Report: onchocerciasis chemotherapy project working group

t @ WORLD HEALTH ORGANIZATIONORGANISATION MONDIALE DE LA SANTE, REPORT ONCHOCERCIAS IS CHEMOTHERAPY PROJECT I^IORKING GROUP 0cP82.4 OR.IGINAL: ENGLISH 1 lr \ t I l \ l- t, CONTENTS Page ,l / / a 1 INTRODUCTION 2. PRIMARY OBJECTIVES 4 3 BASIC STRATEGIES THE DRUG DEVELOPMENT PROCESS General Aspects Synthe s i s Sc re ening /Basic Biochemisrry Toxicity AssessmeClinical Testing nt and Regulatory Clearance 5. THE CURRENT SITUATION 5. r 5.2 Visits to Drug Companies Drug DevelopmenE PROPOSED ACTIVITIES IN 1982 7. PROPOSED MANAGEMENT STRUCTURE FOR THE LONG.TERI.{ 8. FINANCIAL IMPLICATIONS FOR THE LONG.TERM MANDATE OF THE WORKING GROUP FOR THE REMAINDER oF 1982 10. ST'MMARY AND MAJOR CONCLUSIONS Annex I 1 1 t 3 4 5 7 8 4.1 4.2 4.3 4.4 4.5 ) I 9 9 6 l4 11 13 16 16 9 { I Annex II Annex III Membership of Onchocerciasis Chemorherapy Working Group Fund The DevelopmenE of a FitaricidaL Drug Job Description, SecreEary, Onchocerciasis Chemotherapy Steering Connrittee tl l t I I II 1. INTRODUCTION The Onchocerciasis Chemotherapy (OC) Project l^lorking Group was seE up in December, 1981, by the Cormnittee of Sponsoring Agencies of rhe Onchocerciasis Control Programne in Ehe Volta River Basin area, in collaboraEion with the Standing Committee of che WHo/UI{DP/hlorld Bank Special Progranune on Research and Training in Tropical Diseases. The Group was asked to PrePare reconunendations for Ehe mechanism to manage a proposed projecE to develop a new Crug against onchocerciasis. Two specific tasks were assigned: to make recommendaEions on expendiEures and monitor use of funds made available in 1982, and to recommend a permanent mechanism for managing and operating che project. The Group, composed of the members shown in Annex I, met in Geneva on three occasions from January to May 1982, and visited a number of pharmaceutical firrrs to assess cheir interest in the project. 2 PRIMARY OBJECTIVE \ The objective of the OC projecE is to acceleraEe the discovery and developmenE of a safe and effective drug for onchocerciasis which wil-1 meet Ehe following criceria: (a) The drug must kill or permanently sterilize the adult female $rorms of Onchocerca volvulus withouE at che same time causing severe allergic reactions in recipients from microfilaricidal action. It musE be safe under normaL conditions of use, suicable for large scate use oraLly or intramuscularly, of low cost, and be effective in a smalI number of doses. (b) If the drug has microfilaricidal action, it shoul<t be of long duration and reacEions in the host should be minimal. The Group could provide no guerantee that the task of finding and developing such a drug can in fact. be carried out successfuLty. The discovery of a safe and effecEive drug for any disease is inrrinsically a difficult and risky business, and onchocerciasis presents particularly difficult problems as indicated by the above-nentioned objectives. Luck plays a major role in drug discovery and development. Although it could give no guarantees, the Group was of Ehe view, nevertheless, Ehat the chances of successfully finding and developing a drug were sufficiently high Eo merit additional effort. It is obvious Ehar'rthrowing money at a problemtt does not necessarily guarantee success. The Group considered, however, Ehat wise expenditure of funds additional co those currentty being.p".tt o.r onchocerciasis chemotherapy would accelerate progress and significancly increase Ehe chances of success. 3. BASIC STRATEGIES 3.1 Ic is essential to cooperate wiEh the drug industry, academic insEitutes and individuats in the search for new and improved chemocherapeutic agents against onchocerciasis. In doing so, however, great care must. be taken to protect the public inEerest. Ttrus, the responsibilities of Ehe cooperating parties musE be clearLy esEablished and set out in project agreements. a ? F I t. \ 23'2 Because of the low profitability of.the field, reflected in the reraEively lotu level ofindustrial interest in it, the Group considered it essential, if advances are Eo be made, tostimulate and encourage industrial involvemenr in the project by providing financirr.rfio.tfor one or more of the research and development slements involved. However, the Group didnoE consider it advisabl-e to guarantee a market for a particular druf, prior to itsdevelopment. To do so would resulE, in effect, in shulting off orhei initiarives which mightbe more effective. 3'3 Financial incentives can involve ful1 or parEial supporr for synLhesis and screening and biochemistry prograrunes, Eoxicology, clinical trials, or acces" io "linical trialfacilities. rt musE not, however, replace r.rhat industrial firms would do for themselves ifleft to their oqrn resources. Contractual arrangements with companies, academic instiEutionsand oEhers will have to be designed to meet ,..!ing sicuations. For exampre, a drug company might wish to carry out all research and development costs using its own resources, andrequire only.that the.oC project provide access to clinicat facirities for laEe phase Ir andPhase III clinical trials. 3'4 To provide some elemenEs of competition, and improve the chances of success, attempts should be made ro stimulate broad interest in the project, especially in early stages ofsvnthesis and screening. when promising leads are'found they- should be supported strongly,in order to drive the research forward as quickly as possibll. promising compounds.,rs[ 6etested as quickly as Practicable in human subjects, once sufficient evidence on Eheir saferyhas been obtained in animals. 