact. The claim in question, as it appeared within the context of the page and its overall implication of clinical superiority was therefore misleading and could not be substantiated and breaches of the Code were ruled.

3 Page 3 featured a table which compared the oligosaccharide composition, relative amount (%), of Fostimon (urofollitropin), Puregon (follitropin beta) and Gonal-F (follitropin alfa). The table was adapted from Lombardi et al (2013).

Ferring alleged that the page purported to show that study results for Fostimon were somehow transferable to Meriofert. However, the active ingredient in Meriofert was menotrophin (a combination of FSH and LH in a 1:1 ratio), whereas the active ingredient in Fostimon was urofollitropin (FSH); to claim similarity between the two was misleading. There was no data or evidence provided to demonstrate any similarity between Meriofert and Fostimon in terms of composition, acidic FSH, sialylated and branched carbohydrate moieties.

The Panel noted that page 3 of the leavepiece was headed ‘Meriofert Acidic FSH’ and below it was stated that ‘Meriofert, like Fostimon (urofollitropin) contains acidic FSH’. The page went on to describe a study that compared Fostimon with Puregon and Gonal-F and which demonstrated the prevalence in Fostimon of more acidic isoforms, which corresponded to species containing more sialylated and branched carbohydrate moieties. The Panel noted Pharmasure’s submission that the table was included as a comparison against recombinant products such as follitropin alpha and follitropin beta and not Menopur.

The Panel noted Pharmasure’s submission that the FSH in both Meriofert and Fostimon was extracted from the same source of postmenopausal urine using similar techniques, and in addition Meriofert had LH activity (by way of hCG) added. The Panel noted that it was not clear from the page at issue that Fostimon contained only FSH whereas Meriofert contained both FSH and LH activities.

It was not clear from the page what the differences in the table meant in terms of clinical relevance; the Panel noted Pharmasure’s submission that no definitive clinical outcome was claimed but rather an important product characteristic had been presented.

The Panel noted Pharmasure’s submission that the biological nature of these products including differences in extraction, raw material used and purification techniques might all have an impact on why one performed differently to another. This was why Pharmasure considered it was essential to provide a context that informed clinicians of the nature of these products and that each active was not a single molecule but a family of differently glycosylated or sulphated molecules, each variant having differences in biological activity and clearance rate. In this regard the Panel noted that Ferring had provided a comparative evaluation of the quality characteristics of FSH contained in Fostimon vs Meriofert. The evaluation concluded that the characteristics of FSH contained in Fostimon and Meriofert were similar. The authors stated that the result was expected since the purification process was very similar.

The Panel noted that whilst it was clear that the page discussed Meriofert and acidic FSH, it was not clear that Meriofert contained both FSH and LH activities whilst Fostimon contained only FSH as alleged, and the implication that the results of Lombardi et al in relation to the structure of the isoforms and corresponding moieties would equally apply without any qualification to both products meant that the reader was not provided with sufficient information to properly assess the information and form his/her own opinion of its therapeutic impact. A breach of the Code was ruled.

4 Claim ‘LH activity in Meriofert is predominantly from placental hCG which is mainly comprised of glycosylated hCG’ and the associated graphic.

The claim was at the top of page 4 and Ferring noted that the page focussed on the source and activity of LH and attempted to imply that the source of hCG to provide LH bioactivity in Meriofert and Menopur somehow conferred a clinical relevance and an advantage for Meriofert.

Ferring noted that the headline claim appeared immediately above a graphical representation of the source of LH activity for Meriofert and Menopur, below which a table compared sulphate content of pituitary and placental hCG subunits; then further bullet points about placental vs pituitary hCG. The graphic compared LH activity and source (pregnancy urine and menopausal urine for Meriofert and menopausal urine only for Menopur).

Ferring alleged that the combined effect of the headline statement and the graphic implied that Menopur was inferior to Meriofert which was not so.

Ferring alleged that the graphic itself was also misleading because it implied that Menopur was inferior to Meriofert which was not so.

There was no indication of the amount of placental hCG present in Meriofert; and no indication of the amount of placental hCG that might be clinically relevant. The graphic showed that the LH activity for Meriofert was from pregnancy urine, but the relevance of this was not clear; nor was the relationship between pregnancy urine and placental hCG. In the context of the text ‘LH activity in Meriofert is predominantly from placental hCG’, the reader was not given information to understand any relevance to the data.

