pros and cons for the development of new antiepileptic drugs

Pros and Cons for the Development of New Antiepileptic DrugsMeir Bialer,1 Matthew C. Walker2 and Josemir W. Sander2

1 Department of Pharmaceutics and David R. Bloom Centre for Pharmacy, School of Pharmacy,Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel

2 Epilepsy Research Group, Department of Clinical Neurology, Institute of Neurology, University College London, London, UK

Abstract There continues to be an escalation in the number of new antiepileptic drugs,with many recently marketed drugs and many more entering clinical trials. Thisgrowth begs the question as to whether we need additional antiepileptic drugs.We consider the answer to this question from the medical perspective and alsofrom the viewpoint of the pharmaceutical industry, health providers and from amore global, international perspective.

There is undoubtedly a medical need for new antiepileptic drugs, and despitegrowing competition, the antiepileptic drug market remains profitable. However,in health services with limited resources, it is important that this expense is notoffset by failure to research more appropriate use of existing antiepileptic drugsthat may have a greater impact on healthcare. This is especially true for develop-ing countries where resources would be much better spent on prevention andclosing the treatment gap (the difference between those who can be treated andthose who are treated).

CURRENT OPINION CNS Drugs 2002; 16 (5): 285-2891172-7047/02/0005-0285/$25.00/0

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‘It is demonstrable’, said he, ‘that things cannot beotherwise than as they are; for as all things have beencreated for some end, they must necessarily be createdfor the best end…’

Master Pangloss in ‘Candide’ – Voltaire

In recent years there has been a burgeoning ofantiepileptic drug (AED) development with tennew drugs being licensed worldwide in the lastdecade, and many more in development.[1] Thisever-increasing arsenal begs the question as towhether development of further new AEDs is war-ranted. As with all questions, the answer dependsupon the perspective of the respondent. In thetreatment of epilepsy, four main standpoints areencountered: (i) the patient and doctor (i.e. themedical perspective); (ii) the pharmaceutical in-

dustry; (iii) the local health provider; and (iv) theinternational perspective.

This commentary presents the personal viewsof the authors on the development of new AEDs; itis not intended to be a comprehensive review of thesubject.

1. The Medical Need for New Treatments

Epilepsy is one of the most common seriousneurological conditions, affecting around 0.5% ofthe population.[2] There are approximately 20 to 70new cases per 100 000 of the population per year,and the lifetime chance of developing epilepsy is 3to 5%.[2] Thus, the aim of AEDs should be to pre-vent seizures, have good tolerability, improve the

prognosis of the condition and act as effective pro-phylaxis in situations where epilepsy may develop(e.g. following head trauma).

Approximately 70 to 80% of patients with epi-lepsy are successfully treated with present AEDs,and over half of these will be able to stop treatmentsuccessfully.[3] This leaves approximately 20 to30% of patients who have epilepsy that is resistantto present AEDs, and very few of these patients(<5%) are suitable for epilepsy neurosurgery. Re-cently launched AEDs, which are initially licensedfor use in this refractory group, have had little im-pact, possibly rendering fewer than 5% of thisgroup seizure free.[4-6] Thus, effective novel AEDsare still required for the treatment of those withrefractory epilepsy, approximately 0.15% of thegeneral population. A recent study suggests thatonly 3% of patients have their epilepsy controlledby two AEDs, because patients who have many sei-zures before treatment or have inadequate responseto monotherapy with an initial AED are likely tohave refractory epilepsy.[5]

Even in those in whom established AEDs areeffective, adverse effects commonly restrict theiruse. Indeed, in comparative drug studies in newlydiagnosed patients there is more often a differencein treatment failure due to drug adverse effects thanto a lack of efficacy (see for example, Mattson etal.[7]). Thus, improving the tolerability of AEDs isa second and important aim.[8] This aim has beenachieved to some extent with the newer AEDs; forexample, in recent studies comparing carbamaze-pine with lamotrigine there was no difference inefficacy between the two AEDs, although bettertolerability, as indicated by few adverse effects andlower drop-out rates, was reported among the pa-tients treated with lamotrigine.[9-11]

A third aspect is that of prognosis. It has beenargued that failure to control seizures early in thecourse of the epilepsy leads to a later drug resis-tance.[12] An alternative explanation is that mostepilepsy has an inherent severity in response totreatment and that the prognosis is not changed byearly treatment.[3] This latter interpretation is sup-ported by studies of untreated populations in devel-

oping countries in which the prognosis for seizurecontrol is similar to that obtained in the developedworld despite the considerable delay in treat-ment.[8] Furthermore, the probability of long-termremission following a single tonic-clonic seizure isnot influenced by a delay in treatment until the sec-ond seizure.[13]

Thus, there is evidence to suggest that early AEDtreatment favourably alters the prognosis of epi-lepsy, yet there is a growing body of evidence,mainly from untreated populations in developingcountries, to suggest that present AED treatmenthas little or no influence on the prognosis of epi-lepsy.[3,5] Indeed, the prognosis of a patient withepilepsy is likely to relate to the underlying causeof the epilepsy and a number of other factors thathave yet to be identified.

