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Review article with video sequences

Epileptic Disord 2010; 12 (1): 3-15

The evolution of antiepileptic drug development and regulation

Alexis Arzimanoglou1, Elinor Ben-Menachem2, Joyce Cramer3, Tracy Glauser4, Rav Seeruthun5, Miranda Harrison5 1 Institute for Children and Adolescents with – IDEE, University Hospitals of Lyon (HCL) and Inserm U821, Lyon, France 2 Sahlgren University Hospital, Göteborg, Sweden 3 Yale University School of Medicine, West Haven, CT, USA 4 Cincinnati Children’s Hospital, Cincinnati, Ohio, USA 5 Eisai Knowledge Centre, Mosquito Way, Hatfield, UK

ABSTRACT – The early years of antiepileptic drug development were charac- terised by observation and serendipity, rather than a rational, targeted approach to drug development. Control of seizures was seen as the primary aim of ther- apy, with much less focus on safety and tolerability. However, experience with thalidomide in the 1960s brought safety to the fore, resulting in an era of much tighter regulatory control that still persists today. A direct consequence of this was an increased emphasis on the importance of evidence from randomised controlled trials. Despite the continuing reliance on randomised controlled trials for regulatory approval and the formulation of evidence-based guidelines, the modern era has seen an increasing acknowledgment of their limitations and the need for complementary sources of ‘real-world’ evidence. Such sources include registries and studies that are designed to provide a much broader assessment of a drug’s overall effectiveness; for example, by incorporating patient-reported outcomes to assess the effects of treatment on quality of life or functional status. Such changes reflect a more patient-centric approach to treat- ment, since it is now recognised that epilepsy can only be effectively managed if patients’ individual real-life needs are addressed, since a key to successful treat- ment is long-term compliance. Alongside these changes in approach, the mod- ern era has witnessed important advances in antiepileptic drugs themselves, either through development of novel molecules, or targeted, structural improve- ments of older agents. [Published with video sequences and a set of slides] Keywords: antiepileptic drugs, clinical trials, drug development, regulation, QOL, patient-reported outcome

Correspondence: Pr A. Arzimanoglou Head of Epilepsy, Sleep and Paediatric Neurophysiology Department, Institute for Children and Adolescents with Epilepsy – IDEE HFME, University Hospitals of Lyon, This manuscript is based on a symposium held during the 28th International Epilepsy 59 boulevard Pinel, Congress, Budapest, Hungary, 28th June-2nd July, 2009, sponsored by Eisai Europe 69677 Lyon, France Ltd. The slides from the symposium are available on the DVD and can be used for

doi: 10.1684/epd.2010.0303 didactic purposes.

Epileptic Disord Vol. 12, No. 1, March 2010 3 A. Arzimanoglou, et al.