The Panel noted that the graphical representation of the source of LH activity for Meriofert and Menopur appeared below the claim ‘LH activity in Meriofert is predominantly from placental hCG which is mainly comprised of glycosylated hCG’. Below the graphic it stated ‘Menopur is derived from menopausal urine which contains mainly pituitary hCG’ followed by a table which compared the sulphate content of pituitary and placental hCG subunits which was referenced to Birken et al. Below this were three bullet points beneath the heading ‘Placental hCG vs pituitary hCG’: in vivo clearance is lower (longer half-life: placental hCG 36h, pituitary hCG 20h, LH 26 minutes); in vitro biological activity is higher and receptor binding affinity is higher. The first bullet point was referenced to Birken et al and Cole et al, whereas the second and third bullet points were only referenced to Birken et al.

The Panel noted that the graphic in question showed the pregnancy urine for Meriofert LH activity in red. All other components for FSH and LH activity including Meriofert menopausal urine for LH activity were coloured blue. In the Panel’s view, the reader’s eye was likely to link the red graphic for pregnancy urine with the three red bullet points at the bottom of the page the claims adjacent to which favourably compared placental hCG with pituitary hCG. This point had not been raised by Ferring. The Panel noted that the allegation in relation to the graphic appeared to be that it, as a stand alone matter, was in breach of the Code as the amount and clinically relevant amount of pregnancy urine was unclear, the relevance of this was not clear; nor was the relationship between pregnancy urine and placental hCG. In the context of the text ‘LH activity in Meriofert is predominantly from placental hCG’, the reader was not given information to understand any relevance to the data. The Panel did not consider that the reader would consider the graphic in isolation from the rest of the page nonetheless that was the allegation before it. The Panel did not consider that the graphical representation of the source of LH activity for Meriofert and Menopur, when considered in isolation, misleadingly implied that Menopur was inferior to Meriofert as alleged. Whilst pregnancy urine was highlighted in red, the graphic in isolation made no claim based on this difference. In the Panel’s view, Ferring had not established, on the balance of probabilities, that the graphic in isolation, including the amount of placental hCG present in Meriofert depicted, was misleading. No breach of the Code was ruled based on the very narrow allegation.

The Panel noted that Ferring also referred to the three bullet points at the bottom of the page described above and alleged that page 4 implied that the source of hCG to provide LH bioactivity in Meriofert and Menopur somehow conferred a clinical relevance and an advantage for Meriofert. The Panel noted that the three bullets were in the same red colour as the pregnancy urine depicted in the graphical representation of the source of LH activity for Meriofert and Menopur and thereby implied that the lower in vivo clearance (longer half-life: placental hCG 36h, pituitary hCG 20h, LH 26min) the higher in vitro biological activity, and the higher receptor binding affinity of placental hCG vs pituitary hCG referred to in the bullet points was due to the source of hCG and the tertiary structure of placental vs pituitary hCG . The Panel noted Ferring’s submission that the tertiary structure of hCG isoforms (how glycosylated they were) had a direct bearing on the half-life of the molecule and activity at the receptor. Each active was not a single molecule but a family of differently glycosylated or sulphated molecules, each variant having differences in biological activity and clearance rate.

The Panel noted that whilst the table and bullet points were referenced to a second Birken et al study, ‘Metabolism of hCG and hLH to multiple urinary forms’, there was no direct reference to their content within that study. The Panel noted that the original Birken et al study, ‘Isolation and Characterization of Human Pituitary Chorionic Gonadotrophin’ stated that the presence of sulphate on pituitary hCG might play a role in its reduced in vitro biological activity but that this was not clear with regard to earlier studies of Baenziger. The sulphate content of pituitary hCG would be expected to lead to a rapid clearance in vivo by a liver receptor specific for the sulphate-4-GalNAc-GlcNAc-M structure.

The Panel further noted that the first Birken et al study isolated and characterised human pituitary hCG by analysing hCG content from pituitary glands and compared it with hCG purified from the urine of pregnant woman. The study undertook a series of analyses for sulphate and included the original table in question. The second Birken et al study stated that since many of the molecular forms of the two hormones (hCG and hLH) in urine differed from their forms in blood, it might be necessary to produce new immunoassays as well as novel urinary reference preparations to accurately measure these molecules within their urinary matrix.