3.5 The Group suggested Ewo major qrays ro ensure a highly resulr.s-orienced approach to Eheproject. It is critical Ehac the project be managed by pelp1e who are results-oriented, and who understand that the .tbottom linett measure of success is a drug which meets necessary criteria. Furthermore, it is essential the drug industry be closely involved in development of the drug. The industry has been the Tgjor facror in irug development during rhe lasi 40years' Possesses Sreat expertise in che field, and is highly resulti-oriented, by reason ofits profit orientation. Although profitabiliry in the fieli of onchocerciasis chemoEherapy is low, there is strong evidence companies parEicipating in the project will puc Eheir best efforts into the work in order to reap the benefiti of prestige whilh would arEend success. Given the competition which exisEs wichin industrial research organizations for physical andfinancial resources, industrial aspecEs of the oc projecE would 6e requirea to meei rigorousindustrial standards of performance. Ocherwise, companies could noE afford to keep itgoing. Thus, efforrs should be made co enhance industrial activicies in rhe fielri, byproviding supplementary resources which will stimulate indusrrial efforts. 3.6 To encourage the involvement of industrial firms in the project, economic returns outside the human health field from chemicals developed with financial support from theproject should accrue to the participating company involved. If, for example, a chemical is developed by an industrial firm with financial support from the OC project, and is found, in addition to \^rhaEever value it may or may not have as a drug against-on"ho""."iasis, to be of value as an agriculEural nemaEocide, financial benefits from the agricultural use should accrue to the company. 3.7 The OC project musE take full advantage of exisEing research and development programmes in Ehe field, in parcicular that of the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR). TDR has laid the groundwork for an expanded and concentrated effort in research on onchocerciases and has done much to stimulate inEerest in I ) / a / I I .1 ,l t 3 it on the part of industrial concerns and academic experts. Relationships bet,ween Ehe 0C project and TDR wilI require careful development. As progress is achieved in the projecE, the filariasis component of TDR should adjust its activities accordingly, Eo ensure that the two activities mesh together properly, avoiding compeEition and ensuring collaboraEion. 4. THE DRUG DEVELOPMENT PROCESS 4.1 GeneraI AspecEs DevelopmenE of a new drug for onchocerciasis can be expecEed to fol1or.r the general sequence shown in Annex II. 4.1.1 The process must be seen as one which is highly dynamic and iterative, involving close cooperaEion beEween chemists, biologisEs, biochemisEs and clinicians. Basic biochemical scudies may be expected to provide leads for Ehe synt.hesis of poEentially promising compounds. These musE Ehen be screened for the required filaricidal activicv in animal and/or in vitro systems. It will be necessary to develop an assay for this purpose, which atEempts to predict, directly or indirectly the therapeuEic potenEial of the chemicals screened. The results of screening for Ehe required filaricidal activity will influence Ehe chemical synthesis programme. Chemicals which fail to show significant filaricidal activity in appropriate in virro and/or animal screens normally are noE considered further. Those which show significanc filaricidal activity are subjected to preliminary Eoxicity assessment procedures in animals. \ I I I I). I 4.1.2 These may involve acuEe (LD56), range-finding and sub-acute (up to 30 days) studies in one or more animal speciesl- If very serious signs of extreme toxicitv are observed, the chemical may be dropped from further development. If, on the oEher hand, Ehe chemical is not disqualified by reason of Eoxicity, deveLopmenE can proceed further. 4.1.3 Studies will then be undertaken Eo examine in detail Ehe pharmacokinetics, metabolism, disEribution, excreEion, effects on organ systems and other aspecEs of the pharmacology of the chemical. More intensive animal coxicology assessment, involving gross- and histo-pathologicat examinations of tissues, haematological examinations, and effects on clinical chemiscry will be carried out in aE leasE two animal species. WhiLe all of this is going on, che chemists on the team will be developing meEhods to produce the chemical in the amounts necessary for subsequent studies, developing analytical methods Eo ensure sEandardized quality of batches of the subsEance and examining ics stability under various environmental conditions. Pharmaceutical formulations required when the drug is used in man will be worked out. 4.1.4 The data on animal toxicicy and pharmacology provide the basis for deciding r^rhich chemicals proceed to clinical testing. This occurs in step-wise fashion, beginning with a few subjects, wiEh progressive exEensions, if all goes wel1, to increasing numbers thereafter. It is customary to describe Ehis step-wise developmenE as occurring in Phases. 4.1.5 Phase I studies involve a very small number of human subjecEs, $rho are evaluated intensively for a short period of Cime to determine the maximum tolerated dose and Eo assess pharmacological and acute adverse effects in man. If deemed \ ) 4advisable' Phase rr studies are carried ouE to begin to assess efficacy in paEienEsunder controlLed conditions. rf chere are no contra-indications, Eh;;: are thenextended Eo Phase rrr trials which involve."ct taiger numbers oi pacients under fieldconditions' There.is a growing appreciacion of the need Eo carry out phase rv studies,which involve continued ina exiensive surveillance on subject. r[.,o-t,rr"."""ived a drugafter ic has been approved for marketing - i.e. under postrnarketing situations. 4'r'6 while clinical trials are in progress, long-Eerm animal toxicology sEudiesare also 9"gug.- These may involve investigations to detecc reproductive andteratogenic effects of chl drug, speciar sEuaie.-oi-.rt.genesis, ..rJ-ott"rs asind ic ated . ,< 4.2 Dru hesis/Basic Bi ochemi s c 4'2'l The Group $ras aware of historical daEa which show EhaE on average, for each new drug which reaches the market, approximately 10 000 chemical compounds have beentested, buE have failed Eo meeE critlria for saiety and/or effectiveness. Many oftheser however, are ttlibrarytt compounds, or oEhers from non-targeEted progranmres. rfan inteIligenEly-rnanaged lead-directed programne of synthesis, including appropriatebiochemical studiesr-is pursued, available evidence indicates that on average, severalhundred chemicals will have been Eesced before a drug is found. es-. g".re.al rule ofthumb, a single chemist may synthesize from 50-rO0 chemicals a year. it """*" obvious,therefore, thaE a concertei eifort will probabry be-ieq,ri.ea io'.yiit,".ize sufficienc numbers of candidate chemicals for testing. Some chemicals for screening can, ofcourse, be exEracted from ttlibrariest'of already synthesized compounds miintained byindustrial firms, and oEhers may arise from synih".i. p.og.armes intended for oEherPurposes. But in the main, such random efforts "." not ritery to suffice, and anintensive lead-direcEed synEhesis programne, undertaken by scientists who are EotaIlydedicared to iE, will be iequired.' 4'2'2 The Group h'as aware of chemical synthesis activities currently supported, inPart, by TDR. They include the following: Professor C.hl. Jefford, Universiiy ofGeneva, Geneva' switzerland, has synEhesized 30 nitro-heterocyclic compounds, of r"rhichseveral have shown potentiaI fi[aricidal accivity in animal screens.Professor L.B. Townsend, university of Michigan, Ann Arbor, Michigan, usA, hassynthesized a series of benzimidazole compounds, of r"rhich 40 have been passed throughprimarv screens and secondary screening is bein[ periormed on eight. subsEantial-activiEy has been found for several compounds "g"inst LitomosoidJs carinii and Brueia 4'2'3 As noted previously, basic work on the biochemistry of the parasite maysuggest useful approaches for chemical synthesis. There mu6E, therefore, be closeinteraction and cooPeration beEween chemists, biochemists and biologists. unless thisis done, Ehe chances of success are considered to be too small to warrant 1ong-termfinancial conrmitmenE. rt would, however, be unwise Eo assume that formation ofinterdisciplinary SrouPs wi[1 in itself ensure success. To maximize opportunities fordiscovery, contributors should be sough! ".q opportunities seized whenever available.Tttus, in addition to providing suppo.E for fuliy-i"i.e..t"a-i.r".aiJ"i'iti.,".y groups,the projecE should escablish appropriate relatilnship! wirh acade*i"-"ip".as and orhersand screen molecules submitEed to iE from whaEever source. I .1 i I I t 54.2.4 The Group concluded thaE. in order to achieve the critical mass of scientists necessary for an effective synthesis/biochernistry/parasitology comPonenc oi the project, Ewo inEerdisciplinary groups each made up of up to six professionals and related Eechnicians, should be set up during the early stages of the project, as competent people become identified. Setting up cr^,o such groups provides the necessary ntrmbers of people Eo provide reasonable chances of success, encourages competition, and avoids puEting all resources into one approach and a single group. The Group considered it would be very difficult fo find more Ehan Ewo teams compeEent Eo generaEe the ideas necessary and carry ouE the work. 4.3 Drug Screening 4.3.I Based upon informaEion supplied by sEaff of the Special Progranme, and site visits made to various centres, Ehe Group uas aware of the following facilities for screening of chemicals for fitaricidal activity. A11 screens Iisted in uhis section receive aE least partial support from TDR. (a) Primary screening cenEres\ \ 1. Dr. D.A. Denham, of Medical Helminthology, London SchooI Keppel Street of Hygiene and Tropical Medicine, DeparEmenE (Gower Street), London l^lc1E 7HT, UK. This screen uses U.g& pahangi in jirds, and has a secondary screen available with the same parasite in "rE.. It tap" sources of compounds in Ehe UK, Europe and USA. ThecapaciEy is approximaEely L000 compounds per year. 2 Professor H. Tanaka, DepartmenE of ParasiEology, InstiEute of Medical University of Tokyo, 4-6-1 Shiroganedai, Minato-ku, Tokyo 108, Japan.Sc ienc e, This screen employs Litomosoides carinii in cotron rats using intraEhoracic drug dosage. Some second;.y ";;eni"g$6lcy is now being deveioped (Brugiq malayi,Dipetalonema viteae, Dirofilaria inunitis). IE taps sources of compounds in Japan, r^riEh a capaciEy of approximacely 200 compounds per year. 3. Dr. D.C. Jenkins, The Wellcome Research LaboraEories, Langley Court, Beckenham BR3 3BS, Kent, UK. This screen employs B. pahangi in jirds. Approximately 700 compounds per annum can be screened. It is anticipaEed Chis in vivo screen qrill be superceded within Ehe next 6 months by an in vicro screen utiTfz'Ifrhe invasive larvae of B. paha ngi. Thi s latter screen will permic tesEing of 1400 neq, compounds per year. (b) Secondary screening cenEres These also do some primary screening, but are more often engaged in working ouE thedetailed profile of filaricidal acrivity (including dose Eitration) in a varieEy of rodent parasiEes. \ )- 6I Dr. 30602, J. McCal1, USA. Universicy of Georgia, Department of parasitology, Athens, Liebig-UniversiEh'r, I ate Georg ia (c) Te rE ia sc reen Il:t":::::n_uses l.';ar!!i!.and B. pah?ngi in jirds at primary lever and has capacirytor secondary screening with L. carinii in cotton rats, D. viEeae in jirds, g. pahangiincatsanddogs,andD.irrrmiffi-E!s.r..,p.-,iirffi;;:;*o.,"dsinUSA. Capacity is approximatEfiTTGmpounds p". y"".. 