September/October 2001  Vol 19  No 9/10  ISSN 1321-571X
Healthy Scepticism about promotion of asthma drugs in New Zealand.

This edition was intended for publication in New Zealand in February 2001.  There were delays waiting for feedback from New Zealand and also because we needed to focus on some other deadlines.  Then it was decided that this edition would need to be updated because of the publication of new advertisements.  The updating could not be commenced because of work on direct to consumer advertising in Canada and some other projects.  One month before time would have been available to do the updating PHARMAC announced that they were cancelling our contract because of the delay.

Healthy Scepticism NZ
A Second opinion on Drug Promotion for Doctors in NZ
February 2001 Vol 4 No 1

[text for footer on front page]
Healthy Scepticism NZ is produced by MaLAM.  MaLAM aims to defend appropriate, compassionate, scientific medical care, health professionals and the public from marketing practices that may be detrimental to health.  Healthy Scepticism NZ is funded by PHARMAC however this publication has been prepared solely by MaLAM and does not necessarily reflect the views of PHARMAC.  Please address feedback to Peter Mansfield, c/o PO Box 10-545, Wellington or e-mail: peter.mansfield@flinders.edu.au. 

Misleading promotion of drugs for asthma may be harmful
If you only have a minute then please read the conclusions on the back page.

Contents
   Introduction
    Inhaled steroids
        Flixotide (fluticasone)
        Pulmicort (budesonide)
   Alternative to steroids
        Singulair (montelukast)
        Serevent (salmeterol)
        Oxis (eformoterol)
        Bambec (bambuterol)
    Conclusions
    Feedback Form

Introduction
We apologise for not producing this edition earlier.  MaLAM has been busy working on the direct to consumer (DTC) advertising of prescription only drug issue in several countries including New Zealand.

This edition provides opinion on all advertisements for asthma drugs published in New Zealand Doctor and New Zealand GP during 1999 - 2000.  We will quote the main advertising claims and provide contrasting second opinions on the promotion techniques and on the available evidence.  We checked the citations in the advertisements, did medline searches for relevant meta-analyses or randomised controlled trials (RCTs) and consulted New Zealand GPs and respiratory specialists.  We will comment on whether or not the advertising claims are justified in the context of normal general practice where skills vary and where patients may understate their symptoms.^{[1],[2],[3],[4]} 

Inhaled steroids
Are Flixotide or Pulmicort Turbuhaler superior to beclomethasone via spacer?


Flixotide (fluticasone, GSK formerly GlaxoWellcome^[5])

Claim 1  “Flixotide offers superior asthma control, compared with other inhaled steroids.” 
Second opinion 1 
On the available evidence:  Flixotide efficacy is not superior to beclomethasone via spacer.
Fluticasone appears to be slightly more than twice as potent per mg as beclomethasone.^[6]  This provides no advantage because similar or superior effectiveness can be achieved by using slightly more than twice the mg dose of beclomethasone.  e.g. beclomethasone 250mg instead of fluticasone 100mg.^[7]  We are very concerned about patients being started on “same mg” doses of fluticasone and then not being titrated down to safer doses.^[6]

Claim 2: “Studies in children have shown low potential for side effects such as growth impairment and cortisol suppression.”
Second opinion 2: 
Promotion techniques:  Hanging comparator, Exaggeration, DTCA and Personal data collection.
The word “low” is a comparative term.  The claim is ambiguous because it conveys the impression that fluticasone has a low rate of side effects compared to a comparator but fails to specify the comparator.  This type of claim is called a hanging comparator.
GSK has “withdrawn” the Flixotide advertisement targeting children because the Advertising Standards Complaints Board judged that it “exaggerated safety claims”.^[8]  However GSK has not provided New Zealand doctors nor the public with corrective information nor an apology nor compensation. 
We are also concerned about the potential for exploitation arising from the targeting of disadvantaged groups with direct to the consumer advertising of Flixotide and the associated collection of personal data about “almost 10,000” asthmatics via a telephone “information line”.^[9]
On the available evidence:  Adrenal suppression may be equal or worse with Flixotide than with beclomethasone via spacer.
GSK cite one study that found that fluticasone had less adverse effects than an equipotent dose of beclomethasone.^[10]  However GSK also cite contradictory evidence of no significant difference between fluticasone and equipotent doses of beclomethasone or budesonide in larger groups of children.^[11],[12] 
By contrast to GSK’s selected citations one meta-analysis has found a significantly greater potency for adrenal suppression with fluticasone compared to other inhaled steroids.^[13]  An earlier meta-analysis found that fluticasone was superior to budesonide but no better nor worse than beclomethasone.^[14]  Use of spacers may decrease adrenal suppression with beclomethasone but may increase it with fluticasone.^[15],[16] 


