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AN ORGANISATION v PHARMACIA & UPJOHN
Detrusitol advertisement
An organisation submitted a complaint about an advertisement for Detrusitol issued by Pharmacia & Upjohn.
The complainant pointed out that the advertisement included claims such as "Freed by Detrusitol", "help free your patients from the restrictions of unstable bladder" and "Detrusitol effectively and selectivity relieves frequency, urgency and/or urge incontinence". The complainant alleged that such claims appeared to apply only to a small percentage of treated patients. Reference was made to a table of data in the summary of product characteristics (SPC). The complainant alleged that the advertisement was not strictly accurate, nor balanced nor fair to either doctors or patients, not objective and far from unambiguous.
The Panel noted that Detrusitol was licensed for the treatment of unstable bladder with symptoms of urgency, frequency and urge incontinence. The Panel examined the data and considered that whilst Detrusitol had been shown to help improve quality of life patients continued to report some degree of bladder problem. The most prominent claim "Freed by Detrusitol" created the impression that treatment would result in patients having no symptoms of urgency, frequency or urge incontinence which was not the case. The claim "Detrusitol effectively and selectively relieves frequency, urgency and/or urge incontinence" would be read similarly. The Panel considered that "Freed by Detrusitol" overstated the totality of the efficacy data and was not balanced. A breach of the Code was ruled.
An organisation submitted a complaint about an advertisement (ref P4483R/5199) for Detrusitol (tolterodine) produced by Pharmacia & Upjohn Limited which appeared in the BMJ 23 October 1999. The advertisement, which was headed 'Freed by Detrusitol', featured a photograph of an older women sitting by a swimming pool. Beneath the photograph was the claim "Detrusitol effectively and selectively relieves frequency, urgency and/or urge incontinence. With simple b.d. dosing." The strapline "Help free your patients from the restrictions of unstable bladder" appeared beneath the product logo.
COMPLAINT
The complainant queried whether the claims in the advertisement complied with Clause 7.2 of the Code. The reason for doubting it was that the advertisement failed to reflect the important evidence relating to lack of efficacy and/or the modest effect of the medicine that appeared in a table in the summary of product characteristics (SPC). This indicated that fewer than two patients in ten experienced "no or minimal bladder problems after treatment" - very few more than the numbers who recovered without the medicine (ie on placebo).
The advertisement included prominent claims such as, "Freed by Detrusitol", "Help free your patients from the restrictions of unstable bladder", and "Detrusitol effectively and selectively relieves frequency, urgency and/or urge incontinence". Such claims would seem to apply to only a small percentage of the patients treated with this medicine; the complainant's contention was that doctors would need to know this, and that the advertisement was not strictly accurate, nor balanced, nor fair to either doctors or patients, not objective, and far from unambiguous.
RESPONSE
Pharmacia & Upjohn addressed each claim referred to by the complainant in turn.
1 "Detrusitol effectively and selectively relieves frequency, urgency and/or urge incontinence"
Detrusitol had been given a product licence for "the treatment of unstable bladder with symptoms of urgency, frequency and urge incontinence", the efficacy data for Detrusitol having been reviewed by the Medicines Control Agency (MCA) in the European Mutual Recognition procedure in 1997. Owing to the fact that the inclusion criteria for the Phase Ill clinical trials for Detrusitol were almost identical in each study, the pooled results for the four 12 week studies were accepted by the MCA as valid data to assess the efficacy of the medicine. This data was presented in the Detrusitol SPC, and was also published (Appell (1997)). In this publication, it was reported:
a) For the primary efficacy variable, the number of micturitions/24 hours (indicating urinary frequency), a significant decrease from baseline, compared with placebo, was seen for the 1 mg tolterodine (p<0.001), 2mg tolterodine (p<0.001). Each active treatment group reduced mean daily micturition frequency by approximately 20% from the baseline mean.
b) For the number of incontinence episodes/24 hours, pooled results showed a significant decrease from baseline for both tolterodine doses compared to placebo (p<0.05), with a 47% reduction in incontinence episodes for the patients treated with Detrusitol 2mg bd.
c) For the mean volume voided per micturition, which gave a clinical representation of bladder capacity, pooled results showed a significant increase from baseline for both tolterodine doses compared to placebo (p<0.001), with a 22% increase in mean volume voided/micturition for the patients treated with Detrusitol 2mg bd.
Similar results were found in individual studies, the published results of two of these studies having been used as references in the advertisement, Malone-Lee et al (1 997) and Abrams et al (1 998). 1 n addition, the data from long-term open label studies with Detrusitol showed that the number of micturitions/24 hours, the number of incontinence episodes/24 hours, and the mean volume voided/micturition all improved markedly from baseline to six months and that this effect was maintained during the rest of the study and remained at the end of the treatment period of 12 months (Messelink (1999)).
Urgency was not measured during the Phase Ill clinical trials as this variable was considered to be subjective, in addition to the fact that a large number of patients with unstable bladder void frequently to avoid the sensation of urgency occurring. Therefore frequency was considered to be the more favourable efficacy variable. However, the MCA accepted that urgency was part of the symptom complex of unstable bladder, therefore Detrusitol was licensed for the treatment of frequency and urgency.