2- Professor R. Gothe, rnstitut ftir parasitologie, JustusRudolf-Buchheimstrasse 4, D-6300 Giessen, FRG (formerly under theProfessor G. Liinunler). This is the mosr thorough secondary screening facility available. rt also does someprimary screening. Mulcimarunate rats (Mastoiys) are used as hosEs for L. carinii,D'.vitege,.B, pahgngi and B,, malavi. 06ffi-e used as trosrs f;; ;. ."rffitr.,ni3"d.9-s:I!tapsmain1ysourcesofcompoundsfromqrithinffiir,ffirs approximaEely 150 compounds per year. / / 1' Dr' D.B. Copeman, DeparEment of Tropical Veterinary Science, James Cookuniversity of North Queensland, Townsville, Queensrand, 4g1I, Auscralia. This screen involves gnchocerca gibsoni and o. gutturosa in cattle. It provides the closesE currently available approximation to t[E-inEection in man. It is Ehe onlytertiary screen avail-able in che world at presenE, and is now being used by a nunber ofpharmaceuticaL companies as well as by TDR. In general, results o6tained agree withdaEa obtained in human patients trith o. volvulus infecEion. current capaciiy is approximately 50 compounds per year, rith pot,e"tial for expansion if necessary. 4'3'2 A number of drug companies also mainEain primary filaricide screens, to tesEcheir own compounds. They include: Bayer AG Pharm. Forschungszencrum, Ressort Medizin, 56 tluppertaL-Elberfe[d Aprarher, FRG (Dr. H. Thomas); 750-1000 compounds per annum; Ciba-Geigy India Ltd., Bombay, India (Dr. D. Subrahmanyan); capaciry is unknownl Hoechst AG, 6230 Frankfurt-Main 80, FRG (Dr. D. Dijwel); 600-800 compounds per annum; Hoftman-La Roche & Co., annum; 4002 Base1, SwiEzerland (Dr. H.R. Srohler); 600 compounds per Janssen Pharmaceutica, Turnhoutsebaam 30, B-2340 Beerse, over 500 compounds per annum; / "1 Be lgium (or. o. Thienponr ) ,. t 7 Merck Institute, P.O. Box 2000, Rahway, New Jersey 07065, USA (Dr. I{.C. Campbelt); maintains a secondary screen against D. irmnitis; capacity is unknownl Rh6ne-Poulenc Sant6, 22 Cour Albert ler, 75008 Paris, France (Or. C. Jclles); 500 compounds per annum. 4.3.3 In view of the necessity to view the screens as dynamic raEher than staEic procedures for assessment of filaricidal activity, the Group recommended that frequent assessment of the mechods and results should be carried out by the Secretary and Steering ConuniEtee of the OC project, through a workshop format. Procedures should be adjusted in the light of experience, taking inco account the predictive value of rhe various methods. Each method should be fully described by the investigator involved.Criteria used by investigators for proceeding from primary or secondary screens to a tertiary screen need careful idencification. In view of che key role played by the tertiary cattle screen, it should be kept under cLose surveillance and expanded if necessary to make cerEain it does not become a bot,tle-neck slowing down further drug deve lopment . 4.3.4 The Group concluded that for maximum efficiency and effecciveness, a common synthesis/primary and secondary screening activiEy should serve both Ehe OC project and the filariasis component of TDR. The tsro main aspecrs of filariasis chemoEherapy, namely onchocerciasis and lymphatic filariasis, would then diverge at che point of tertiary screening. As already ment.ioned, Ehe tertiary screen for onchocerciasis is in cattle. The terEiary screen for lymphatic filariasis uses B. matayi in leaf monkeys. 4.4 Toxicity Assessment and Regulatory Clearance 4.4.1 The Group noted hiscorical data which shows EhaE an average I0-15 years and and 40-60 million US dollars are no$, required to develop a drug for markecing and geE ic cleared by leading national regulatory agencies. Much of the Eime ancl costs involved are required for Eoxicology assessment. A well designed and properly conducEed tsro-year toxicity study in rats or dogs, for example, can be expecced to cosE upwards of US dollars 5OO OOO, at 1982 prices. 4.4.2 In mosE indusrrialized counEries exEensive legaI requirements must be meE before a drug can be regisEered. Significant inter-counEry differences in the amount and Cype of data required for this purpose are, however, apparent. Many developing countries, on the other hand, lack the legislative/regulacory base and/or the Lechnical expercise required to evaluate the safety and efficacy of new drugs. 4.4.3 The Group was of Ehe view that in developing a neq, drug againsE onchocerciasis, great care must be taken Eo ensure that the popularions who witl be exposed Eo it will not be subjected to undue risks. In oEher words, the product involved musE be cesEed for safery and effecEiveness according to Lhe besc available scientific standards. 4.4.4 It must, however, be recognized EhaE unless a reasonable balance is sEruck between risk and benefit, populations in need may be deprived of useful therapy. Some risk is inescapable. There can be no subscitute for informed judgemenEs based on scientific evidence as a basis for rational decisions on drug regulatory requirements. ). L 84.4.5 The amounE of data required to obtain approval for the clinical trials and/ormarketing of a new drug against onchocerciasis obviousty will play a major role indetermining the cost and time required for drug development. Since regulaEory agenciesin indusrrialized counEries vary significantly in the amount of data they reqli." fo.these PurPoses, Ehe Group reconmended that t.lHo Eake the lead in determi.ring itt" amount and kind of data needed to establish the drug's safety, and effectiveness, based uponthe besE scientific advice available. A meeEing of experEs to identify these requirements should be held as early as possiblE in ctri drug develop."nt process. IE witl be important to obEain the views of ehe national governments involved in this aspecE of che OC project. 4.5 Clinical Testing 4'5.1 The Group was of the view thaE a major aim of the oC project should be Eostart Eesting of potenEial drugs in human subjects as soon "s po".ible, provided, ofcourse' that animal efficacy and safety assessment data so $rarrant. C1ose and continuing atEention must Eherefore be paid to the availability of qualified clinicalinvestigators and to the development of clinical facilities, so that the high standardsof scientific excellence required in clinical studies for submission to.egil"tory agencies can be met. l 4.5.2 trials The Group was aqrare of the existence of clinical facilities of an onchocerciasis drug at the following inscitutions: for carrying out (a) At Tamale in Northern Ghana under the direcEion of Dr K. Awadzi; (b) At University College, Ibadan, Nigeria, under the direction of Dr O.O. Kale; (c) At t^lau in Sudan under che direction of Dr Hadi el-Sheikh in associacion with Professor Barrie Jones of the Institute of ophthalmology, London; (d) AT Dr Lom6 in Togo where Togolese physicians have been working in associacion with Schulz-Key and Dr Giese from Germany and others; (e) AE San Cristobal Dr Rivas-Alca1a, de las Casas, Mexico, where trials are carried out by in association with US physicians. Consideration should be given to strengthening these institutions as required, byproviding sEaff, training opportunities, equipment, eEc. Every opportunity should be Eaken to sErengthen the involvement of local professionaL and cechnical personnel inthe institutions. Final decisions on Ehe need to strengthen clinical faciLities can only be taken when the number of drugs available for Eesting becomes known. A meeting of experEs should be held before che end of 1982 t,o improve sEandardizarion of clinicalprotocols. Many individuals with onchocerciasis are aiso infected with other filarialparasiEes. The effects of any new onchocercal drug on other filariae, therefore, mustbe taken into account. The Group also noted that careful epidemiological sEudies must accompany Phase III clinical trials of any new drug. ,1 I ,'1 I I I I ,l I I 95. THE CURRENT SITUATION 5.1 Drug Development 5.1.1 The Group noted that TDR has done much to stimulate research and developmentin the field of onchocerciasis chemotherapy. Prior to its establishmencr industrial and academic interest in the chemotherapy of onchocerciasis was exEremely limited. Currently, however, TDR provides nearly US $1 million annually for research in chisfield, and its efforts have played an important role in stimuiating industrial interest. 5.1.2 Research into che chemotherapy of onchocerciasis supported by TDR includes clinical trials on knoqm filaricides, to learn how to use Ehem more safelyl clinical testing of anthelminthic or antiparasitic drugs for accivity againsE Onchocerca volvulus; support for filaricide screening cenEres, (see Settion 4.3.D, supp,ort for small-scale chemical synthesis programmesl and basic work on filarial mecabolism. Over 8000 chemicals originaLing in the drug industry, having now passed through one or more of the various screening procedures esEablished. DeE,aiLs of filariasis research conducted by TDR are given in the annual reports of che TDR programme. The Scientific and Technical Advisory Conrnittee (STRC) of TDR periodically reviews and evaluaEes Ehe work, on behalf of the JoinE Coordinating Board. The Group concluded thaE the work is of high quality, but, as mentioned previously (Section 2), provision of addicional funds would accelerate progress and significantly increase the chances of finding anddeveloping a new drug. 5.2 Visits to Drug Companies 5.2.L Visits were made by members of the Group Eo a number of drug companies with ahistory of involvement in research on parasiEology. Two or more members of ihe Group visited each of rhe foLlowing: Hoechst AG, Frankfurt-Main, FRG Merck, Sharpe & Dohme, Rahway, New Jersey, USA Pfizet Inc., Groton, Connecticut, USA Rh6ne-Poulenc Sant6, paris, France The Upjohn Company, Kalamazoo, Michigan, USA A11 members of Ehe Group visited the following; Janssen PharmaceuEica, Beerse, BelgiumIt )' Ir The WeIlcome Foundation, Beckenham, Kent, UK I ) T 10 In addition, a delegation from Bayer AG, FRG, visited LIHo, Geneva, for discussions with one of the members of the Group, and one member visited Hoffman-La Roche & Co. and Ciba-Geigy Ltd., Basel, Stlitzerland. Proposals for research support were received fromCiba-Geigy, Base1, Switzerland and from tire.Wellcome Foundation,'n.ctent"m, KenE, UK.Both of these organizations have maintained close links with the TDR programne sinceits inception. 5.2.2 Senior represenEacives of all companies visited envinced great interesr in the OC project and sympathy with its aims and objectives. It was, hoirever, evidentthat a major impediment to concerEed industrial involvement in the project is the lowprofitability of drugs intended solely for onchocerciasis, coupled wich che high risks inherenE in drug developmenE progranmes in general. Thus, several companies currentlyinterested in drugs for onchocerciasis and in Ehe much larger markeE for drugs against lymphatic fiLariasis appear Eo be acEinB out of a sense of corporate responsibility co assisE with a major health problem in poor developing countries, and/or areinvestigating filaricides as a spin-off from a moie direct invoivemenE in commercially viable aspects of parasitology, such as veterinary anthelmintics. Nevertheless, it was aPparent that wich moderate leve1s of financial assistance, several companies would be prepared to invest time and resources in the OC project. The assistance required could take several forms: provision of screening facilities; support of biochemistry/synthesis programmesl assessment of the coxicological and/or pharmacological properties of chemicals; provisions of or support for clinical facilities. If such assistance is not made available, the Group concluded that. industrial interest would reqrain limited and unlikely to be of the scope and magnitude necessary to make significant advances in the field. 5.2.3 The research proposal from Ciba-Geigy referred to in Section 5.2.1 above deals with preclinicaL development of three macrofilaricidal drugs, which have successfully passed the primary, secondary and tertiary screens. The sEages to which these compounds have been developed are as follows: Z of work 1 completed for ccP 21835Study tvpe Specific Accivity General Pharmacology Fate of Drug Studies(absorption, distribution, metabolism, exc retion) Tox ico logy Chemical development 80 50 95 70 0 30 A ccP 6140 CcP 20376 0 ccP 24914 50 00 0 5 80 0 0 { / I / { /l 20 90 5 20 50 lPercentage of work to fu1fil the requirements for initiating a Phase IIITa study in man. +11 5.2.4 As noted in Section 5.2.1, a proposal for research support has also been received from the tlellcome Foundation. In summary, the Foundacion proposes Eo carry out an integrated progranme of parsitotogical, biochemical and chemical research aimed at development of a safe and effective macrofilaricide. 5.2.5 The Group noted Ehe excensive experience and sErong cornmitmenE of the hlellcome Foundation co research in tropical parasiEic diseases. Forty staff currently are involved in research on the chemoEherapy of parasiEes. The Group was impressed wirh the enEhusiasm and competence of the t{ellcome Foundation scaff,-and recommended suPPort for the research proposal. Detailed reconunendations are given in Section6.2(b). 5.2.6 The Group also noted significant activity in the field by staff of Janssen Pharmaceutica. ImporEant r.rork has been done on Lhe chemoEherapeutic value of mebendazole and related compounds against O. volvulus, W. bancrofEi and B. malayi. It has been found that daily doses of mebendazole over a 3 week period, alone or combined wich priming doses of levamisole, are capabLe of significantly reducing microfilarial concentraE.ions of O. volvulus for up to 12 monE.hs af Eer treatmenE. An embryosEatic action of mebendazole on the adulc worms of O. rrqlllulus, which appears to last for several months, uras observed. A new formulat 10n o fme ndazole, which produces significanEly increased leveLs of the drug in the blood has been produced recently. 5.2.7 The Group concluded that clinical trials should be conducted with some urgency to tesC the new formulation of mebendazole alone and in combination with levamisole. This should include deEermination of optimal drug requiremenEs, and i.nvestigacions on wheEher che combined treatment exerts deleEerious effecEs on the eyes of patients. Detaileo recommendaEions on supporE for this aspect of rhe work are given in Section 6. 2(c ) . 6. PROPOSED ACTIVITIES IN 1982 6.1 The Group had before it tencative recoflrmendations on the esEablishmenE of an OCP Chemotherapy Fund, and proposed expenditures thereon in 1982, as presenEed to Ehe Joint Progranune Conunittee of the OCP. This proposal made the following reconunendaEions: (a) toxicology to bring one or two new drugs(a Ciba-Geigy drug & diethylcarbamazine N-oxide) up Eo Phase I clinical trials us $ 850 000 (b) reserve for resynthesis of promising new c ompounds us $ 50 000 (c) finance Ehe Wellcome Foundation filaricide screen and establish an associated chemical synthesis programne us $ 250 ooo(minimum 3-year guaranEee) l {' \ a. l-- r t2 6.2 Given Lhe need to puE major emphasis on building a balanced long-term activity,Group approved the following disposition of funds for 1982 (a) Toxicoloqv of Ciba-Geiey Compounds the The current sEatus recommended the following CGP 21835, as decided by of these compounds is shown in Section 5.2.3 above. The Group studies be completed on compounds CGP 6140, CGp 20376 (or the Company) and CGP 24914: I \ 1 month Eoxicology in rats and dogs absorption, distribution, metabolism and excretion studies in the mo6t suitable drug of those lisced above, based on evaluation of all available data. In by addition, acute the Company) and on ccP 249L4. The estimaced cotal cost of these studies is LD56 scudies should be conducred on CGp 20376 (or CGp 21835, as decided us $ 500 000. (b) s nthesis Sc reeni The Group noted that TDR currently supports the t{ellcome Foundation to the extent of LIS $ 95 000 for filaricide screening activities in 1982. In addicion ro that amounr theGroup approved that US $ afO 000 be allocated to rhe Wellcome Foundation for 1982, wirh unsPent funds Eo be carried over to 1983. These funds should be spent on lead-directed andbiochemical-target based synthesis and on basic biochemistry studies, as outlined in the applicacion for research support from the Wellcome Foundation. The droup noted that theproposal cited calls for recruitment of four qualified professionals (two each in chemistry and biology) and four Eechnicians. They will supplement two qualified parasitologists already on staff. In rhe opinion of the Group, recruitment of high quality staff is an essential steP in laying Ehe groundwork for a long-term programne in onchocerciasis drug deve lopment. (c ) C1 inical Srudies A meeEing of exPerts should be held on the strengthening of ctinical protocols. The esEimaEed cost is US $25 000. SupporE should be provided to strengthen clinical testing capabilities in Togo (Dr. Schulz-Key et a1) to enable tesEing of mebendazole formulations and dosage regimens, and to lay the groundwork for.a long-rerm (two year) study wich a large ntrmber of patienrs. The estimaEed cosE is US $ 5 000. Effecrs tn the eyel of pariencs receiving the new formulation of mebendazole in combination wich levamisole (see SecEion 5.2.6) should be carried out. Estimated costs are US $ ZO OOO. (d) Regulatory Requ i remenE s ( 7l A meeting of expercs should be held co idencify regutaEory requirements registration of an onchocerciasis drug. The estimated cost is US $ 25 O0O. for { In summary, therefore, the Group approved the following disposition of funds for 1982: a 13 - Toxicology