Pulmicort Turbuhaler (budesonide, AstraZeneca)
Claim 3  “Turbuhaler may reduce the medication needed for asthma control by up to half”
Second opinion 3 
Promotion techniques: Flawed studies – wrong doses, too small, too short.
AstraZeneca cite 2 small studies.  One compared 1.5 mg beclomethasone via spacer per day vs 0.8 mg budesonide via Turbuhaler per day for only 2 months and included only 176 subjects. ^[17] Both found no significant difference in asthma control nor adverse effects.  Because increasing the dose of beclomethasone above 1 mg per day does not increase efficacy the same efficacy results could be expected with 1 mg or with 8 mg as was found with 1.5 mg.  Had they used 8 mg of beclomethasone they could have claimed that “Turbuhaler may reduce the medication needed for asthma by ten times!” but then the trick used would be more obvious.  The second study concluded that after dose titration over 2 years, 0.6 mg per day of budesone via Turbuhaler was not significantly different from 1 mg per day of beclomethasone via spacer but included only 102 subjects. ^[18]  It is possible that a clinically important difference (eg 1 extra death per 100 patients during 5 years) exists but was not detected because the trials were too small and/or too short. 
On the available evidence:  Pulmicort Turbuhaler is not superior to beclomethasone via spacer.  It is more convenient but may be less reliable.
AstraZeneca have not produced evidence of significantly less adverse effects with budesonide via Turbuhaler versus equally effective doses of beclomethasone via spacer.  The Turbuhaler is more convenient but we are concerned about patients getting less steroid than they need when deteriorations in their asthma lead to lower inspiratory flow rates for activating a Turbuhaler.  Also, humid weather or breathing on the device can cause the powder to clump.  Valved spacers with face masks are recommended for young children and the elderly.^[19] 


Alternatives to inhaled steroids
A cohort study has suggested that the relative risk of death decreases by 21% for every additional canister of inhaled steroid used during the previous year.^[20]  Consequently, we are concerned that symptom control with alternatives may lead to less use of inhaled and oral steroids and thus worsening inflammation without symptoms leading to preventable deaths.  MSD has promoted use of Singulair instead of starting steroids.  The advertisements for the Long acting b-2 agonists (LABA) lack clear statements on this key issue.


Singulair (montelukast, MSD)

Claim 4  “MSD reports that 600 GPs (20 per cent) prescribed Singulair in the first two weeks it came on the market.”
Second opinion 4
Promotion techniques: Social proof, “New”.
GPs do not have time to examine all the evidence about drugs.  Consequently, it is normal for us to use short cut decision making.^[21]  For example “If opinion leader Dr X recommends drug Y then I can make a quick decision to start prescribing it also.”  Our short cuts often lead to correct conclusions but advertisers know how to manipulate our short cuts so as to lead us to conclusions that suit them.  Different GPs rely to different extents on different short cuts and drug companies classify us accordingly.  The “Followers” of opinion leaders can be manipulated via “support” for those opinion leaders who are willing to promote the company’s drugs.  About 20% of GPs are classified as “Innovators” because they often use the short cut that “If it is new it is probably better”.  Advertisers have known for at least 80 years that they can gain increased sales just by adding the trigger word “new” to their advertisements.^[22]  Drug companies usually start promotion of new drugs by targeting “Innovators”.  Next they target the GPs they classify as “Sheep” with claims designed to trigger the “social proof” short cut i.e. “if many GPs are prescribing drug X then so should I.”  Claim 4 is likely to influence some GPs in that way.^[23]
Results of a PreMeC asthma case study (March 1999) for “other drugs” including montelukast found that only 2% of 1005 GPs indicated they would prescribe other drugs for worsening asthma and only 7% of 1014 GPs would prescribe other drugs for severe asthma.  Possible explanations of this discrepancy include 1) PreMeC participants may include a lower proportion of “Innovators” than non-participants and/or 2) the use of Singulair may have dropped quickly after the rapid uptake in the first 2 weeks.