The Panel noted that according to the first Birken study there were some differences between placental hCG vs pituitary hCG. The Panel noted its comments above and considered that the overall implication of page 4 was that Menopur was inferior to Meriofert based on its LH activity being predominantly from placental hCG which was mainly comprised of glycosylated hCG and its low sulphate content. The Panel noted that it appeared that the bullet points on page 4 had been referenced to the incorrect Birken et al study and, in the Panel’s view, the reader should have been provided with details of the original Birken et al study. The Panel noted its comments at point 1 above about Lockwood et al and non-inferiority. Further information should have been provided to enable the reader to properly assess the information on page 4 including in relation to the claim ‘Menopur is derived from menopausal urine which contains mainly pituitary hCG’ and form his/her own opinion of the relative clinical value of Meriofert compared with Menopur. The Panel noted its comments above and ruled a breach of the Code.

5 Table: Comparative sulphate content of pituitary and placental hCG subunits

This table appeared on page 4 and was referenced to Birken et al (1996).

Ferring alleged that the table of data was misleading. Birken et al analysed hCG content from pituitary glands and not from urine. As Meriofert contained hCG derived from the urine of postmenopausal and pregnant women, the data for sulphate content from Birken et al could not be extrapolated to Meriofert. Even Birken et al explained that many of the molecular forms of hCG in urine differed from their forms in blood. As far as Ferring knew, there was no evidence to show that data from pituitary extract could be extrapolated to products containing urinary human menopausal gonadotropins (hMG).

Ferring also noted that the table was incorrectly referenced to Birken et al, ‘Metabolism of hCG and hLH to multiple urinary forms’, however, this was only a secondary reference and the original data and table was from another Birken et al paper, ‘Isolation and Characterization of Human Pituitary Chorionic Gonadotrophin’, also published in 1996. Ferring also noted that the descriptions beneath the heading ‘protein’ had been altered and were not the same as in the original article.

The Panel did not consider that it was necessarily unacceptable to use data from the second Birken et al publication and reference it to that publication rather than the original provided the way in which it was used complied with the Code.

The first Birken study, ‘Isolation and Characterization of Human Pituitary Chorionic Gonadotrophin’, isolated and characterised human pituitary hCG by analysing hCG content from pituitary glands and compared it with hCG purified from the urine of pregnant woman.

The second Birken study was entitled ‘Metabolism of hCG and hLH to multiple urinary forms’. The table as reproduced in the detail aid was present in both studies. The second Birken study stated that the table in question was reproduced from the first Birken study.

The Panel noted that the table in both Birken studies referred to pituitary hCGᾱ and hCGꞵ and urinary hCGᾱ and hCGꞵ, whereas the detail aid referred to pituitary hCGᾱ and hCGꞵ and placental hCGᾱ and hCGꞵ. The Panel noted Pharmasure’s submission that purified hCG from pregnant women’s urine was also called placental hCG. The first Birken et al trial stated that the hCG excreted by pregnant woman into urine was designated urinary hCG in the report, and thus it appeared to the Panel that the urinary hCGᾱ and hCGꞵ referred to in the table was from the urine of pregnant women.

In the Panel’s view, whilst the table appeared in both Birken studies, the reader would need to look at the original study, ‘Isolation and Characterization of Human Pituitary Chorionic Gonadotrophin’, in order to fully understand the implication of the table at issue. The Panel considered that it was therefore misleading not to reference the first Birken study in this regard and a breach of the Code was ruled.

The Panel did not accept Pharmasure’s submission that it had ‘not extrapolated the Birken et al data to apply to Meriofert’. The table appeared prominently on a page headed ‘Meriofert LH Activity from Placental hCG’ which then referred to Meriofert and placental hCG, illustrating the proportion of LH activity derived from pregnancy urine. The table then presented data for placental hCG. It was difficult to understand how the table including placental hCG could be viewed in isolation from the claims for Meriofert on the page. In the Panel’s view, a reader would relate the data to Meriofert.

The Panel noted Ferring’s submission that Birken et al analysed hCG content from pituitary glands and not from urine and as Meriofert contained hCG derived from the urine of postmenopausal and pregnant women, the data for sulphate content from Birken et al could not be extrapolated to Meriofert as had been done in the detail aid. Pharmasure stated that it had used Birken et al to illustrate the difference between placental and pituitary hCG, which was one way in which Meriofert and Menopur were different and that it was clear from Birken et al that a pituitary form of hCG, which was sulphated, was in postmenopausal women’s urine.