Furthermore, there is substantial evidence thatestablished AEDs have no effect when used as pro-phylaxis to prevent the occurrence of epilepsy fol-lowing head injury or neurosurgery.[14,15]

Novel agents are thus required: to treat patientswith refractory epilepsy; to improve AED toler-ability; to prevent epileptogenesis and to cause dis-ease modification in epilepsy; and to improve theprognosis of epilepsy.[11,16,17] There is thus nodoubt that we need more effective treatments.

2. The Pharmaceutical Industry Perspective

The main aim for the pharmaceutical industry isthe generation of profit for shareholders; conse-quently, the overriding motivation for the develop-ment of new AEDs is a financial one. Ease of de-velopment of new drugs and the potential formaximum profit at the earliest opportunity are im-portant determinants.

The average cost of developing a drug is in ex-cess of $US500 million. A successful AED can,however, generate a profit well in excess of this.For instance, in 2000, the annual sales in the US ofvalproic acid (sodium valproate) were $US880million, and gabapentin had, in 2000, annual salesin the US of $US1.1 billion.[18] In 2000, lamotrig-ine and topiramate produced $US223 and $US220

286 Bialer et al.

© Adis International Limited. All rights reserved. CNS Drugs 2002; 16 (5)

million, respectively, in annual sales in the US.[18]

Compared with their 1999 sales, these sales repre-sent a growth of 50% for gabapentin, 31% forlamotrigine and 105% for topiramate.[18] The rev-enue flow continues despite a less than optimal effi-cacy (pharmacodynamic) profile, adverse effects,teratogenicity, patent expiration and competitionfrom generics.

Any new AEDs that are well tolerated and havebreadth of utilisation can achieve a good marketshare of this therapeutic area within a couple ofyears following launch (e.g. gabapentin). Further-more, the approval of new AEDs is used as a lever-age for utilisation in other CNS conditions. NewAEDs are used extensively in other therapeuticareas. The major prescription for gabapentin isnow for pain rather than epilepsy. Carbamazepinewas initially launched for the treatment of trigem-inal neuralgia and only later approved for epilepsy.The pharmaceutical industry has now adapted thestrategy of evaluating their AED lead compoundsin other therapeutic areas following the successfulphase II controlled efficacy trials in epilepsy.

It is not only the potential profit that makes thedevelopment of AEDs attractive. In epilepsy thereare good animal models for antiepileptic activityand objective outcome assessment criteria for clin-ical trials. Only approximately 2000 patient expo-sures are needed for approval of a drug for partialseizures. This number decreases with some of theless common seizure types. These facts make thedevelopment of new AEDs relatively easy com-pared with therapies for other CNS disorders.

At present, large multinational corporations arethe main sponsors of research into the numerousareas of new therapies, and this is unlikely tochange. The development of new drugs is depend-ent on the interest of these companies, and it islikely that further advances will require collabora-tion between academia, government and the phar-maceutical industry.

3. The Cost to Society

The cost of developing new drugs is huge, andthese costs are reflected in the prices of new AEDs,

which are many times higher than those of conven-tional therapies.[19,20] With increasing awarenessof healthcare costs, these high prices may soon befelt to be unacceptable, particularly when the cost-effectiveness of these new drugs remains un-proven.[21] For example, a cost-benefit analysis forlamotrigine (500mg) as adjunctive therapy calcu-lated a cost of $US41 000 per quality-adjusted lifeyear gained; this was estimated to be higher thanmany other pharmacological interventions (e.g.chemotherapy for breast cancer, antihypertensivetherapy, and so forth).[22]

This study, however, assumed that patients witha minimal response to treatment continued lam-otrigine lifelong, when most patients, even re-sponders, do not continue treatment. It also as-sumed a dose of lamotrigine that is higher than thedose usually used. These particular problems arenot typically encountered with other pharmacolog-ical interventions, which are usually used for afixed period with a well-defined dose, but in thisinstance these false assumptions had a massive ef-fect on estimated cost. Thus, the conclusion of thestudy that lamotrigine (and by association othernew AEDs) is ‘too expensive relative to the bene-fits’ is questionable. Nevertheless, epilepsy sur-gery, when effective, is far more cost-effective thandrug treatment despite the high financial outlay as-sociated with assessment and surgery.[6,23] Thus,from the viewpoint of the health provider, the cost-benefit of new AEDs still remains unproven.