Claim 5  “The company’s [MSD’s] managing director, Alister Brown, says the idea behind the free month’s supply of Singulair was to let patients ‘try before they buy’”^[24] 
“MSD spokesperson Phil Johnstone says the company has not advertised the prescription drug but provides an 0800 line to doctors and asthma groups and offers a free one month trial to all patients.  Information kits were sent to the media which debated the promotion for days…
Although Auckland GP [Dr X] agrees the information he received on Singulair was inadequate, he found what he needed to know on the MSD internet site. “He prescribed the drug for about 20 patients and takes it himself.  ‘It’s fast acting – you notice in a day or two. If its useless, you risk nothing, it’s a generous offer from the company.’… One woman can barely afford it but her asthma was so bad and the drug made such a dramatic improvement now she’s paying for it.”^[25]
Second opinion 5 
Promotion techniques: “Free”, Post hoc ergo propter hoc
“Free trials” would be a good way to evaluate drugs if the drug alone caused any changes that occurred after starting it.  You have to believe that if B occurs after A then A caused B.  Logicians call this belief the “post hoc ergo propter hoc” (after that therefore because of that) fallacy.  In the case of asthma, fluctuations are normal.  Patients are more likely to see GPs and be given additional treatment when they are worse than usual.  Consequently, whilst some will continue to deteriorate, many would be about to improve even without additional treatment.  Such improvement can give the impression that Singulair is more effective than it really is. 
On the available evidence:  Singulair is faster but less effective than steroids.
Although montelukast 10mg per day has a faster onset it is less effective than inhaled beclomethasone 200mcg bd.^[26]  The woman mentioned by Dr X above is likely to have achieved better asthma control with oral prednisolone followed by inhaled beclomethasone without the severe financial adverse effects.  How montelukast compares with inhaled steroids in the long term for preventing adverse events including deaths is not known. 


Serevent (salmeterol, GSK)

Claim 6  “Less exacerbations”
Second opinion 6
On the available evidence: Adding Serevent rather than increasing steroids has not been shown to lead to less minor exacerbations and may lead to more severe exacerbations.
GSK support their hanging comparator claim with a study that compared the LABA salmeterol to salbutamol and to placebo but not to any inhaled steroid.^[27]  By contrast, a meta-analysis of trials of salmeterol vs increasing the dose of inhaled steroid found no significant difference in exacerbation rates during the first 6 months.^[28]  Use of LABA to control symptoms with lower doses of steroids may reduce long term steroid adverse effects.  However symptom control with LABA may mask deterioration of the underlying inflammation and thus lead to more deaths.  In one trial of 16,787 asthmatics for 4 months found that 12 died on salmeterol which was 3 times the death rate with salbutamol but this difference was not statistically significant.^[29]  It is possible that a trial of longer duration would find a statistically significant and clinically important difference.  A review of 30 RCTs of long acting b-2 agonists for children concluded that “the evidence does not support a recommendation for long-acting b-2 agonists as monotherapy, nor does it support their general use as regular add-on therapy.”^[30] 


Oxis (eformoterol, AstraZeneca)

Claim 7  “a proven reduction in exacerbation rates”
Second opinion 7
On the available evidence: Adding Oxis rather than increasing steroids has not been shown to lead to less minor exacerbations and may lead to more severe exacerbations.
AstraZeneca support this hanging comparator claim with a study that only shows that eformoterol is superior to placebo.^[31] By contrast to the claim that study also found that eformoterol 12mcg plus budesonide 100mcg bd was significantly less effective at reducing exacerbations than budesonide 400 mcg bd.  It appears that if asthma is not controlled by low dose inhaled steroid it is better to increase the dose of the steroid than to add eformoterol.  Our concerns about exacerbations and preventable deaths expressed in the salmeterol section above also apply to eformoterol.