Thus Pharmacia & Upjohn submitted that it could be seen that Detrusitol did effectively relieve frequency, urgency and/or urge incontinence.
The promotion for Detrusitol as being selective for the bladder in the treatment of detrusor instability was consistent with the SPC which stated under section 5.1, Pharmacodynamic Properties, that "tolterodine is a specific cholinergic receptor antagonist with a selectivity for the urinary bladder rather than the salivary glands in vivo". Pharmacia & Upjohn referred to the relevant pages in the Pharmacological and Toxicological Expert Report for tolterodine.
Cholinergic, muscarinic receptors were thought to be the prime mediators of detrusor muscle contractions, and therefore blocking these receptors with anticholinergic, antimuscarinic medicines decreased the activity of the overactive detrusor muscle - thus improving the symptoms of unstable bladder, ie frequency, urgency and/or urge incontinence. In pre-clinical trials the binding of tolterodine and DD01 (the only metabolise with significant activity) was tested at more than 50 receptors and binding sites; the results of these tests indicated that Detrusitol and DD01 were pure and specific muscarinic receptor antagonists, with negligible effects at other potential cellular targets. The risks of side effects from the medicine affecting other receptors in other organs were thus reduced.
Five sub-types of muscarinic receptor had been identified molecularly(ffll-M5), four of which had been identified pharmacologically (M1-M4). The bladder contained a mixed population Of M2 and M3 receptors, constituting approximately 80% and 20% respectively of the total muscarinic receptor population in the bladder. Despite the M3 receptors being in the minority, it had always previously been considered that the M3 receptors were the prime mediators of detrusor muscle contractions. Thus many medicines that had previously been licensed for treatment of the unstable detrusor muscle, including oxybutynin, and others in development for unstable bladder, for example darifenacin, had been M3 selective. The problem was that the salivary glands were also rich in M3 receptors, thus whilst M3 selective drugs inhibited the unwanted overactive detrusor muscle contractions, they also inhibited the salivary glands - causing a dry mouth. These M3 selective medicines were therefore not organ selective for the bladder, as they also affected the salivary glands to a high degree.
In Pharmacia & Upjohn's pre-clinical studies, it was discovered that tolterodine was not selective for any of the muscarinic receptor sub-types. However, whereas tolterodine was found to be equipotent to oxybutynin with respect to the inhibition of detrusor muscle contractions, oxybutynin bound to the muscarinic receptors in the salivary glands with 8-times higher affinity than tolterodine (Nilvebrant et al (1 997a) and Nilvebrant et al (1 997b)), presumably due to the higher impact of oxybutynin on the M3 receptors in the salivary glands. Pharmacia & Upjohn referred to two graphs taken from Nilvebrant et al (1 997a) which showed the impact of tolterodine and oxybutynin on both the inhibition of detrusor muscle contractions and salivation in the anaesthetised cat.
Whereas with oxybutynin it was not possible to obtain inhibition of the detrusor muscle contractions without a significant inhibition of the salivary glands, with tolterodine, throughout most of the pre-clinical dose range, the inhibition of the detrusor muscle contractions could be obtained with a much reduced inhibition of the salivary glands. The organ selectivity of tolterodine for the bladder in vivo could not be attributed to a single muscarinic receptor sub-type. However the combined in vitro and in vivo data on tolterodine and oxybutynin might indicate either that muscarinic M3 receptors in salivary glands were more sensitive to blockade than those in bladder smooth muscle, or that the role of the M2 receptors in the bladder, which tolterodine was also blocking, might have previously been underestimated, and that they were also contributing to the detrusor muscle contractions. Indeed, it had been proposed that the M2 receptors had a function of reversing sympathetically mediated detrusor relaxation Hegde et al (1 997) - ie blockade of these receptors caused relaxation of the overactive detrusor muscle. This would account for the effect of tolterodine on the detrusor muscle being equivalent to that of oxybutynin, despite lack of muscarinic receptor selectivity. However the decreased effect on the salivary glands accounted for the organ selectivity of tolterodine.
The pharmacological basis for the organ selectivity of Detrusitol had therefore been clearly demonstrated, resulting in a clinical activity of the inhibition of overactive detrusor muscle contractions with an equal efficacy to oxybutynin, the gold standard treatment for unstable bladder, but with a much reduced clinical effect on the salivary glands. This was demonstrated in a Phase 1 tolterodine study, looking at urodynamic variables in addition to subjective outcome measures, the results of which suggested that a selective effect on the bladder, as demonstrated in an animal model, could also be obtained in humans, (Stahl et al (1 995)). In addition, the Phase 11 data was pooled, and the results illustrated that although treatment with tolterodine caused dose-related improvements in micturition diary and urodynamic variables, the main adverse effects of tolterodine were non-serious, mild or moderate antimuscarinic effects, with no patients withdrawing from treatment as a result of antimuscarinic adverse events other than urinary retention Larsson et al (1999). LikewisethetolterodinePhasellidatarevealedthattolterodinehadanequalefficacyto oxybutynin on the symptoms of unstable bladder, with a much improved tolerability profile (Appell (1997)).