The Panel further noted that the second Birken et al study stated that since many of the molecular forms of the two hormones (hCG and hLH) in urine differed from their forms in blood, it might be necessary to produce new immunoassays as well as novel urinary reference preparations to accurately measure these molecules within their urinary matrix.

The Panel noted that it was not clear that the data within the table on page 4 of the leavepiece was from the second Birken et al study rather than the original and referred to hCG content isolated from pituitary glands rather than from urine. In the Panel’s view, the reader did not have sufficient information to form his/her own opinion of the relevance of the data which was misleading and a breach of the Code was ruled.

6 Claim ‘On average for each patient TWO more mature oocytes were retrieved and ONE more cleaved embryo on day 2 was observed during a shorter period of stimulation in the Meriofert group’

This was the main claim on page 5 which was headed ‘Meriofert High Ovarian Yield’.

Ferring alleged that the claim, which was referenced to Lockwood et al, was misleading. Differences in oocyte maturity, embryo cleavage or duration of stimulation were not primary endpoints of the study. To imply a clinically meaningful difference was therefore misleading, especially in the context of the capitalised ‘TWO’ and ‘ONE’. The statistical analysis was not planned to proceed hierarchically or adjusted for multiplicity, therefore it was misleading to refer to secondary endpoints and attempt to imply clinical differences.

Ferring alleged that to imply clinical differences between Meriofert and a dose of Menopur which was less than that licensed in the UK was misleading. Lockwood et al prematurely discontinued the administration of Menopur compared with the licensed Menopur dose – thus patients were triggered earlier than recommended in the Menopur SPC which stated ‘It is recommended there should be at least 3 follicles greater than 17mm in diameter with 17 beta-oestradiol levels of at least 3500pmol/L (920picograms/ml; Human chorionic gonadotrophin should not be administered if these criteria have not been met’.

Ferring noted that the Menopur SPC was mentioned in the small print at the foot of the page, however, case precedent had clearly established that misleading claims could not be corrected by a footnote.

The Panel considered that its comments at Point 1 above were relevant. Page 5 of the leavepiece implied that Meriofert was more efficacious than Menopur based on the higher mature oocytes retrieved and the number of cleaved embryos on day 2 as well as the total oocytes retrieved and inseminated injected oocytes and the duration of stimulation. The page did not state that Lockwood et al concluded that Meriofert was non-inferior to Menopur in terms of clinical efficacy or the author’s views that IVF efficacy corelated with the number of fertilized oocytes obtained and no statistically significant differences between Meriofert and Menopur were reported for most of the clinically significant endpoints including embryo quality, fertilization rate, implementation rate, ongoing pregnancy rate and live birth rate.

The Panel further noted that according to both companies Lockwood et al was designed in such a way that Menopur was stopped earlier than recommended in its SPC. The Panel queried whether the number of oocytes or MII (mature) oocytes retrieved for Menopur would have been different had the recommendation as referred to by both companies had been followed.

The Panel noted that the trial design of Lockwood et al appeared at the top of the page and it was stated in small font in a footnote at the bottom of the page the recommendation in the Menopur SPC as referred to by both companies. The Panel noted, however, that unlike the footnote on page 2, the footnote on page 5 did not specifically state that the study had been designed in such a way that the Menopur SPC recommendation as referred to by both companies was not followed.

The Panel considered that the reader was not provided with sufficient information to properly assess the claim and form his/her own opinion of the therapeutic value of Meriofert vs Menopur. The Panel noted its comments above and considered that the claim in question was misleading and a breach of the Code was ruled.

7 Claim ‘Efficiency of (Meriofert) appears to be higher due to reduced quantity of drug used and the higher yield of mature oocytes retrieved’

This claim, referenced to Alviggi et al, appeared on page 6, beneath a figure which compared results of the primary endpoint (mean number of total collected oocytes) and secondary endpoints (ratio of MII/total oocytes retrieved, controlled ovarian stimulation (COS) duration, total HMG units) using Menopur and Meriofert. The page was titled Meriofert High Efficiency followed by a description of the study design and a claim in the largest blue font on the page that ‘7% more mature oocytes were obtained with 14% less gonadotrophin being administered during a shorter period of stimulation in the Meriofert group’.