The separation of drug costs from health serviceresearch funding has had a more harmful effect,because it is rare to compare drug costs with thoseof research. A more worthwhile approach in a sys-tem with limited resources may be to sponsor re-search into rational approaches to the use of exist-ing AEDs. In our use of AEDs, we have beenhampered by a lack of both comparative studiesand trial results that have direct clinical applicabil-ity.[24] This has led to a culture in which one AEDis tried after another in a largely arbitrary fashion.This may provide plenty of ‘treatment options’ –with nine drugs there are many (>100) combina-tions of three or fewer drugs – but it is difficult to

Development of New Antiepileptic Drugs 287


see how this approach can be ‘for the best’. A cru-cial issue for new AEDs is their cost effectivenessand not their cost, and as stated by Chadwick[8] ‘thereal question is not whether new AEDs justify theirexpense so much as can we afford to ignore newAEDs?’.

4. The International Perspective

If we consider the cost of treatment in a globalsetting, then the argument against further develop-ment of AEDs becomes more compelling. It couldbe argued that some of the huge resources presentlyused in the development of new AEDs could beredirected towards the great majority of individualswith epilepsy who live in the countries of the de-veloping world where AED treatment is not usuallyavailable. Indeed, the treatment gap (i.e. peoplewith epilepsy not receiving treatment versus thosewho could be treated) has been estimated to be over80%.[24] Providing treatment with establisheddrugs to patients not currently receiving any treat-ment would probably contribute more to the atten-uation of the global burden of epilepsy than yetanother ‘me too’ AED.

There is a strong argument for preventing epi-lepsy. Infections and parasitic diseases are the com-monest cause of epilepsy in the tropical belt. Neu-rocysticercosis, a parasitic condition, isresponsible for more than half of the cases of epi-lepsy in parts of Latin America, Africa andAsia.[25,26] Provision of basic sanitation in theseendemic areas can break the life-cycle of the para-site and would, in the medium and long term, havea much larger impact on the burden of epilepsy thanany new AED. Astudy conducted in Kenya showedthat 53% of newly diagnosed patients becomeseizure free within 6 months following treatmentwith phenobarbital (phenobarbitone) or carbamaz-epine;[27] this rate is similar to that seen in newlydiagnosed patients in the developed world.[27]

5. Conclusion

The main impetus for the development of fur-ther AEDs comes from physicians in developedcountries seeking ‘better’ drugs for patients, and

this, with their profitability and ease of develop-ment, will provide the fuel for continued AED de-velopment. Although new AEDs have high acqui-sition costs, there are no good data showing that theexpense to society is excessive, explaining thecompliance of health providers in the face of thegrowing AED bill.

The greatest argument against the continued ex-pense of new AEDs is that the money could bebetter spent elsewhere. On a parochial level, themoney could be better spent on trials and researchinto the optimisation of the use of existing drugs.In the global setting, there is little justification forthe expense of new AEDs, when less than 10% ofthe resources that are currently devoted to the de-velopment and marketing of new drugs couldrender the majority of people with epilepsy in theworld (i.e. those who are not treated) seizure freewith the currently available drugs.

Whatever the standpoint, there can be littledoubt that the treatment of epilepsy needs to ad-vance. Epilepsy is such a heterogeneous conditionthat it is unlikely that a drug that is efficacious forall patients will ever be found. New paradigms forthe development of drugs need to be advanced, in-corporating clinically useful outcome measuresand cost effectiveness assessment into their design.Studies to delineate the range of epileptic syn-dromes should be strongly encouraged. But mostimportantly, an understanding of the basic mecha-nisms of epileptogenesis is paramount in order toachieve what is needed – drugs that prevent or‘cure’ epilepsy.

Voltaire’s figure of fun, Master Pangloss, had adeterministic, optimistic philosophy that remainedunaltered despite the suffering that ensued. Thisintransigence is still encountered in the treatmentof epilepsy, in which drug trial follows drug trialusing the same questionable criteria and definitions.

Acknowledgements

No funding was used to compose this commentary.The initiative to write this commentary came during a

mini-sabbatical of M. Bialer in the summer of 1999 at theDepartments of Neuroscience Drug Discovery and Metabo-lism and Pharmacokinetics (MAP) of the Pharmaceutical

288 Bialer et al.


Research Institute of Bristol-Myers Squibb in Wallingford,CT and Princeton, NJ, USA.