Thus Detrusitol had been clearly shown in both pre-clinical and clinical studies to have organ selectivity for the bladder. This had been accepted by the regulatory bodies of the EU member states when approving the wording in the SPC, which confirmed the selectivity of Detrusitol.
2. Claims: "Freed By Detrusitol" and "Help Free Your Patients from the Restrictions of Unstable Bladder"
Pharmacia & Upjohn stated that unstable bladder was known to severely restrict the lives of patients, not just because of urge incontinence which could often be managed with the use of containment products, but more importantly because of the frequency and urgency of micturitions from which patients suffered. Frequency could be defined as passing urine > 8 times per 24 hours, thus typically a patient might pass urine 12 times during the day and get up three times at night to pass urine. Owing to the urgency associated with these frequent micturitions, patients were often afraid to go out, gave up work, and could become socially isolated. The quality of life of patients suffering with unstable (overactive) bladder had been studied using various quality of life instruments, and a recent publication showed that Short Form 36 scores for patients with overactive bladder were significantly lower than those of the normal population (p<0.001). This paper also showed that when a disease specific quality of life instrument was utilised, in this case the Kings Health Questionnaire, the quality of life of patients suffering with overactive bladder was significantly improved with treatment with tolterodine. This was more clearly seen in the Data on File, (Study 031 (UK)) for one of the studies on which this paper was written - which showed that treatment with tolterodine resulted in a significant improvement in the following quality of life domains; emotions, incontinence impact, physical limitations, role limitations, severity measures, sleep/energy and social limitations. If a patient had a frequency of 15 micturitions per 24 hours, Detrusitol - as illustrated earlier - could be expected to decrease the frequency by 20%. This would lead to a longer time between each micturition, with less urgency, enabling patients to perform tasks they had previously been unable to do - freeing up their lives.
A classic patient history and testimonial was published in the 'You' magazine on 31 October 1999. A patient reported her history of treatment with both oxybutynin and Detrusitol, and although she still suffered from incontinence she reported "I can now last up to four hours without needing to go to the toilet. I've got my life back again".
Clearly freedom from the restrictions of unstable bladder involved more than simply making incontinent patients dry, it involved decreasing frequency and urgency such that patients could restart their normal activities and improve their quality of life. This had undoubtedly been shown in studies with Detrusitol, which did improve patients' quality of life and their ability to perform normal activities, freeing them from the restrictions of unstable bladder.
Pharmacia & Upjohn, therefore, believed the claims for Detrusitol in the above mentioned advertisement were accurate, balanced, objective and it certainly believed the claims were not ambiguous and not to be in breach of the Code.
PANEL RULING
The Panel noted that Detrusitol was indicated for the treatment of unstable bladder with symptoms of urgency, frequency or urge incontinence.
Data presented in the Detrusitol SPC from 12 week studies showed a statistically significant decrease from baseline, compared to placebo in the number of micturitions per 24 hours (p:50.01), the number of incontinence episodes/24 hours (p<0.05) and a statistically significant increase from baseline in the mean volume voided per micturition. There was no statistically significant difference as against placebo in the percentage of patients with no or minimal bladder problems after treatment at 12 weeks. The 4 week studies showed a statistically significant difference between placebo and Detrusitol in relation to the number of patients with none or minimal bladder problems after treatment (p<0.01). Malone-Lee et al (1 997) demonstrated a significant effect on incontinence and increase in volume voided at 2mg. Abrams et al (1 998) showed a significant effect on the frequency of micturition and volume voided but not on the number of incontinence episodes. The Panel noted that Kobeit et al (1 999) was a review, which discussed quality of life aspects of the overactive bladder and the effect of treatment with tolterodine and concluded that tolterodine had the potential to increase compliance with treatment and thus patients' overall well-being. The Panel also noted the Kings Health Questionnaire. The Panel considered that whilst Detrusitol had been shown to help improve quality of life patients continued to report some degree of bladder problems.
The Panel considered that the heading and most prominent claim, "Freed by Detrusitol" was a strong statement. "Freed" was an absolute term and the claim created the impression that treatment with Detrusitol would result in patients having no symptoms of urgency, frequency or urge incontinence which was not the case. The heading set the tone for the advertisement and dictated how other claims within it would be read. In the Panel's view the word "relieves" in the claim "Detrusitol effectively and selectively relieves frequency, urgency and/or urge incontinence" would be read in the same way as "Freed" in the heading. The Panel noted that the strapline "Help free your patients from the restrictions of unstable bladder was a more qualified claim but it was not sufficient to negate the overall impression of the advertisement.
In the Panel's view the complainant was concerned that the efficacy of Detrusitol had been overstated and was not questioning its pharmacological selectivity. The Panel considered that "Freed by Detrusitol" overstated the totality of the efficacy data and was not balanced. A breach of Clause 7.2 was ruled.
Complaint received 28 October 1999
Case completed 4 January 2000
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