of selected Ciba-Geigy compounds Sychesis and biochemistry studies aE Ehe Wellcome Foundation Strengthening clinical protocols Clinical studies on new formulation of mebendazo le US 5C0 000 410 000 25 000 25 000 25 000 OC projet must be such that decisio,rs can red tape, as priorities and opportunities be built in to ensure EhaE funds are $(i)(ii) (v)(vi) (iii) ( iv) V Identification of regulatory requiremenEs Travel and other costs of progranme admini- straEion, including secretariat 50 000 Total 1 035 000 This is somewhat less than che US $ t.fS million originally proposed for expendirure in 1982, buc the Group was of the view thaE a small- reserve should be reEained, in order to be able co Eake advanEage of unforeseen progranme needs, e.g. possible further testing of diethylcarbamazine N-oxide and/or preparation of sufficienE amounts of promising compounds for the catEle screen. 7. PROPOSED MANAGEMENT STRTICTURE FOR THE LONG-TERM 7.1 The Group considered that managemenE of the be raken rapidly, with a minimum of bureaucratic change. At the same E.ime, adequate controls must expended effectively and efficiently. - 7.2 A reconrnended management sEructure for the OC project is as follows: 7.2.L The OC projecc will be financed by OCP, which will act on Ehe scientific andtechnical advice of Director, TDR. 7.2.2 A Steering Conrmittee on the Chemotherapy of Onchocerciasis will be established by DirecEor, TDR in consulcation wich Director, OCP. The Steering Conrnitree will develop a plan of action and progranrne budgec for che oC projecE, reviewproposals, recontrnend projects for Eechnical approval and financial support and monitor Progress. The Steering Committee wilt direct all vork on Ehe chemotherapy of onchocerciasis financed Ehrough OCP and TDR in a manner similar Eo rhac of TDR SteeringConunittees. Membership of the Steering Committee will overlap with that of theSteering ConrmiEtee on Filariasis, in order to provide liaison and coordinaEion. 7.2.3 The proposed plan of acEion and programme budgeE will be presented by che Steering Conrmittee to the Scientific and Technical Advisory Conrnittee (slnc) of TDR,through DirecEor TDR. sTAC using its Scienrific and Technical Review conrniEree (srnc) and/or oEher appropriaEe mechanisms, will review and evaluaEe che progress, plans and Progranme budgets of the OC project at each of its sessions and prepare a special reporE on-the projecr. One or more members of the ExperE Advisory ConunitEee of OCP will parcicipate in this process. )^ 7.2.4 The report of STAC on Ehe proposed plan of action, progranme budget andprogress of the OC project will be submitted, along with the proposed plan-and ) 0. T4 progranme budget' to the cormnictee of sponsoring Agencies (cSA) of ocp and the scandingcormnitcee of TDR. rf required, the two conunittles-wil1 hold a joini ieeting coconsider Ehe report. 'ltrese in Eurn.will submit them, Lrith comn;nts as appropriate, toboch the Joint Progranune committee (JPC) of.ocP and ih" Joi.,t coordinating soard (jca)of TDR. 7.2.5 Contracts for research and development projects financed by OCp will signed and processed by OCP after technical approval from Ehe Direcclr, TDR. be 7.3 The Group was of the view that the highly specialized naEure of the oC project requires an individual to be designated as SecreEary of the Onchocerciasis Chemotherapy Steeringconunittee referred to in Section 7.2.2 above, with full responsibifity to move the projeccforward.as quickly as possible. He (she) should be exrremely knowledleable in che field ofindustrial drug research and development and be highly results-orienrEa. He (she) should work in close association with the SecreEaries of the Filariasis SWG and of its Steering conrnictee, and serve as the link beEween cooperating industrial and academic organizations and the pro.iect, ensuring cooperation and avoiding duplication of efforrs. RecruiEmenE should proceed as quickly as possible. If no suitable candidate is immediately available consulEancy services should be uciLized. Although Ehe precise duties of the inaiviauatinvolved wi11, Eo some extenc, be conditioned by agreemenEs reached with industrial and academic collaborators in the project, he (she) musc be pro-active, rather than reactive.That is, opportunities for collaboration must actively be sought out, and the individuaLinvolved should-participate_to Ehe maximum extent possible in day-to-day decision making. Adraft proposed job descriprion for rhe secrerary ii attached (Annex rrr). 8. FINANCIAL IMPLICATIONS FOR THE LONG-TERM 8.1 Investment in the proposed OC project must be seen as a long-term conrmitment. The chances of high short-term pay-off must be considered as slight at besE. As noted above(Section 5.2.3) a few (3-4) chemicals have been found to date which exhibir macro-filaricidal activicy aga inst Onchocerca species in animal screening models. Experience has shown, however, ChaE on average only a sma I1 percenEage of chemicals which show acEivity in screening programnes survive tesEs of safety and effecciveness and go on to fu1l-scale application. The chances are only slight, therefore, that any of the chemicals idencified ro dace will in Ehe long-run be found to be safe and effective in man, and be developed to Ehepoint of being available for public use. PotentiaL donors to Ehe oC project should prepare themselves for a long-term efforr of a decade at leasE. 