References1. Bialer M, Johannessen SI, Kupferberg HJ, et al. Progress report

on new antiepileptic drugs: a summary of the Fifth Eilat con-ference (EILAT V). Epilepsy Res 2001; 43: 11-58

2. Sander JW, Shorvon SD. Epidemiology of the epilepsies. J Neu-rol Neurosurg Psychiatry 1996; 61: 433-43

3. Sander JW. Some aspects of prognosis in the epilepsies: a re-view. Epilepsia 1993; 34: 1007-16

4. Wong IC, Chadwick DW, Fenwick PB, et al. The long-term useof gabapentin, lamotrigine, and vigabatrin in patients withchronic epilepsy. Epilepsia 1999; 40: 1439-45

5. Kwan P, Brodie MJ. Early identification of refractory epilepsy.N Engl J Med 2000; 342: 314-9

6. Wree S, Blume WT, Girvin JP, et al. A randomized, controlledtrial of surgery for temporal lobe epilepsy. N Engl J Med2001; 345: 311-8

7. Mattson RH, Cramer JA, Collins JF, et al. Comparison of carba-mazepine, phenobarbital, phenytoin, and primidone in partialand secondarily generalized tonic-clonic seizures. N Engl JMed 1985; 313: 145-51

8. Chadwick D. Do new antiepileptic drugs justify their expense?Arch Neurol 1998 Aug; 55 (8): 1140-2

9. Brodie MJ, Richens A, Yuen AW. Double blind comparison oflamotrigine and carbamazepine in newly diagnosed epilepsy.UK Lamotrigine/Carbamazepine trial group. Lancet 1995;345: 476-9

10. Brodie MJ, Overstall PW, Giorgi L. Multicentre, double-blind,randomized comparison between lamotrigine and carbamaz-epine in elderly patients with newly diagnosed epilepsy. UKLamotrigine Elderly Study Group. Epilepsy Res 1999; 37:81-7

11. Reunanen M, Dam M, Yuen AW. A randomised open multi-centre comparative trial to lamotrigine and carbamazepine asmonotherapy in patients with newly diagnosed or recurrentepilepsy. Epilepsy Res 1996; 23: 149-55

12. Reynolds EH. Do anticonvulsants alter the natural course ofepilepsy? BMJ 1995; 310: 176-7

13. Musicco M, Beghi E, Solari A, et al. Treatment of first tonic-clonic seizure does not improve the prognosis of epilepsy.Neurology 1997; 49: 991-8

14. Foy PM, Chadwick DW, Rajgopalan N, et al. Do prophylacticanticonvulsant drugs alter the pattern of seizures after cranio-tomy? J Neurol Neurosurg Psychiatry 1992; 55: 753-7

15. Schierhout G, Roberts I. Prophylactic antiepileptic agents afterhead injury: a systematic review. J Neurol Neurosurg Psychi-atry 1998; 64: 108-12

16. Serge JCP-L. New drugs: which should be included in the for-mulary? Arch Neurol 2000; 57: 272-3

17. Sander JWAS, White HS. Disease modification in epilepsy.Prog Neurol Psychiatry 2001; 5 Suppl.: 1-12

18. International Marketing Service (IMS-HEALTH). London:IMS World Publication Ltd, 2001

19. Hachinski V. New antiepileptic drugs: the cost of innovation.Arch Neurol 1998; 55: 1142

20. Bergen DC. Restrictions on the availability of antiepilepticdrugs. Arch Neurol 2000; 57: 273-4

21. Heaney DC, Shorvon SD, Sander JW, et al. Cost minimizationanalysis of antiepileptic drugs in newly diagnosed epilepsy in12 European countries. Epilepsia 2000; 41 Suppl. 5: S37-44

22. Messori A, Trippoli S, Becagli P, et al. Adjunctive lamotriginetherapy in patients with refractory seizures: a lifetime cost-utility analysis. Eur J Clin Pharmacol 1998; 53: 421-7

23. Heaney DC, Sander JW. Ensuring appropriate care in epilepsy:an overview of epidemiological and cost of illness consider-ation. Dis Manage Health Outcomes 1999; 4: 303-13

24. Walker MC, Sander JW. Difficulties in extrapolating from clin-ical trial data to clinical practice: the case of antiepilepticdrugs. Neurology 1997; 49: 333-7

25. Shorvon SD, Farmer PJ. Epilepsy in developing countries: areview of epidemiological, sociocultural, and treatment as-pects. Epilepsia 1988; 29 Suppl. 1: S36-54

26. Pal DK, Carpio A, Sander JW. Neurocysticercosis and epilepsyin developing countries. J Neurol Neurosurg Psychiatry 2000;68: 137-43

27. Feksi AT, Kaamugisha J, Sander JWAS, et al. Comprehensiveprimary health care antiepileptic drug treatment programmein rural and semi-urban Kenya. Lancet 1991; 337: 406-9

Correspondence and offprints: Prof. Meir Bialer, Depart-ment of Pharmaceutics and David R. Bloom Centre forPharmacy, School of Pharmacy, Faculty of Medicine, TheHebrew University of Jerusalem, P.O. Box 12065, Jerusalem,91120, Israel.

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pros and cons for the development of new antiepileptic drugs

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