ILAE 110th anniversary review paper* Epileptic Disord 2019; 21 (4): 319-29 Antiepileptic drugs: evolution of our knowledge and changes in drug trials Emilio Perucca Past President of the International League Against Epilepsy Division of Clinical and Experimental Pharmacology, Department of Internal Medicine and Therapeutics, University of Pavia, Pavia and IRCCS Mondino Foundation, Pavia, Italy Received April 30, 2019; Accepted June 01, 2019 ABSTRACT – Clinical trials provide the evidence needed for rational use of medicines. The evolution of drug trials follows largely the evolution of regulatory requirements. This article summarizes methodological changes in antiepileptic drug trials and associated advances in knowledge starting from 1938, the year phenytoin was introduced and also the year when evi- dence of safety was made a requirement for the marketing of medicines in the United States. The first period (1938-1969) saw the introduction of over 20 new drugs for epilepsy, many of which did not withstand the test of time. Only few well controlled trials were completed in that period and trial designs were generally suboptimal due to methodological constraints. The intermediate period (1970-1988) did not see the introduction of any major new medication, but important therapeutic advances took place due to improved understanding of the properties of available drugs. The value of therapeutic drug monitoring and monotherapy were recognized dur- ing the intermediate period, which also saw major improvements in trial methodology. The last period (1989-2019) was dominated by the introduc- tion of second-generation drugs, and further evolution in the design of monotherapy and adjunctive-therapy trials. The expansion of the pharma- cological armamentarium has improved opportunities for tailoring drug treatment to the characteristics of the individual. However, there is still inad- equate evidence from controlled trials to guide treatment selection for most epilepsy syndromes, particularly in children. Second-generation drugs had a very modest impact on drug resistance, and a change in paradigm for drug discovery and development is needed, focusing on treatments that target the causes and mechanisms of epilepsy rather than its symptoms. Testing potential disease modifying agents will require innovative trial designs and novel endpoints, and will hopefully lead to introduction of safer and more effective therapies. Correspondence: Emilio Perucca Key words: epilepsy, therapy, antiepileptic drugs, clinical trials, history, th Division of Clinical and Experimental review, ILAE 110 anniversary Pharmacology, Department of Internal Medicine and Therapeutics, University of Pavia, *To celebrate the 110th anniversary of the International League Against Epilepsy, Epileptic Via Ferrata 9, Disorders is publishing a series of educational manuscripts on ground-breaking topics 27100 Pavia, Italy that have significantly influenced the field of epilepsy, written by past Presidents of the <[email protected]> doi:10.1684/epd.2019.1083 ILAE. Epileptic Disord, Vol. 21, No. 4, August 2019 319 E. Perucca marketing of medicines in the US (table 1). Inter- “On the 20th of May 1747, I took twelve patients in the scurvy, on board the Salisbury at sea. Their estingly, demonstration of efficacy was made a cases were as similar as I could have them... They requirement only in 1962 in the US, and several years lay together in one place...and had one diet com- later in Europe. mon to all. Two of these were ordered each a quart of cyder a day. Two others took twenty-five drops of elixir vitriol three times a day...Two others took The age of the pioneers (1938-1969) two spoonfuls of vinegar three times a day...Two... ... were put under a course of sea water Two oth- The discovery of phenytoin and its legacy ers had each two oranges and one lemon given to them every day... The two remaining patients The introduction of phenytoin by Merritt and Put- took ...an electary recommended by an hospital- nam can be regarded as the beginning of modern surgeon, made of garlic, mustard feed, rad. raphan. AED development. In fact, Merritt and Putnam’s stud- ... balsam of Peru and gum myrrh The consequence ies have been described as ‘monumental landmarks was, that the most sudden and visible effects were in the history of epilepsy, pharmacology, and neu- perceived from the use of the oranges and lemons; rology’ (Rowland, 1982). This is not only because the one of those who had taken them, being at the end ... clinical value of phenytoin at that time was truly of the six days fit for duty The other was the best ‘revolutionary’ (Lennox, 1940), but also because the recovered of any for this condition; and being now methodology applied to the development of pheny- deemed pretty well was appointed nurse to the rest toin (preclinical screening in a seizure model, e.g. of the sick.” electrically induced convulsions, followed by clini- James Lind MD. A treatise on the scurvy. London : Printed by A. Millar in the strand, 1757 : 140-50. cal testing) applied a paradigm that continues to be used to date (Friedlander, 1986). Yet, in terms of clini- cal trial methodology, the development of phenytoin can hardly be described as exemplary. Shortly after Although the first implementation of the random- completing their laboratory experiments towards the ized controlled trial dates back to the 18th century, its end of 1936, Merritt and Putnam started trying the use to evaluate the efficacy and safety of medicines compound in 200 patients with uncontrolled seizures became established only 200 years later, with the pub- and by June 1938 they were ready to present their lication of the iconic MRC trial of streptomycin for the findings at the section on Nervous and Mental Dis- treatment of tuberculosis (Medical Research Council, eases of the American Medical Association (AMA) 1948). In fact, the medications used in the treatment (Merritt and Putnam, 1938). Based on their observa- of epilepsy in the first half of the 20th century were tions, they concluded that phenytoin ‘was effective introduced in the market without any kind of con- in controlling convulsive seizures in a great major- trolled assessment. Admittedly, during that period, ity of a selected group of patients who were not effective treatments were introduced that remain part helped by other methods of therapy’ even though, of the modern armamentarium (bromides, phenobar- perhaps surprisingly, the drug was considered ‘more bital, phenytoin, and the ketogenic diet), but lack of toxic than bromides and the barbituric compounds’. rigorous scientific assessment also led to utilization of In the same month, phenytoin (Dilantin) was added many agents of questionable value. A standard British to the catalogue price list of Parke-Davis, as there textbook published in 1940 listed borax, belladonna, was no requirement for a license by a regulatory and nitroglycerine among drugs of definite benefit authority at that time (table 1). So, it took only two for the treatment of epilepsy (Kinnear-Wilson, 1940), years from the first experiments in animal models while an article by Lennox (1940) listed not only phe- to the marketing of the drug, and the clinical devel- nobarbitone and phenytoin, but also brilliant vital red, opment program lasted about one year, without any borotartrate, and antirabies vaccine among epilepsy controlled study. Although it is unclear how many treatments used in America in the mid-30s. patients had been exposed at the time phenytoin The evolution of the methodology for the clinical was marketed, a review of the evidence made in late assessment of potential antiepileptic drugs (AEDs) 1939 by the AMA Council on Pharmacy and Chem- is a fascinating history, which also bears witness to istry listed 13 clinical studies with a total of 595 advances in our understanding of these drugs and patients, including the original series reported by Mer- therapeutic achievements (Arzimanoglou et al., 2010). ritt and Putnam (Council on Pharmacy and Chemistry, This article provides an overview of clinical trials and 1939). Based on these data, phenytoin was included advances in knowledge since 1938 – the year of intro- in the Council’s New and Nonofficial Remedies, with duction of phenytoin and also the year in which the indication for use in ‘epileptic patients who are evidence of safety was made a requirement for the not benefited by phenobarbital or bromides and in 320 Epileptic Disord, Vol. 21, No. 4, August 2019 AEDs : evolution of knowledge and drug trials Table 1. Some milestones in regulations affecting drug development and marketing. 1906 The US Food and Drug Act organizes the establishment of the Bureau of Chemistry, charged with preventing distribution of adulterated food and medicines. The Bureau changes its name to Food, Drug and Insecticides in 1927, renamed Food and Drug Administration (FDA) in 1930. The remit of the FDA expanded over the years in response to regulatory changes (see below). 1938 The American Congress passes the Food and Drug and Cosmetics Act, which requires that new drugs show safety before sale. The Act was in response to the elixir of sulphanilamide tragedy which occurred in the previous year, in which use of a toxic vehicle (diethylene glycol) in the manufacturing of the medicine without safety testing caused the death of 107 people, including many children. 1962 The thalidomide tragedy, which caused severe birth defects in an estimated 10,000 babies exposed prenatally to the drug, stimulates public demand for stricter regulations of drug assessment. The same year, the American Congress passes the Kefauver-Harris Drug Amendments, which require demonstration of effectiveness and safety prior to marketing. 1971 In the UK, pharmaceutical companies are required to submit to the Committee on Safety Medicines evidence of safety and efficacy to obtain a marketing license for new drugs. The new scheme complies with the 1968 Medicines Act. 1979 The Fund for Adverse Reactions Suffering Relief is established in Japan.