2009 marks the centenary of the formation of the Animal models: a great leap forward (slides 11-14) International League Against Epilepsy (ILAE) and provides The next major advance in AED discovery was the intro- a timely opportunity to reflect upon the progress of epi- duction of epilepsy animal models; these models allowed lepsy management over this period. A fundamental aim for the screening of multiple compounds for antiepileptic of epilepsy therapy has always been seizure control, but activity prior to testing in humans. The pioneering work of other goals have evolved over time and treatment has Drs. Houston Merritt and Tracy Putnam focused on become more individualised and patient-focused. This screening compounds for antiseizure activity using elec- article reviews the evolution of antiepileptic drug (AED) trically induced seizures in cats. Their team subsequently therapy (see video sequence), discusses how some of discovered the properties of the molecule the key regulatory changes came about and how these diphenylhydantoin, later known as (Merritt and impacted on AED development, and also assesses how a Putnam, 1938). The identification of phenytoin’s antisei- more patient-focused approach may improve epilepsy zure activity through animal models was a significant management in the future. event for several reasons. Phenytoin was subsequently shown to be beneficial for a large number of epileptic patients in whom and were ineffec- Early years of AED development tive. Secondly, clinically efficacious doses of phenytoin were not associated with the sedative effect of these The value of observation (slides 3-10) other agents. Thirdly, the success of testing using an ani- mal model demonstrated that a systematic approach to In the modern era, potassium was the first drug screening could be utilised to discover compounds with considered to have value for treating people with epi- clinical efficacy. This meant that subsequent costly and lepsy. On 11th May 1857, Sir Charles Locock presided at time-consuming clinical trials could be reserved for the a meeting of the Royal Medical and Chirurgical Society at most effective compounds identified by these animal which Dr. Edward H. Sieveking presented an analysis of experiments. Lastly, the compounds screened by Merritt his care of 52 patients with epilepsy. In the subsequent and Putnam were provided by Parke-Davis; this was prob- discussion, Locock commented that he had successfully ably the first successful industry-academia collaboration used to treat women with what he in AED discovery, a relationship that has subsequently called hysterical epilepsy (catamenial epilepsy). At the flourished up to the present day (Krall et al., 1978). time it was believed that bromide could dampen the sex- Phenytoin soon proved its value clinically, showing greater ual excitement thought to cause these seizures (Williams, efficacy than in reducing various seizure types 1866; Pearce, 2002). Subsequent reports of its efficacy without the associated CNS side effects (Mattson et al., 1985; eventually led to widespread use of bromides for the treat- Heller et al., 1995). It became established as a first-choice ment of seizures, often in combination with other agents AED for partial onset seizures, and is still widely used in such as digitalis, belladonna, and iron (Gowers, many markets today. However, phenytoin was also found 1881; Friedlander, 2000). to have multiple major limitations, including non-linear Bromides remained the foundation of epilepsy treatment , extensive drug interactions (Richens, for many years. Their use was, however, associated with 1979), and chronic toxicities such as hirsutism, gingival dermatological conditions, such as severe rash, and psy- hyperplasia and the coarsening of facial features, all of chological symptoms, such as irritability, emotional insta- which can stigmatise patients (Johnson, 1984; Scheinfeld, bility and even a schizophrenic-like psychosis in many 2004). Serious delayed effects, such as carcinogenicity and patients (“bromism”). Serendipity then played a key role teratogenicity, have also been associated with its use in the discovery of the antiepileptic efficacy of phenobar- (Azarbayjani and Danielsson, 2001; Singh et al., 2005). bital. Barbiturates were already widely used as The discovery of phenytoin was followed by the rapid iden- and sedatives in 1912, when Albert Hauptmann, a young tification and introduction of several new drugs produced clinical assistant in Freiburg, Germany, gave phenobarbi- largely by altering the basic chemical moiety of known tal to his epilepsy patients as a tranquilizer and observed AEDs. These included analogues of phenytoin such as that the frequency of their seizures was reduced , and those of phenobarbital such as metharbi- (Hauptmann, 1912). Subsequent studies revealed that tal and , many of which are no longer widely used. phenobarbital was more efficacious than bromides and, : first of a new generation of AEDs since it was not associated with their ‘bromism’ problems, (slides 15-20) phenobarbital eventually became a widely used AED. Some physicians treating epilepsy also began to use bro- Carbamazepine (CBZ) was the next major advance in mide in combination with phenobarbital at variable doses AED development and, to this day, remains the gold (Shorvon, 2009a). This can be considered the beginning standard for partial onset epilepsy in Europe. The anticon- of “rational polytherapy”. vulsant properties of this tricyclic compound were

4 Epileptic Disord Vol. 12, No. 1, March 2010 The evolution of antiepileptic drug development and regulation

discovered by Walter Schindler at Geigy in 1953 during rigid trial designs relating to long-term safety. However, the development of the antidepressant drug this all changed with one of the most infamous chapters (Schindler and Häfliger, 1954). Animal screening later in the history of drug development and regulation. showed CBZ had potential utility for trigeminal neuralgia, Thalidomide entered the German market in the late 1950s which was confirmed by clinical trials, and it was as a sedative to treat insomnia, as well as to reduce nau- first marketed for this indication (Blom, 1962). CBZ’s sea associated with pregnancy, and was widely available antiepileptic effects were initially reported by two small in Europe by 1960. However, in 1961 Lenz (Lenz et al., open-label studies (Bonduelle et al., 1964; Lorge et al., 1961) and McBride (McBride, 1961) independently 1963), but confirmed by larger subsequent trials. By the reported that prenatal use of thalidomide was resulting mid-1960s the drug was marketed in most European in severe birth defects. By 1961, > 8,000 children were countries, but approval in the USA for epilepsy was born with severe limb abnormalities and other organ delayed until 1974 because of reports of aplastic anaemia defects as a result of prenatal exposure to thalidomide (Fertig and Mattson, 2007). It also emerged that CBZ use (Annas and Elias, 1999). In the USA, the Food and Drug was associated with idiosyncratic rash, hyponatraemia, Administration (FDA) had not granted approval of the haematological toxicity and hepatic dysfunction, as well New Drug Application submitted by Richardson-Merrill, as rare adverse events (AEs) such as thrombocytopenia because of concerns about peripheral neuropathy and Stevens-Johnson syndrome (Durelli et al., 1989; associated with use of the agent. Although around Tohen et al., 1991; Dong et al., 2005; Devi et al., 2005). 20,000 patients received the drug during experimental By the mid 1980s, CBZ became the most prescribed AED clinical investigations, only 17 affected infants were in Europe and remains a recommended first-line mono- reported in the USA, and the company withdrew its appli- therapy for partial seizures in major international guide- cation after the effects were widely publicised (Annas and lines (French et al., 2004; NICE, 2004; Glauser et al., Elias, 1999). It was later discovered that thalidomide pos- 2006). It is also currently the comparator of choice for sessed anti-inflammatory and immunomodulatory proper- non-inferiority trials used to obtain a monotherapy licence ties, leading to its use for the treatment of erythema nodo- for new AEDs (Brodie et al., 2007). sum leprosum, a severe dermatological complication of The first Veterans Administration Epilepsy Cooperative Hansen’s disease (formerly known as leprosy), and for Study (VA Cooperative Study) prospectively compared the treatment of multiple myeloma (Annas and Elias, CBZ, phenobarbital, phenytoin and primidone in newly- 1999; Palumbo et al., 2008). treated partial and secondarily generalised tonic-clonic At the time of thalidomide, the USA was operating seizures (Mattson et al., 1985). CBZ and phenytoin were under the 1938 Food, Drug and Cosmetic Act, which found to be the most effective in terms of retention and did not require demonstration of efficacy for a drug to seizure control. The second VA Cooperative Study, be approved. In the early 1960s the drug approval comparing CBZ and for partial-onset seizures, process was under considerable criticism, which led also showed unsurpassed efficacy for CBZ (Mattson to the introduction of the Kefauver-Harris Drug et al., 1992). However, only one-third of the combined Amendments in October 1962. This legislation included 1,100 patients achieved seizure freedom, and all drugs proof of efficacy, “informed consent” from clinical trial were associated with multiple AEs. Over time, increasing participants, and reporting of all adverse reactions. In clinical experience and the emerging availability of brain 1968, the FDA initiated the Drug Efficacy Study imagining techniques helped to improve the safety profile Implementation (DESI) programme to retrospectively of AEDs, since the delineation of specific epilepsy syn- review the effectiveness of drugs marketed between dromes allowed the identification of the aggravating 1938 and 1962. The thalidomide tragedy also provided effects of certain AEDs in specific patient groups. For the impetus for the introduction in European countries example, it was discovered that myoclonic seizures are of regulatory control of drugs to be marketed, leading aggravated by CBZ (Horn et al., 1986; Genton et al., to the EU Council Directive 65/65/EEC. In the United 2000). However, there was clearly still a need for effective Kingdom, the result was the Medicines Act 1968 and new AEDs with improved safety profiles. the establishment of the Licensing Authority (Shah and Griffin, 2006). The new FDA legislation requiring a degree of proof of Changing regulatory environment: efficacy resulted in delayed AED development in the effect on AED development USA. This was for several reasons, including lack of appropriate populations for controlled trials, a reluctance from patients to try drugs in clinical trials, and difficulties Thalidomide: a consequence of poor regulation (slides 22-25) in designing studies with multiple drugs. Furthermore, there was controversy over definition of specific seizure In the 1950s and 1960s drug development continued in types, as brain imaging techniques were not yet available an environment lacking either strict regulatory control or and EEG monitoring was not routinely used, and also a

Epileptic Disord Vol. 12, No. 1, March 2010 5 A. Arzimanoglou, et al.

lack of rigorous methodology for measuring response. In Randomised controlled studies: “Gold standard” evidence? fact, between 1961 and 1973 no new drug was marketed (slides 25-33) in the USA with control of epilepsy as a primary indica- tion (Krall et al., 1978). Sir Austin Bradford Hill, an English statistician, is credited The first novel AED in the new regulatory era was valproate with developing the first randomised controlled trial (VPA), which was first synthesised in 1881 and used as an (RCT), which examined streptomycin in patients with organic solvent (Shorvon, 2009b). The anticonvulsant prop- pulmonary tuberculosis (Streptomycin in Tuberculosis erties of valproate were identified by Pierre Emyard in Trials Committee, 1948). He also demonstrated the link France in 1962 and it was marketed in France in between smoking and lung cancer (Doll and Hill, 1954) “ 1967 (Loiseau, 1999). It then rolled out in other EU coun- and published the landmark paper The environment and ” tries from 1970 onwards, but did not receive a license in disease: association or causation? (Hill, 1965). Medical the US until 1978. VPA is a broad-spectrum AED, effective researchers were initially slow to undertake RCTs, but against all seizure types (Perucca, 2002). It became they have subsequently become the “Gold standard” of the most widely prescribed AED worldwide, generally evidence: properly conducted, they provide a means of regarded as a first-choice agent for most forms of idiopathic assessing the specific effects of an intervention, since ran- and symptomatic generalised , many of which are domisation ensures that, on average, all other possible associated with multiple seizure types, including tonic- causes of effect are equal between groups. By the late clonic, myoclonic and absence seizures (Perucca, 2002). 1980s there were approximately 5000 RCTs published Although the agent was shown to have clear efficacy for each year (Devereaux and Yusuf, 2003). RCTs have the treatment of idiopathic generalised epilepsy, there evolved in design and outcomes from the first small were concerns over its safety profile, including cognitive RCTs, primarily in the area of infectious disease, to large problems, teratogenicity and weight gain (Sztajnkrycer, simple RCTs that evaluate major clinical outcomes and 2002; Wirrell, 2003; Duncan, 2007). It remains the drug form the basis of clinical practice guideline development of choice for generalised seizures (NICE, 2004; Glauser (figure 1). In the field of epilepsy, the VA Cooperative et al., 2006). Study Group was the first to develop a modern clinical

1948: first RCT of 1962: FDA requirement Growing acceptance streptomycin in patients for proof of efficacy + that RCTs provide with pulmonary TB safety (Kefauver-Harris optimal assessment of amendment) an intervention

Late 1980s: ~5000 Present day: evidence RCTs published/year Increasing focus on from RCTs and other evidence-based sources used to develop medicine specific clinical practice guidelines e.g. ILAE guidelines 1993: Cochrane Collaboration set up

1999: QUOROM 1996: first CONSORT 1995: Cochrane statement published to statement published to Database of improve standards of improve standards of Systematic Reviews meta-analysis RCTs launched

Figure 1. Evolution of randomised controlled trials. CONSORT: consolidated standards of reporting trials; FDA: Food and Drug Administration; ILAE: International League Against Epilepsy; QUOROM: Quality of Reporting of Meta-analyses; RCT: randomised controlled trial; TB: tuberculosis.

6 Epileptic Disord Vol. 12, No. 1, March 2010 The evolution of antiepileptic drug development and regulation

trial with quantifiable endpoints, using long-term reten- epilepsy. Within 1 year, it had been prescribed to tion as well as seizure severity and adverse effects scales 126,000 patients with epilepsy. However, in September (Mattson et al., 1985). 1994 the FDA had to issue a “Dear Doctor” letter, warn- However, there are limitations to RCTs. They are rela- ing of a higher than expected incidence of aplastic anae- tively short in duration, while chronic diseases, such as mia and hepatic failure among patients receiving felba- epilepsy, require long-term treatment, and they are diffi- mate (French et al., 1999). The FDA decided to allow it cult to conduct in patients with rare conditions, due to to remain on the market, but with restricted use. It can be low patient numbers. RCTs provide evidence of short- considered for use in those patients who respond inade- term efficacy and safety for regulatory purposes, and fol- quately to alternative treatments and whose epilepsy is so low set protocols which contain inclusion/exclusion crite- severe that the risks of aplastic anaemia and hepatic fail- ria and a set dosing schedule. However, in the clinic treat- ure are outweighed by the benefits of the drug ( ment is tailored to ensure that individual patients receive Prescribing Information, 2008). Similarly, felbamate is an AED at a dose that they find both effective and tolerate available in Europe on a patient-by-patient basis. well, as this encourages compliance. There are also methodological issues associated with conduct- Registries vs RCTs (slides 34-40) ing RCTs. The majority of regulatory RCTs are placebo- controlled, but the use of placebo can itself be problem- The cases outlined for and felbamate illustrate atic. For example, in RCTs of AEDs, placebo response – that RCTs reveal only the top-line impact on short-term – seizure reduction and acute tolerability (at specific but not response to active treatment has been shown to ‘ ’ be higher in children than in adults, leading to age- doses). They cannot monitor safety in the real world or dependent differences in treatment effects that should be naturalistic setting and may not pick up safety signals that accounted for in the design of paediatric trials (Rheims are rare or take time to develop. Registries include wider et al., 2008). However, despite increasingly stringent disease populations than RCTs and are useful to confirm recommendations on how AEDs and other drugs should whether the safety and efficacy of drugs observed in RCTs be developed for use in paediatric populations, the design translate into everyday clinical practice, after the drug is of pivotal paediatric trials is typically based on extrapola- available for general prescribing. They can also provide tions from trials conducted in adult populations (Caldwell supplemental safety data in patients with rare conditions, et al., 2004; Garofalo, 2006; Chiron et al., 2008). in circumstances where RCTs are limited due to low The limitation of RCTs can be illustrated by the case of patient numbers. Although registry studies may at times vigabatrin, the first in a new class of AED that selectively be subject to case selection (since they are not rando- inhibits gamma aminobutyric acid (GABA) transaminase, mised), they can produce a wealth of valuable data when the enzyme responsible for the metabolism of GABA properly managed. For example, they can produce long- (Graham, 1989). The agent was undergoing clinical evalu- term data collection with less administrative burden of ation in the USA, but the trials were halted in 1983 when traditional trials and provide additional data on patient- white matter changes were found to occur in mice, rats and related outcomes and healthcare resource utilisation. dogs (Laxer, 1994). Since no serious neurological or neuro- Several AED registries now exist, some requested by regu- physiological toxicity was observed in humans, clinical lators, some not, and they now exist to monitor AED effects testing subsequently resumed. By the mid-1990s the drug in pregnancy (Beghi and Annegers, 2001; Vajda et al., was widely available in Europe, but then reports began 2007; Krishnamurthy, 2008) and also to monitor the effects emerging suggesting that it caused visual field defects, of adjunctive vagal nerve stimulation (Labar, 2002). with up to 50% of patients affected (Lawden et al., 1999). A European registry of AED use in patients with LGS has This led to the licensing authorities heavily restricting also recently been initiated (Seeruthun et al., 2009). the use of vigabatrin, and subsequent monitoring of The Orphan Drug Act of 1983 was passed in the USA, 563 patients in a multinational, prospective, observational to encourage pharmaceutical companies to target rare study confirmed that there was an increased risk of visual conditions, such as LGS. Subsequently, similar legislation field defects associated with its use (Wild et al., 2007). was implemented by the European Medicines Agency However, vigabatrin remains an option for partial seizures (EMEA), and in 2007 both regulatory bodies agreed a com- where other options have failed and where the risks of its mon application process to simplify orphan drug develop- use are outweighed by the benefit. It has also become a ment. Although Phase III statistical burden for proof of drug of choice for infantile spasms (Wheless et al., 2007). efficacy lessened as a result, there was a requirement for Felbamate is another example of where the full toxicolog- long-term safety monitoring. For example, , a ical risk of the drug was not evident on licensing with triazole derivative structurally unrelated to other marketed evidence from RCTs. The drug was approved by the US AEDs, was licensed for LGS based on data from only FDA in August 1993 for adult partial seizures, with or one RCT involving 138 patients (Glauser et al., 2008), without secondary generalisation, and for Lennox- and European regulators felt a post-marketing registry Gastaut Syndrome (LGS), a serious form of childhood was appropriate to assess the drug’s safety profile in this

Epileptic Disord Vol. 12, No. 1, March 2010 7 A. Arzimanoglou, et al.

population. The registry will include 100 LGS patients ini- providing patients and physicians with a wealth of alter- tiating rufinamide and up to 300 LGS patients receiving native treatment options. The availability of more than other AEDs, and will look at the impact of long-term LGS 15 AEDs has not, however, resulted in a commensurate treatment on maturation and development of patients, improvement in patient outcomes. For example, the rate seizure control, health-related quality of life (QoL) and of seizure freedom achieved in the VA Cooperative Study healthcare resource utilisation (Seeruthun et al., 2009). – approximately 30% – has not been improved upon sig- For clinical conditions in which RCTs are particularly dif- nificantly (Mattson et al., 1985; Mattson et al., 1992), and ficult to perform, the role of “Expert Opinion” has also problems with AED tolerability persist. In addition, there developed to fill gaps in clinical knowledge; for example, has been increasing recognition of the need to evaluate this has been important for certain paediatric epilepsy the wider effects of AED therapy on patients, such as the syndromes (Wheless et al., 2007). Although of limited sci- impact of treatment on mood and cognitive function entific value, expert opinion can provide valuable guid- (Loring et al., 2007). There is also a need for therapies ance to the practicing physician who may otherwise that are capable of altering the natural evolution of some have to rely on their own clinical judgement to select epilepsy syndromes, which may necessitate trying new the most appropriate treatment for an individual patient. treatments early on during the course of the disease. For Thalidomide changed the landscape of drug development example, although it is important to be able to control forever, with regulatory emphasis on safety as well as effi- drop attacks in severely mentally impaired LGS patients, cacy, and with approval now requiring RCTs controlled earlier treatment with an appropriate agent might help down to the finest detail. However, effective epilepsy avoid the development of cognitive impairment. management is much more than just satisfying regulatory Patient populations used in RCTs are carefully selected requirements: drug profiles must be optimised to ensure and tightly defined in order to limit the impact of con- that individual patients can tolerate long-term treatment, founding factors, thereby allowing the effects of an inter- since retention is key to success. This became the main vention to be clearly revealed. In the case of AEDs, regu- focus as AED development entered the modern era. latory trials focusing solely on the efficacy and safety of the agent in question cannot provide information on how The modern era of AED development new should be used in ‘real life’ for ‘real’ (slides 42-43) individual patients, who vary in terms of their (often Focusing on the patient multiple) concomitant medications, co-morbidities, age An increasing number of new AEDs have become avail- and other special requirements (e.g. renal function). able over recent years (figure 2; see video sequence), Moreover, the overall success of an AED is not just depen-

Eslicarbazepine acetate 2009 2008 Rufinamide (EU) 2007 2005 (EU) 2005 /Zonisamide (US) 2000 1999 1997 1996 1994 Felbamate/ 1993 Vigabatrin/Zonisamide (Japan) 1989

Carbamazepine 1965 Valpproate 1967 ILAE founded 1909 Phenytoin Bromide 1938 1958 1857

Phenobarbital 1912 1900 1920 1940 1960 1980 2000

Figure 2. Timeline for antiepileptic drug development over the past 100 years.

8 Epileptic Disord Vol. 12, No. 1, March 2010 The evolution of antiepileptic drug development and regulation

dent on its efficacy and tolerability, but on a global extremes of this spectrum of evidence, allowing the impression of treatment satisfaction that also encompasses objective evaluation of a drug under typical clinical prac- a patient’s functional status (independence, ability to tice conditions (in terms of patient populations and dosing work, psychological condition, etc.) and QoL. schedules), together with an assessment of patient- It is particularly important to recognise that epilepsy is a reported outcomes (PROs), such as functional status, chronic condition, requiring long-term – often life-long – global evaluation of patient status, and QoL (table 1). treatment, and the key to its effective management is to Effectiveness studies are typically open-label in design and provide treatment options that patients are able and will- included as part of a drug’s post-approval (phase IV) devel- ing to continue taking long-term. In order to achieve this, opment. For example, the Zonisamide in the European a broader, more holistic approach to epilepsy manage- Union Study (ZEUS) (Dupont et al., 2009) was a prospec- ment is required, which is focused on the needs ofpatients tive, Phase IV, non-comparative study, conducted in nine as individuals. There is consequently a need to bridge the European countries, which was designed to assess the effi- gap between clinical trials and clinical practice, and pro- cacy and safety of zonisamide (ZNS) add-on therapy for vide physicians and patients with the type of information partial-onset seizures in an adult population that was they require in order to make informed and appropriate more heterogeneous and less refractory to treatment than treatment choices in the real world. the patients included in previous pivotal RCTs (Schmidt et al., 1993; Faught et al., 2001; Sackellares et al., 2004; (slides 44-48) Importance of effectiveness studies Brodie et al., 2005). In addition to confirming ZNS ’s toler- RCTs provide a specific type of clinical evidence required ability and efficacy (in terms of seizure frequency reduc- for regulatory approval, but clinical evidence can come tion), and identifying the most common daily dose used from a wide variety of sources. At one end of the spec- (300 mg), ZEUS demonstrated improvements in Clinical trum, a single-centre, retrospective chart review can Global Impression, health-related QoL and seizure sever- reveal certain subjective treatment trends, while, at the ity, in a setting that was reflective of clinical practice ® other end, RCTs provide statistically robust, objective (Dupont et al., 2009). Similarly, the Keppra Epilepsy assessments of efficacy and short-term tolerability in care- Evaluation of the Patient timE to Response (KEEPER™) fully defined patient populations (table 1). In addition to trial was a prospective, Phase IV, open-label, multicentre the limitations previously outlined, RCTs may give a false study, conducted in the USA, which was designed to gather impression of a drug’s tolerability, since they usually additional information on the safety and efficacy of levetir- involve forced titration schedules and require the report- acetam (LEV) add-on therapy for adult partial-onset sei- ing of every AE, whereas, in clinical practice, lower and zures in a real-world setting of community-based practice slower titration schedules can be used, which help to pro- (Morrell et al., 2003), following regulatory approval based vide a better indication of effective clinical doses and on the results of several RCTs (Cereghino et al., 2000; thereby minimise the occurrence and impact of AEs. Shorvon et al., 2000; Ben-Menachem and Falter, 2000; Effectiveness studies provide a balance between the Boon et al., 2002). In addition to confirming LEV efficacy

Table 1. Effectiveness studies within the spectrum of clinical evidence.

Study type Method Drawbacks Advantages Example Chart review, one centre Review charts for seizure Single site, treatment Reveals trends Kwan and Brodie, 2001 frequency, AEs evolves over time, minimal records Observational chart study, convenience Prospective follow-up Wide variation in Proof of concept sample, one centre using standard format patients, typically small N (even if multicentre) Effectiveness study, Open-label, flexible- No control group Typical clinical practice, ZEUS (Dupont et al., multicentre, dose treatment, PROs less refractory patients, 2009) observational focus on PROs KEEPER™ (Morrell et al., 2003) Interventional study, randomised vs Clinical trial Specific eligibility, Adequate N, defined VA Studies (Mattson intervention or active follow-up, planned N primary outcome et al., 1985; Mattson treatment et al., 1992) Interventional study, Clinical trial Specific eligibility, Adequate N, defined Phase III clinical trial randomised vs placebo follow-up, planned N primary outcome treatment AE: adverse event; PRO: patient-reported outcome.

Epileptic Disord Vol. 12, No. 1, March 2010 9 A. Arzimanoglou, et al.

and tolerability in a setting reflective of clinical practice, presence and severity of specific adverse neurological KEEPER™ demonstrated that almost three-quarters of and systemic problems (Cramer et al., 1983; Gilliam patients improved, either slightly (11.3%), moderately et al., 2004). Physicians should always be prepared to (26.0%), or markedly (37.0%), based on the investigator- consider changing a patient’s dose or AED in order to completed Global Evaluation Scale (Morrell et al., 2003). improve outcomes. Effectiveness studies therefore provide important and unique evidence, by gathering data under conditions Third-generation AEDs and beyond (slides 51-56) more closely mirroring routine clinical practice, using ’ diverse populations that are reflective of the real word By tailoring an individual patient s needs to the treatments (in terms of refractoriness to treatment, concomitant med- available, a more patient-focused approach to epilepsy ication and comorbidity) and flexible and clinically rele- management will undoubtedly lead to improvements in vant dosing schedules. By including patient-reported out- patient-perceived outcomes, but there is clearly also a comes, effectiveness studies are also more patient-centric, need to continue improving and expanding the therapeu- providing valuable evidence of a drug’s impact on aspects tic options on offer, since history has shown there to be of patients’ lives that are most likely to predict whether or continued unmet needs with existing AEDs, in terms of not the treatment will be acceptable (and therefore main- both tolerability and seizure control. Hope for the future tained) long-term (figure 3). is provided by the development of new AEDs that are either structural advances of older agents, or completely Determining the individual needs of patients (slides 49-50) novel molecules. Importantly, PROs are increasingly being acknowledged as useful endpoints to include, in The use of patient-reported outcomes in clinical studies addition to those for efficacy and tolerability, when asses- provides an important means of assessing what is impor- sing the clinically-relevant benefits of new AEDs. tant to patients in clinical practice, but only effective “ ” direct communication between clinician and patient can Many third-generation AEDs have resulted from struc- determine the latter’s specific needs. Physicians should be tural advances of existing agents, including , encouraged to ask their patients at every visit about their pregabalin and (ESL) (figure 4). functional status, QoL and emerging/ongoing AEs, in In addition, several novel molecules are currently being terms of both the patient’s condition and their medication. assessed as potential AEDs in phase III trials. Moreover, it is important that physicians elicit information is a synthetic analogue of the endogenous from patients by asking directed questions, particularly (Rogawski, 2006), a metabolite of pro- since many epilepsy patients are depressed (Kanner, gesterone that lacks hormonal activity (Monaghan et al., 2008) and therefore likely to experience difficulty in 1997). Ganaxolone acts as potent of communication, and to suffer more AEs. To facilitate this the GABAA complex, binding to a receptor site distinct process, physicians can use a standard format to obtain from that bound by (Rogawski, 2006; information and take notes to chart changes over time. Nohria and Giller, 2007). Preclinical models have A combination of neurological or physical examination revealed no signal for tolerance (Rogawski, 2006) and plus interview can be utilised, in order to determine the early open-label clinical studies have indicated that

Routine clinical practice Less refractory Diverse patient patients population Functional status Effectiveness studies Patient-centric Phase IV, open-label Reflective of endpoints "real-life"

Quality of life No control group Flexible dosing

Global improvement

Figure 3. Characteristics of effectiveness studies.

10 Epileptic Disord Vol. 12, No. 1, March 2010 The evolution of antiepileptic drug development and regulation

() Levetiracetam Brivaracetam

O O O NH2 NH2 N NH2 N O N O O

Talampanel

H3C O O N O H3C N O N N

NH2 N

Gabapentin Pregabalin

NH2 O H O

OH OH NH2 Eslicarbazepine acetate (Tricyclic) Carbamazepine Oxcarbazepine

O H3C O O N N N O NH2 O NH2 N

O NH2

Figure 4. Development of new antiepileptic drugs as structural advances on existing agents. ganaxolone is effective in reducing complex partial inhibit voltage-gated sodium channels (Rogawski, 2006; seizures and infantile spasms (Monaghan et al., 1999). Matagne et al., 2008); and , a novel potassium Perampanel is a novel selective α-amino-3-hydroxy-5- (Rundfeldt and Netzer, 2000). Retigabine methyl-4-isoxazole-propionic acid (AMPA)-type gluta- has recently been filed for regulatory approval with mate . Since AMPA receptors play a both the US FDA and EMEA, for use as adjunctive key role in cortical transmission (Prince therapy to treat adult patients with partial-onset seizures et al., 1995), AMPA antagonists might be expected to (GlaxoSmithKline and Valeant Pharmaceuticals reduce excessive activity and excitotoxicity, and peram- International Press Release 2009). panel has demonstrated antiseizure effects in a broad The modern era has been characterised by increasing rec- spectrum of rodent models (Hashizume et al., 2007; ognition of the need to assess the effects of any treatment Hashizume et al., 2008). In addition, perampanel showed on individual patients, not only in terms of efficacy and preliminary evidence of efficacy and favourable safety tolerability, but also in terms of QoL and other patient- and tolerability in two phase II trials (Krauss et al., 2009). related outcomes. The use of PROs and effectiveness stud- Other agents that have undergone phase III trials are: car- ies is helping to provide a more patient-centric approach isbamate, which is structurally related to felbamate and to AED development, which is improving patient out- has been primarily shown to inhibit voltage-dependent comes and encouraging better patient retention. Since sodium channels (Liu et al., 2009); brivaracetam, which, the ultimate aim of epilepsy management – a cure – like its parent compound levetiracetam, is thought to act remains elusive, and since there are still unmet needs (in on the synaptic vesicle protein 2A, as well as additionally terms of efficacy and tolerability) in the therapeutic

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options available, the need for new AEDs persists, and is “ ” being addressed by the development of third-generation The times they are a-changing AEDs and novel molecules. AED development is also Presentation slides and video sequence being assisted by global organisations, such as the Introduction – video sequence Epilepsy Therapy Project (www.epilepsy.com/epilep- sy_therapy_project), which aims to accelerate the devel- Slide Title opment of new and better treatments. Tracy Glauser 2 Learning from the past: Learning from history 3 Lessons From The Past Conclusion 4 Bromide - The Start of the Modern Journey 5 Bromide - The Start of the Modern Journey The centenary of the ILAE has provided an opportunity to 6 Bromide - The Start of the Modern Journey reassess the evolution of AEDs, which mirrors the develop- 7 Bromide - Efficacy with Toxicity 8 Multiple Combinations Recommended Throughout History ment and regulation of drugs in general. At its outset, AED to Treat Seizures development focused primarily on controlling seizures, 9 Barbiturates - A New Class of Sedatives with less regard for tolerability and safety profile, but expe- 10 Phenobarbital - Observation + Serendipity 11 Phenytoin - Great Leap Forward rience with thalidomide brought safety to the forefront and 12 Phenytoin - Unique Pharmacokinetics the development of all drugs, including AEDs, to a tempo- 13 Phenytoin - Variety of Adverse Events rary standstill, resulting in an era of much tighter regulation 14 The Era of Look Alike AEDs 15 Carbamazepine - New Generation that persists to this day. The development of the RCT and 16 Comparative Effectiveness Trial: VA Cooperative Study I evidence-based medicine is key to the regulatory process, Overall Results but RCTs have important limitations, which are increasingly 17 VA Cooperative Study I: Seizure Freedom 18 VA Cooperative Study I: Retention and Seizure Freedom acknowledged. These limitations are being addressed in 19 Carbamazepine and Phenytoin Multiple side effects terms of regulatory law (Orphan Drug Act), the type of clin- 20 Lessons From The Past ical evidence gathered (e.g. registries and effectiveness Elinor Ben-Menachem studies), and the incorporation of PROs into clinical devel- 21 The evolution of our understanding opment programmes. Importantly, AED development has 22 Thalidomide: What Can Happen Without Proper Regulation now evolved to the point where the primary focus has 23 Kefauver-Harris Amendment 24 Impact on AED Development shifted from purely efficacy parameters towards individua- 25 Valproate (VPA): First AED in New Regulatory Era lising treatment related to PROs. It is now recognised that 26 Development of Modern RCT epilepsy can only be managed effectively by addressing 27 Aspects of Association ’ 28 Why are RCTs Considered ‘Gold Standard’ Evidence? each patient s real-life needs; AED therapy can only help 29 Evolution of RCTs a patient if they are compliant with it. There have been 30 Limitations of RCTs significant improvements in the available AEDs, either 31 Importance of Safety through development of novel molecules or structural 32 Vigabatrin 33 Vigabatrin advances of older agents. Some aspects of the story, how- 34 Registries: Requirement and Importance ever, remain unchanged: there is still a need for new thera- 35 Orphan Drug Law pies and the search for a cure continues. □ 36 Lennox-Gastaut Syndrome (LGS): Background and Diagnosis 37 Rufinamide 38 European Registry of AED Use in LGS Patients Acknowledgments. 39 Post ‘Thalidomide’ Drug Development has Evolved Preparation of this manuscript was supported by Eisai Europe Ltd, and 40 Beyond EMEA/FDA Approval editorial assistance was provided by Harjinder Chahal from mXm Joyce Cramer Medical Communications. 41 Challenging the present to shape the future 42 Treating Epilepsy Every Day Disclosure. 43 Adverse Effect Profiles: Data from Add-On Trials ’ of New AEDs in Adults (at Recommended Dose) Alexis Arzimanoglou received speaker s or consultancy fees and/or 44 Types of Evidence research grants from Cyberonics, Eisai, GlaxoSmithKline, Johnson 45 Change to Measures That Reflect Your Clinical Practice: and Johnson, Novartis, Pfizer, Sanofi Aventis, Schwartz Pharma, Evolution to Naturalistic Studies UCB Pharma and Valeant. 46 Zonisamide ZEUS Study: Patient Reported Outcomes Elinor Ben-Menachem received speaker’s or consultancy fees and/or 47 KEEPER Study research grants from Cyberonics, Eisai, Johnson and Johnson, Pfizer, 48 Value of Naturalistic Studies Sanofi Aventis, UCB Pharma and Lundbeck. 49 How Can Doctors Learn What is Most Important For Patients? Joyce Cramer received consultancy fees from Eisai, Johnson & 50 Neurological and Systemic Toxicity Rating Scales Johnson, and UCB Pharma. 51 What Have We Learned From History? Tracy Glauser received speaker’s or consultancy fees and/or 52 Progression with Established Structures 53 Newly Available and Pipeline AEDs researchgrants from Eisai, UCB Pharma, Johnson & Johnson, 54 Ganaxolone Questcor and Lundbeck. 55 Perampanel AMPA-type antagonist Rav Seeruthun is a current employee of Eisai Europe. 56 The Challenges Ahead? Miranda Harrison is a current employee of Eisai Europe.

12 Epileptic Disord Vol. 12, No. 1, March 2010 The evolution of antiepileptic drug development and regulation

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