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(1998; 113 pages)
WHO and Bayer cooperation
Bayer contacted WHO at an early stage of drug development and asked for advice and support for the further clinical development of praziquantel. According to Wegner (1981), “A close and fruitful cooperation was established, which resulted in the setting up of well coordinated trial protocols. Case report sheets were standardized as far as possible for the first intercontinental multicentre trials in investigational phases IIA, IIB, and III.” An overview of the literature about these first stages of clinical trials and conferences is given by Dollery (1991).
In this collaboration, clinical trials of tolerance to praziquantel and of its therapeutic effects against the three common species of schistosomes infecting man (S. haematobium, S. mansoni, and S. japonicum) were conducted jointly by the WHO Parasitic Diseases Programme, and the Medical Department in the Pharmaceutical Research Centre of Bayer, in Africa, Japan, the Philippines and South America (Wegner, 1981). The studies on S. haematobium infections were carried out in Zambia, at the clinical pharmacology unit of the WHO Tropical Diseases Research Centre, Ndola Central Hospital, Ndola (Davis et al., 1979); and on S. mansoni infections at the Centro de Pesquisas, Belo Horizonte, Brazil (Katz et al., 1979). In the case of S. japonicum infections, double-blind studies of tolerance were conducted in the Koma-Kyoritsu Hospital, Yamanashi, with the advice of the National Institute of Health, Tokyo, Japan (Ishizaki et al., 1979), complemented by clinical trials of tolerance and efficacy performed by the Schistosomiasis Control and Research Team at Palo, Leyte, Philippines (Davis and Wegner, 1979; Santos et al., 1979). In all endemic areas, the double-blind trials confirmed not only good tolerance in patients but also high efficacy against the local schistosoma species (Wegner, 1981).
Dose-finding is a difficult and time-consuming process. Animals tolerate drugs quite differently than man. Mice, for example, tolerate praziquantel 20 times better than man, and in baboons a single dose of 75 mg/kg body weight was effective against S. haematobium (Webbe et al., 1981). The task was to determine the dose that eliminated the parasite in mice without adversely affecting humans. Phase IA studies showed that healthy volunteers tolerated the compound in oral doses of 50 mg/kg body weight as a single dose, and in three doses of 25 mg/kg body weight each. Could these results be confirmed in schistosomiasis-infected patients who were of different ethnic origins? Was the effect on schistosome species pathogenic to man experimentally observed in different test animals the same when those parasite species were found in man? (Wegner, 1981) Did strains of different geographical areas behave differently? Could certain groups of patients be treated safely, such as young children and pregnant women? And would the dose found to be effective in healthy volunteers be appropriate for large-scale treatment? All these questions had to be addressed and answered.
The investigational clinical trials were started in selected medical centres with extensive facilities and highly trained staff, where the drug was tested for tolerance and efficacy. Then a broader spectrum of trials was conducted in hospitals without special facilities and at offices of medical practitioners. The last step was field trials.
Investigational Phase IIA studies confirmed the efficacy of praziquantel and the absence of significant side-effects in uncomplicated infections of the three major human schistosomes in people of different ethnic origin. Davis et al. (1979) conducted double-blind trials to test the tolerance and efficacy of oral doses of 20 mg praziquantel in a single dose, two doses of 20 mg each, and three doses of 20 mg each, in 79 patients with uncomplicated infections in Zambia (Davis et al., 1979; Davis et al., 1981). J.E. McMahon (1981) at the Helminthiasis Research Unit MCC/WHO found that increasing the dose above 30-35 mg/kg body weight did not increase efficacy. The findings of these studies on tolerance and efficacy were so encouraging that extended investigational Phase IIB studies were started. In these studies, patients were allotted to three strata to find out different dose levels, according to the degree of worm burden, patient's age, and the occurrence of severe adverse reactions in patients with hepatosplenic complication in advanced stages. Simultaneous infections with different schistosome species were studied, and finally the dose best suited under field conditions was identified (Wegner, 1981).
In all these trials, praziquantel was well tolerated in a battery of tests. The tests confirmed the absence of toxic effects of the drug on vital organs, systems and functions. According to a study by da Silva and co-workers (1981), praziquantel can even be safely given to patients with hepatosplenic complications. The overall results of the clinical multicentre trials showed that a single dose of 40 mg/kg body weight for S. haematobium and S. mansoni, and two doses of 30 mg/kg body weight for S. japonicum gave cure rates at six months between 75% and 100% in the various samples of patients treated (Wegner, 1984). The final phase of the clinical trial programme was the use and evaluation of the preferred doses under field conditions in large-scale community projects that were undertaken by numerous investigators in different countries (Davis, 1993). In 1984, Wegner reported the safe and successful treatment of 25,000 patients in 3 continents up to 1982. Trials were conducted in as many as fifty different sites scattered over the globe (Davis, 1982). A list of trial places is given by Wegner (1984).
By 1985, approximately one million persons had been treated with praziquantel (WHO, 1985). From the discovery of praziquantel until 1983, over 400 publications were written to document the preclinical and clinical observations about the new drug (Andrews et al., 1983). Many experiments, broad clinical experience, and large-scale field control programmes all confirmed the therapeutic validity of the initial trials (Davis, 1993).
While the collaboration between Bayer and WHO was quite successful in conducting clinical trials for praziquantel, the relationship apparently did not include a written agreement on issues of pricing or distribution methods once the product was fully developed and registered. Some observers mentioned the existence of a “good faith agreement” between individuals involved in the two organizations. Our research, however, was unable to identify any documents that would support the existence of an agreement between the two organizations or the individuals on critical questions of how praziquantel would be made available.
In 1994, anecdotal reports emerged about the resistance of certain strains of schistosomes to praziquantel (Brown, 1994). However, as Cook and Reich (1996) noted, “Although there have been case reports of increased tolerance to praziquantel, resistance (in the sense of single-step complete resistance, as seen in bacterial infections) has not been reported. Tolerance to praziquantel is possible, but resistance has not been reported to be a problem.” Unless the situation changes dramatically, praziquantel remains the drug of choice and the mainstay of treatment for schistosomiasis (WHO, 1993). It should be noted that the remarkable effectiveness of praziquantel against various helminthic species (including schistosomes) has directed attention away from further research and new drug development. This unintended consequence of praziquantel’s success may well prove to be an Achilles’ heel, should resistance to praziquantel become more widespread in the future. On the other hand, the development of an effective vaccine for schistosomiasis could reduce the demand for praziquantel significantly.