Bambec (bambuterol, AstraZeneca)

Claim 8  “When inhaled long-acting ß₂-agonists are out of the question, just add Bambec”
Second opinion 8 
On the available evidence:  We were unable to locate any evidence to support the use of Bambec.
AstraZeneca did not cite any trials of bambuterol vs inhaled steroids nor were we able to find any.  Our concerns about exacerbations and preventable deaths expressed in the salmeterol and eformoterol sections above also apply to bambuterol.


Conclusions
We have examined 8 claims for 6 drugs for asthma in the medical tabloids New Zealand Doctor and New Zealand GP during 1999 - 2000.  We believe that in every case the claims are misleading because of failure to disclose problems.  The promotional techniques used included: Hanging comparators, Exaggeration, Personal data collection, Flawed studies, Social proof, “New”. “Free” and Post hoc ergo propter hoc.

On the available evidence:
Flixotide efficacy is not superior to beclomethasone via spacer.  Adrenal suppression may be equal or worse with Flixotide than with beclomethasone via spacer.
Pulmicort Turbuhaler is not superior to beclomethasone via spacer.  It is more convenient but may be less reliable.
Singulair is faster but less effective than steroids.
Adding Serevent or Oxis rather than increasing steroids has not been shown to lead to less minor exacerbations but may lead to more severe exacerbations.
We were unable to locate any evidence to support the use of Bambec.




Feedback on Healthy Scepticism about asthma drugs
Please fax your feedback to (an appropriate fax number in New Zealand was never decided.) 

Regarding this edition of Healthy Scepticism I am:
Very dissatisfied 1 2 3 4 5 6 7 Very satisfied
Comments:

As a result of reading this edition of Healthy Scepticism I intend to change my prescribing:
Not at all 1 2 3 4 5 6 7 Significantly

Feedback to the companies
(Please comment on the drug and then on the advertisement regardless of your assessment of the drug.)

I feel that use of Flixotide (fluticasone) in normal general practice is:
Inappropriate 1 2 3 4 5 6 7 Appropriate
I feel that GSK’s advertisement for Flixotide (fluticasone) is:
Inappropriate 1 2 3 4 5 6 7 Appropriate
Comments:

I feel that use of Pulmicort Tubuhaler (budesonide) in normal general practice is:
Inappropriate 1 2 3 4 5 6 7 Appropriate
I feel that AstraZeneca’s advertisement for Pulmicort Tubuhaler (budesonide) is:
Inappropriate 1 2 3 4 5 6 7 Appropriate
Comments:

I feel that use of Singulair (montelukast) in normal general practice is:
Inappropriate 1 2 3 4 5 6 7 Appropriate
I feel that MSD’s advertisement for Singulair (montelukast) is:
Inappropriate 1 2 3 4 5 6 7 Appropriate
Comments:

I feel that use of Serevent (salmeterol) in normal general practice is:
Inappropriate 1 2 3 4 5 6 7 Appropriate
I feel that GSK’s advertisement for Serevent (salmeterol) is:
Inappropriate 1 2 3 4 5 6 7 Appropriate
Comments:

I feel that use of Oxis (eformoterol) in normal general practice is:
Inappropriate 1 2 3 4 5 6 7 Appropriate
I feel that AstraZeneca’s advertisement for Oxis (eformoterol) is:
Inappropriate 1 2 3 4 5 6 7 Appropriate
Comments:

I feel that use of Bambec (bambuterol) in normal general practice is:
Inappropriate 1 2 3 4 5 6 7 Appropriate
I feel that AstraZeneca’s advertisement for Bambec (bambuterol) is:
Inappropriate 1 2 3 4 5 6 7 Appropriate
Comments: