The Importance of Achieving Additional Drug Benefits at a Reasonable Cost

The Importance of AchievingAdditional Drug Benefits at aReasonable CostA Review of the Fluoxetine Years

Nick Freemantle and James MasonMedicines Evaluation Group, Centre for Health Economics, University of York, York, England

Abstract Fluoxetine continues to be remarkably successful; greater volumes of this drugare sold than for any other antidepressant in the world. Prozac® has also becomea household name. In this article we examine the circumstances that surround thissuccess, and the evidence base that supports it. Rather than being a major stepforward in the treatment for depression, the evidence for fluoxetine and for theselective serotonin reuptake inhibitors in general suggest at best a modest im-provement in tolerability, with no evidence of improved efficacy. We note thatthe road to success was not problem free for fluoxetine, and highlight the responseof the sponsor in the development of subsequent drugs for CNS disorders.

CURRENT OPINION Pharmacoeconomics 2000 Apr; 17 (4): 319-3241170-7690/00/0004-0319/$20.00/0

© Adis International Limited. All rights reserved.

This year, fluoxetine (Prozac®) lost its patent inthe UK. This has already occurred in Canada, ac-companied by ignominious (and unsuccessful) at-tempts by the manufacturer to patent the ‘green andwhite capsule’. Fluoxetine is the most commonlyprescribed antidepressant in the UK and in manyother health systems. To quote the advertisers,‘Lead-ership isn’t given. It’s earned . . . Prozac . . . theWorld’s No.1 prescribed antidepressant brand’.[1]Fluoxetine is also the first drug since diazepam

(Valium®) to have broken through to ‘popular cul-ture’, with frequent references in both the lay newsand media. It was even found in the spell checker(Prozac) of the word processing software used whendrafting this paper. In this article, we reflect on thephenomenal success of fluoxetine and considerwhat lessons may be drawn when evaluating newpharmaceuticals.

1. Is Fluoxetine a Better Drug?

One potential explanation for the widespread

introduction of a new health technology is that itprovides substantial benefits when compared withother available interventions. For example, thepublication of major trials demonstrating the effec-tiveness of ACE inhibitors [e.g. Studies of LeftVentricular Dysfunction (SOLVD)][2] and their su-periority over existing treatments [Veterans Ad-ministration Cooperative Vasodilator Heart FailureTrial (VHeFT II)][3] could have been expected toincrease the use of these drugs. However, clinicaltrial evidence does not translate directly intochanges in routine use;[4] UK general practice stud-ies suggest that only 20 to 30% of patients assessedby general practitioners (GPs) as having heart fail-ure are prescribed an ACE inhibitor.[5,6] Conversely,Prozac® some new drugs receive widespread adop-tion even though, in health terms, the evidence fortheir use is equivocal.[7]Fluoxetine belongs to a group of drugs known

as selective serotonin reuptake inhibitors (SSRIs).Inhibition of the reuptake of serotonin is a pharma-

cological action shared by many antidepressantdrugs.[8] The selective action of these drugs is pur-ported to be the rationale for potential advantagesover other existing therapies. Rather than a truebreakthrough in pharmacology, the development ofSSRIs may be seen as a process of refining the ac-tion of existing and commonly used alternatives. Thisprocess may be clinically important. For example,recently developed pharmacological treatments forAlzheimer’s disease mimic the therapeutic effectsof tacrine, while avoiding the unpleasant and po-tentially dangerous adverse effects of the drug.[9]Thus, rather than acting via a different pharma-

cological mechanism, the advantages of fluoxetineand other SSRIs arise from a reduction in some ofthe troublesome adverse effects commonly obser-ved with some of the tricyclic antidepressant drugsand the relative ease by which a full therapeuticdose may be achieved without dose titration. Also,the promise of reduced toxicity in overdose, partic-ularly in comparison with the older tricyclics anti-depressants, is a therapeutic advantage.[10]

Various systematic overviews have examined theeffectiveness and relative tolerability of SSRIs.[11-13]Despite the purported tolerability advantages,there is a consistent message that SSRIs are asso-ciated with only a small improvement in tolerabil-ity compared with older antidepressants. Our mostrecent analysis suggests a relative risk of treatmentdropout of 0.87 [95% confidence interval (CI):0.80 to 0.95; fig. 1], corresponding to an absolutereduction in dropout of about 4%.[11] Efficacy ap-pears similar among commonly used antidepres-sants (fig. 2).SSRIs are safer in overdose than the majority of

tricyclic antidepressants, although death from over-dose is relatively rare. A recent epidemiologicalstudy in England and Wales summarised data oningested antidepressants associated with fatal tox-icity during 1993 to 1995.[14] Overall, antidepres-sants were associated with 1 death for every 3000patient-years of treatment. For the tricyclic drugs(excluding lofepramine), the association was 1 death

0.5 0.8 1.25 20.25 1

Favours alternativeFavours SSRI

Relative risk

Citalopram (8 trials)Fluoxetine (50 trials)Fluvoxamine (27 trials)Nefazodone (4 trials)Paroxetine (23 trials)Sertraline (6 trials)Venlafaxine (5 trials)Overall (123 trials)

Fig. 1. Relative risk of treatment dropout: individual selectiveserotonin reuptake inhibitors (SSRIs) or related drugs versusalternative antidepressants (amitriptyline, imipramine,clomipramine, maprotiline or moclobemide). Randomised trials(mostly short term) comparing SSRIs and alternative antide-pressants in patients with major depressive episode (total of9554) were reviewed systematically.

−0.2 0.2 0.4 0.6 0.8−0.4 0

Favours alternativeFavours SSRI

Standardised weighted mean difference

Citalopram (8 trials)Fluoxetine (38 trials)Fluvoxamine (25 trials)Nefazodone (2 trials)Paroxetine (18 trials)Sertraline (4 trials)Venlafaxine (4 trials)Overall (99 trials)

Fig. 2. Efficacy of individual selective serotonin reuptake inhib-itors (SSRIs) and related antidepressants versus alternative an-tidepressant drugs (amitriptyline, imipramine, clomipramine,maprotiline or moclobemide). Randomised trials (mostly shortterm) comparing SSRIs and alternative antidepressants in pa-tients with major depressive episode (total of 13 366) were re-viewed systematically.

320 Freemantle & Mason

© Adis International Limited. All rights reserved. Pharmacoeconomics 2000 Apr; 17 (4)

for every 1750 patient-years of treatment. For theSSRIs, the ratewas about 1 death in 100 000 patient-years of treatment. Interestingly, lofepramine, anatypical tricyclic that is commonly used in theUK, was associated with 1 death for every 59 000patient-years of treatment, a result not statisticallysignificantly different from that for the SSRIs. If it isreasonable to assume that fatal toxicity proxies thebroader pattern of nonfatal poisoning events, thena clinician’s concern that a patient is at increasedrisk of overdose should prompt the choice of a ‘lowrisk antidepressant’without the inevitable recourseto a SSRI.Furthermore, a UK regional evidence-based

guideline group that reviewed the role of the vari-ous antidepressants available in primary care,[15]concluded that, on cost-effectiveness grounds, therewas no case for using SSRIs as first-line treatmentfor depression.[11]Fluoxetine was not the first SSRI to be licensed

in the UK: the first licensed drug, zimelidine, waswithdrawn frommarketing because of rare adverseeffects. Today, fluoxetine is a market leader in theUK in terms of prescribing volume. However, it isunclear why this drug has gained such popularitywith prescribers and patients. It doesn’t appear tobe due to a clear-cut demonstration of improvedeffectiveness or cost effectiveness, although somedoctors and patients may believe otherwise. Per-haps the most striking result from a naturalistictrial of fluoxetine versus tricyclic antidepressantswas the 32% of patients switching away from tri-cyclics to fluoxetine during the course of thestudy:[16] at least half of these switches occurredwithin the first month. However, there are a num-ber of limitations of this study and challenges to itsinternal validity which limit the extent to which itsresults may be taken at face value.[17]

2. A Rocky Road to Success?

Fluoxetine has not had an event-free journey toits successful place in prescribing. Early in the pe-riod of marketing in the UK, concern developedthat treatment with fluoxetine was associated withan increased rate of suicidal ideation in patients

who were depressed. This was refuted in the Brit-ish Medical Journal through the publication of ameta-analysis undertaken by scientists in EliLilly’s Division of Clinical Neurosciences in theUS.[18] The analysis included data from about 3000patients and found no differences in suicidal actsbetween recipients of placebo, tricyclics or fluox-etine. Although several of the studies includedwere not published, the analysis supported the con-clusion that fluoxetine was not associated with anincreased risk of suicidal acts or emergence of sub-stantial suicidal thoughts among patients whoweredepressed. This conclusion is supported in proxyby our fatal toxicity data when analysed by acci-dental or deliberate intent.[14]The acquisition cost of fluoxetine and the other

SSRIs, coupled with their rapidly increasing vol-ume of use, raised concerns about the cost effec-tiveness of switching from the older to the newerantidepressants. In 1995, in English family prac-tice, about 1 million patient-years of antidepres-sant treatment were reimbursed.[11] Of course, oneshould not confuse the purchase cost of a drug andits value for money. However, the sheer magnitudeof the budgetary implications of the switch fromolder to newer antidepressants guaranteed thatSSRIs would receive close attention.Perhaps crucially, in 1993, the acquisition cost

of fluoxetine to the National Health Service (NHS)was reduced by about 35%. This price reductionmay have been important for determining theconsequent market penetration of fluoxetine. Ifthe cost was reduced as a response to the renegoti-ation with the Pharmaceutical Pricing RegulatoryScheme (PPRS), then this would seem to have beenparticularly shrewd. The PPRS is a voluntaryagreement between the Department of Health andthe domestic pharmaceutical industry (through theAssociation of the British Pharmaceutical Indus-try). Participating companies are required to priceproducts at a level that does not exceed a negoti-ated return on historic capital.[19] The PPRS re-quires companies who have exceeded agreed profitlevels to make adjustments to account for this ex-cess, either through direct payment to the Treasury,

Achieving Drug Benefits at Reasonable Cost 321


or through the reduction in price of a product.Changing the price of a product to the NHS is arelatively unusual step during patent protection, soit seems quite plausible that the PPRS contributedto the decision to reduce the price of fluoxetine.The company exploited this price advantage overalternative SSRIs in its subsequent advertisingcampaigns. To again quote the advertisers: ‘Whatshould you do with the money you save by pre-scribing Prozac rather than other SSRIs? MakeProzac available to even more patients.’[19]

3. Effects of Information on Prescribing

In the early 1990s, no real mechanism for influ-encing the way in which GPs used licensed prod-ucts existed in the NHS beyond the provision ofinformation. One source of information, an Effec-tive Health Care bulletin,[20] appraised the effec-tiveness and cost effectiveness of treatments fordepression in primary care. This work led to thepublication in the British Medical Journal of a sys-tematic overview identifying the SSRIs as having,at best, only a small difference in tolerability andno efficacy advantage over traditional antidepres-sants.[12] In 1993, the Chief Medical Officer (CMO)of the NHS distributed a report describing the over-view and summarising information on the effec-tiveness and cost effectiveness of treatments of de-pression in primary care to all GPs in England. Theinformation from the CMO, accompanied by thebulletin, asked prescribers to apply cautionwhen pre-scribing the newer drugs instead of tricyclics. Thisadvice was acted upon in many health authoritieswhere pharmaceutical advisors visited practices toprovide guidance on efficient prescribing.An interrupted time series analysis, using an au-

toregressive integrated moving average (ARIMA)model, was conducted to explore the effect of ad-vice sent to family practitioners.[21] Interestingly,this identified a robust, statistically significant ef-fect of the distribution of the Effective Health Carebulletin and the CMOadvice (fig. 3). The estimatedreduction in the volume of subsequent SSRI pre-scribing was estimated to have saved £40 million($US70 million) between 1993 and 1997 in SSRI

prescribing. However, in respect of the subsequenttrends in prescribing, the absolute effect of the dis-tribution of advice was, at best, small.Contemporaneous influences upon prescribing

were working in the opposite direction to the CMOadvice and bulletin. These influences included for-mal promotional activities and material from thesponsoring company, as well as articles and pro-grammes in the lay media and even popular fiction.The extent of these activities could be consideredas a mass media campaign. This does not imply acoordinated set of activities, but a form of mediaadvocacy, where a topic is picked up and developedby individual providers of information. Two exam-ples of this kind of activity can be found in News-week and Time: ‘Caveats aside, the evidence to datesuggests that Prozac is a big improvement over theolder treatments.’[22] ‘The drug is much more thana fad: it is a medical breakthrough that has broughtunprecedented relief to many patients with severedepressions . . .’.[23]A systematic overview of the effects of similar

mass media campaigns has shown there is quitegood evidence that such campaigns may lead tochanges in the utilisation of healthcare.[24] In thisoverview, 17 time series analyses of the effects ofmass media information were examined, and a

200 000

175 000

150 000

125 000

100 000

75 000

50 000

25 000

0Q1-91 Q1-92 Q1-93 Q1-94 Q1-95 Q1-96 Q1-97

Bulletindistributed

ARIMA prediction ofSSRI use without bulletin

SSRI

Tricyclic

Fig. 3. Utilisation of antidepressants in England (shown quarterlyin person-year equivalents). An interrupted time series analysis,using an autoregressive integrated moving average (ARIMA)model, was conducted to explore the effect of advice sent tofamily practitioners.[18] Q1 = quarter 1; SSRI = selective serotoninreuptake inhibitor.

322 Freemantle & Mason


fairly consistent positive effect upon health ser-vices utilisation was identified. The studies exam-ined a range of therapeutic areas, including cancerprevention and sexual health. In light of this evi-dence, it is quite plausible that the range of mediaactivities used has contributed to the considerablepopularity of fluoxetine.This leads to a central problem: it is possible to

debate the science and findings of randomised con-trolled trials with trained health professionals, butin the media it may be very difficult to argueagainst the individual interpretations of cliniciansor personal experiences of patients. A practisingpsychiatrist, Peter Kramer comments in his bookListening To Prozac: ‘Then I wrote about patientswho became better than well, patients who ac-quired extra efficient energy and became sociallyattractive. My mnemonic for this effect was cos-metic psychopharmacology.’[25]In the epilogue of her book Prozac Nation,

which provides a moving account of her personalexperience of depression, Elizabeth Wurtzel re-flects on the depression culture seemingly envel-oping the US and the rest of the western world:‘And yet I can’t escape the icky feeling I get everytime I’m sitting in a car and everyone but the driveris on Prozac. I can’t get away from some sense thatafter years of trying to get people to take depres-sion seriously – of saying I have a disease, I needhelp – now it has gone beyond the point of recog-nition as a real problem to become something thatappears totally trivial’.[26]Was the success of fluoxetine down to timing –

a socially acceptable answer to the cultural stressescaused by modern living? Did the marketing andthemedia serve to grow the culture ormerely respondto a perceived need? To be clear, fluoxetine and theother SSRIs remain a worthwhile innovation,which, for some patients, will provide a successfulalternative when other therapies fail. The questionhas been for the SSRIs, and will remain for othernew treatments showing initial promise: what istheir proper place in the treatment of disease?

4. Could It Happen Again?

It is notable that in phase IV of fluoxetine de-velopment, company research policy appears to bechanging from the sponsorship of many small tri-als, which were conducted in part for marketingpurposes, to the sponsorship of a small number oflarger trials. For example, we are aware of 50mostly small trials including nearly 4794 patientscomparing fluoxetine with an alternative antide-pressant other than a SSRI. In contrast, there areonly 6 trials currently in the public domain thatcompare olanzapine (another drug by Eli Lilly)with alternative antipsychotic drugs, althoughthese trials include nearly 3217 patients. There area number of potential interpretations for thischange in policy. Most of all, greater coordinationof research activity enables greater control and ap-plication of the data. In the UK and other countries,there is increasing need for the availability of betterdata on the effectiveness and cost effectiveness ofinterventions in order to provide justification fortheir introduction and widespread use.[27] Thus, itis likely that research programmes for new drugswill be based increasingly upon a smaller numberof larger phase III/IV trials. This should enable bet-ter evaluation of the benefits of different productsby policy analysts, clinicians and patients and alsoaid companies with good, well-evaluated productsto gain appropriate commercial reward. The limi-tations of small trials are well known;[28] smallphase IV trials may be better considered as market-ing rather than as scientific trials.The latest round of reforms introduced in the

UK may allow evidence on new treatments to beaired more clearly and influentially in the fu-ture.[29] An evidence-based approach to assessingnew products at the time of their launch may helpclinicians, confronted with patient expectations, torespond with the known facts and uncertainties.The best outcome may be for the ‘free’ press tobecome an ‘informed’ press. As with the clinicalfraternity, this will mean becoming far more criti-cal of the information put before them.



5. Conclusions

Fluoxetine has been a remarkable commercialsuccess story. However, it does not appear to have‘earned its leadership’by delivering additional healthbenefits worth the substantial additional costs.Fluoxetine did not appear to be affected by themixed publicity associated with its introduction,although it is possible that even greater sales mayhave been achieved had all the news been positive.Two themes suggest that the fluoxetine experi-

ence may not be repeated on such a scale in thefuture. First, the posited changes in the policy ofthe Division of Clinical Neurosciences at Eli Lillyand, in particular, the increased coordination andcontrol over the phase IV research programme, prob-ably reflect a general change of style in researchthat is broader than a single company. Consequently,the scope for interpretation (or misinterpretation)of clinical evidence will be reduced. Second, theevaluative culture evolving in health services is byno means peculiar to the UK, and it is possible thatpublic debate will become both more informed andmore critical in the future. There are increasing de-mands for evidence on effectiveness and cost ef-fectiveness in many health systems.For these reasons, fluoxetine may be one of the

last instances of a drug becoming ablockbuster,with-out good evidence of additional benefits at a costthat may be considered affordable and worthwhile.

References1. Fundholding [advertisement]. 1996; 5 (9)2. SOLVD Investigators. Effect of enalapril on survival in patients

with reduced left ventricular ejection fractions and congestiveheart failure. N Engl J Med 1991; 325: 293-302

3. Cohn JN, JohnsonG, Ziesche S, et al. Acomparison of enalaprilwith hydralazine-isosorbide dinitrate in the treatment of chroniccongestive heart failure. N Engl J Med 1991; 325: 303-10

4. Freemantle N. Are health decisions taken by health care profes-sionals rational? Anon systematic review of experimental andquasi experimental literature. Health Policy 1996; 38: 71-81

5. Mair FS, Carowley TS, Bundred PE. Prevalence, aetiology andmanagement of heart failure in general practice. Br J GenPract 1996; 46: 77-9

6. Clark KW, Gray D, Hampton JR. Evidence of inadequate in-vestigation and treatment of patients with heart failure. BrHeart J 1994; 71: 584-7

7. Freemantle N. Cost effectiveness of non steroidal anti inflam-matory drugs: what makes a NSAID good value for money?Rheumatology. In press

8. Tatsumi M, Groshan K, Blakely, R et al. Pharmacologicalprofile of antidepressants and related compounds at humanmonamine transporters. Eur J Pharmacol 1997; 340: 249-58

9. Eccles M, Clarke J, Livingstone M, et al. North of England evi-dence based guidelines development project: guideline for theprimary caremanagement of dementia. BMJ 1998b; 317: 802-8

10. Anderson IM, Tomenson BM. Treatment discontinuation withselective serotonin reuptaker inhibitors compared with tricy-clic antidepressants: a meta analysis. BMJ 1995; 310: 1433-8

11. Eccles M, Freemantle N, Mason JM, for the North of EnglandGuidelines Development Group. The choice of antidepressantsfor depression in primary care. Fam Pract 1999; 16: 103-11

12. Song F, Freemantle N, Sheldon TA, et al. Selective serotoninreuptake inhibitors: meta-analysis of efficacy and accept-ability. BMJ 1993; 306: 683-7

13. Anderson IM, Tomenson BM. Treatment discontinuation withselective serotonin reuptake inhibitors compared with tricy-clic antidepressants: a meta analysis. BMJ 1995; 310: 1433-8

14. Eccles M, Freemantle N, Mason J. The choice of antidepres-sants for depression in primary care. Newcastle upon Tyne:Centre for Health Services Research, 1998

15. Eeeles M, Freemantle N, Mason JM. Mehtods of developingguidelines for efficient drug use in primary care: North ofEngland Evidence Based Guidelines Development Project.BMJ 1998; 316: 1232-5

16. Simon GE, Vonkorff M, Heilingenstein JH, et al. Initial antide-pressant choice in primary care: effectiveness and cost offluoxetine vs tricyclic antidepressants. JAMA 1996; 275:1897-902

17. Freemantle N, Drummond MF. Should clinical trials with con-current economic analyses be blinded? JAMA1997; 277: 63-4

18. Beasley Jr CM, Dornseif BE, Bosomworth JC, et al. Fluoxetineand suicide: a meta-analysis of controlled trials of treatmentfor depression. BMJ 1991; 303: 685-92

19. Fundholding [advertisement]. 1994; 3 (3)20. Effective Health Care. The treatment of depression in primary

care, Bulletin No. 5. Leeds: University of Leeds, 199321. Mason J, Freemantle N, Young P. The effect of the distribution

of Effective Health Care Bulletins on prescribing selectiveserotonin reuptake inhibitors in primary care. Health Trends1998/9; 30: 120-2

22. Cowley G, Springen K, Leonard EA, et al. The promise ofProzac. Newsweek 1990; Mar 26: 42-5

23. Brown ED, Epperson SE. The personality pill. Time 1993; Oct11: 59-60

24. Grilli R, Freemantle N, Minozzi S, et al. Impact of mass mediaon health services utilisation (Cochrane review). Oxford: TheCochrane Library, 1998: issue 3. Update software

25. Kramer PD. Listening to prozac: a psychiatrist explores antide-pressant drugs and the remaking of the self. New York: Vik-ing, 1993: xvi

26. Wurtzel E. Prozac nation: young and depressed in America.New York: Riverhead, 1995. 302

27. Freemantle N. Does the UK need a fourth hurdle for pharma-ceutical reimbursement to encourage the more cost effectiveprescribing of pharmaceuticals?Health Policy 1999; 46: 255-65

28. Bland JM, Jones DR, Bennett S, et al. Is the clinical trial evi-dence about new drugs statistically adequate? Br J Clin Phar-macol 1985; 19: 155-60

29. Smith PC. Reforming markets in health care: an economic per-spective. Buckingham: Open University Press, 2000: 211-45

Correspondence and offprints: Dr Nick Freemantle, Medi-cines Evaluation Group, Centre for Health Economics, Uni-versity of York, Heslington, York Y010 5DD, England.



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The Importance of Achieving Additional Drug Benefits at a Reasonable Cost