Ferring alleged that the claim was misleading. Alviggi et al was a non-inferiority study for the primary endpoint of total number of oocytes retrieved, with no statistical adjustment for hierarchical analysis or multiplicity on the depicted secondary endpoints (ratio metaphase II (MII) oocytes retrieved, controlled ovarian stimulation (COS) duration, total HMG units). Ferring reiterated that it was thus misleading to imply statistically significant differences between the comparators.

Ferring added that Alviggi et al stopped Menopur earlier than recommended in the SPC. This had clinical relevance because if the product was not used as per the SPC, the outcomes shown might not be those obtained in clinical practice and therefore they formed the basis of misleading claims.

The Panel noted that Alviggi et al was a prospective, randomised, investigator-blind, controlled non-inferiority clinical trial to evaluate the clinical efficacy and tolerability of a highly purified human menopausal gonadotrophin preparation (Merional-HG) and Menopur when administered to patients undergoing controlled ovarian stimulation (COS) for IVF procedure. The study authors stated that Merional-HG and Menopur were proven to be equally effective to achieve proper outcome of assisted reproductive technology (ART). In this regard, the Panel noted its understanding of a non-inferiority trial as referred to at Point 1 above.

The Panel noted that according to the authors Merional-HG appeared to be more efficient than Menopur in this setting as it allowed reducing drug consumption and might provide additional practical advantages in the management of ART procedures; not the higher yield of mature oocytes as implied by the page at issue.

The Panel further noted that Alviggi et al was designed in such a way that Menopur was stopped earlier than recommended in its SPC. The Panel queried whether the number of oocytes or MII (mature) oocytes retrieved for Menopur would have been different had the recommendation as referred to by both companies had been followed.

The Panel noted that although it was stated in small font in a footnote at the bottom of the page the recommendation in the Menopur SPC and the trial design of Alviggi et al appeared at the top of the page, unlike the footnote on page 2, it was unclear that the study design was such that the Menopur SPC recommendation as referred to by both companies was not followed. The Panel considered that the reader was not provided with sufficient information to properly assess the claim and form his/her own opinion of the therapeutic value of Meriofert vs Menopur. The Panel noted its comments above and considered that the claim in question was misleading and a breach of the Code was ruled.

8 Safety claim table on Page 7

Ferring noted that page 7 compared the safety of Meriofert and Menopur. The second table on page 7 depicted several adverse events including injection site pain, persistent redness, tenderness and itching. Ferring alleged that the table was misleading. Neither table had explanatory text to accompany the numbers.

Ferring submitted that the table showed the total number and percentage of specified adverse events. The information could easily be read as though Menopur had higher numbers than Meriofert and therefore had a worse adverse event profile, which was not so. The lack of p values on the table could be read as implying no statistically significant difference between the two products in terms of side-effects, however, this was also not the case as the table was selective in its presentation.

Ferring noted that the cited publication (Lockwood et al) was a non-inferiority study for total number of oocytes retrieved; it was not powered to show differences in adverse events. It was stated in the paper that ‘No difference was reported in the frequency of the adverse events with the exception of vascular disorders (hot flushes) that were reported more often in the Meriofert group (8.2% vs 1.5%, p=0.02)’. The paper therefore clearly showed no clinically relevant differences between the products except for hot flushes.
Ferring was particularly concerned that the important and clinically relevant adverse event of hot flushes, which was reported more frequently in the Meriofert group was omitted from the table, although a statement about hot flushes appeared beneath it. However, it did not state the numerical differences, as was done for the other stated adverse events in the table. The statement also appeared at the end of a paragraph that began ‘Meriofert has good tolerability’. Given that hot flushes were the only adverse event that was significantly different, this appeared to be a deliberate attempt to hide this information from the reader.

The Panel noted that below the table at issue it was stated that Meriofert had good tolerability and that cases of injection site pain were mainly mild and did not last after the time of injection followed by hot flushes were reported more frequently in the Meriofert group. The Panel noted that it was misleading to provide data showing the difference between Meriofert and Menopur with regards to injection site pain and persistent redness, tenderness and itching which implied that there was a difference without including the p number or stating that tolerability at the injection site was found to be very good in both groups as stated in Lockwood et al. The table did not give a clear, fair, balanced view of the data and breaches of the Code were ruled.

The Panel considered that it was misleading to state that hot flushes were reported more frequently in the Meriofert group without stating that there was a significant difference in the reporting of hot flushes (8.2% vs 1.5%, p = 0.02).

In the Panel’s view, the safety data was not adequately reflected in the leavepiece and a breach of the Code was ruled.