8.2 As noted above (Section 4.2.4) the Group reconunends that turo dedicaced interdisciplinary groups of up to six professionals and related technicians each should be set uP to carry out synthesis/biochemistry/screening aspects of the OC project. Since continuity of funding is a prerequisite for building up a group of qualified people, until 1984, at least, one of those interdisciplinary groups should be thaE in the Wellcome Foundation, identified in Section 6.2(b) above. In other words, a firm conrniEment should be made to support Wellcome Foundation acEivities in snythesis/biochemistry/screening for ar least a three-year period, beginning in 1982. It must be made clear rhac chis would be expected to enhance lrlellcomers activities in rhe field, speeding up their research programme on filariasis, introduced with the support of TDR, and increasing the chances of successfuLty finding and developing a new drug. The onchocerciasis chemotherapy projecE at Wellcome draws ( - .t r\ { \ )15 upon Lhe total involvemenc of the Company in parasite chemotherapy. Since Wellcome already las a hg",ry investment in che field of parasite chemoEherapy (approximarely US $ 2.5 millionin 1982), there trould be strong incentives for it co spen,il suppiemencary flnds wisely. 8.3 The other dedicaEed interdisciplinary group is yeE to be idenrified and may bedifficult to find. It may well come from the drug indusrry, but the possibilicy ofdeveloping an academic group for single o. "oope.ating institucions sirould be invesrigatedfurther. 8.4 Based on historical cost. data from the US and UK drug industries, ic is esrimated chat Ehe annual cost of one inter-disciplinary group from each counEry, each composed of up Eo sixprofessionals and Ehe same number of cecirnicians, would amount co'us $ 1.2 million. 8.5 The Group noEed that it will take time to build up rhe oC projecr Lo ir.s fuII operaEional capacity. Although this must. be done as quickly ". po..iUre, greaE care musr be taken noE to sacrifice quality of personnel or performance in the process. 8.6 It is essential thac financial management of the oC project be such thaE advanrage canbe taken quickly if unexpecEed advances occur. Rapid changes-in priorities and movement of resources must readily be accomplished. At the same time ic is excremely difficult toforecast accurately the precise financial requirements over rhe next five years. With thesefactors in mind, the Group recomnended the following amounEs should be budgeted for each of che nexE five years (based on 1982 US dollars). These amounts are in excess of those currenEly budgeted by TDR for studies on the chemotherapy of onchocerciasis. us $ (000)Support for two interdisciplinary groups of chemi sr s/b iochemi st s /bio logisr s / r200 200 700 800;. 300:. t Basic biochemistry Chemica I synthes is/screening Toxicology assessment of screened chemicalsCIinical sEudies, phase I and II Secretariat, administration, travel and meetings 8.8 It is difficult Eo make firm financial projecrions beyond 1987, thaE large-sca1e phase rrr clinical trials could be expecEed Eo cosE do 1 lars . 34 50 The amounl needed may be significantly more or less Ehan Ehat indicaced depending on the success of the earlier phases of the project. 8.7. Ig provide necessary flexibility in funding promising leads, and Eo have a reserveavailable for this purpose, the Group recommends thaE the OC projecc be funded aE Us $ 17.25 million for the next five years (1982-87). ExpendiEure of over US $:.4: million in anygiven year should require Lh" rpp.oral of che Conrmictee of Sponsoring Agencies of oCp and theStanding ConrnitEee of TDR. Surplus funds not used in any given year should be held in reserve, for release to support promising leads. 250 but ir should be noEed upwards of one million l 9- 16- MANDATE OF THE WORKING GROUP FOR THE REMAINDER OF 1982 The Group concluded that pending final decisions on theproject, Ehere remains useful preparaEory work for it to do.proposed Ehat the Group carry out Ehe following: esEablishment of the OC During the rest of. L982, ic is { \ (a) Identification of a second Wellcome Foundacion; interdisciplinary group in addition to Ehar aE rhe (b) Identificacion of possible candidaces for Onchocerciasis Chemotherapy Steering Committee; the post of Secretary of the (c) Investigacion and encouragemenE of academic and industrial links with the project; (d) Monitoring of the Wellcome and Ciba-Geigy research projects. Pursuanc to accomplishment of September, L982. that Eask, the Group plans to meet in Geneva in 10. SUMMARY AND MAJOR CONCLUSIONS The Onchocerciasis Chemotherapy (OC) Project Working Group met, in accordance with instrucEions received from the ConunitEee of Sponsoring Agencies of the Onchocerciasis Control Programme in the Volca River Basin area, (OCP), to prepare reconunendations for the mechanismto manage a proposed projecE Eo develop a new drug against onchocerciasis. The Group also approved expenditure of funds made available in 1982. The Group: (a) noEed chaE the objective of the OC project is to find and develop a safe, effective, low cost and convenienc to use drug for onchocerciasis which will Permanently sterilize or ki11 the adult female worms of Onchocerca volvulus, withouE aE Ehesametimecausingseverea11ergicreactionsi.'recipffiiffiEraricida1 acEion. Although no guarantee could be given thac this task can successfully be accomplished, che Group considered thac wise expenditure of funds in addition to those currently being spenE on onchocerciasis chemocherapy would accelerate progress and significantly increase the chances of success; (b) decided Ehac cooperation with the drug industry, academic insricutions andindividuals is essential in rhe developmenE of an onchocerciasis drug. Although it was not considered advisable Eo guarancee a market for a particular drug prior to it. development' the low profitability in the field and relatively low level of currentindustrial inEeresE requires that industrial support be stimulated by providingfinancial assistance for one or more of the research and development-eiemenEs involved. This supporE musE noE replace what companies would be prepared co do with Eheir own resources, but should supplemenE their efforts by providing ful1 or parEial suPPorE for synchesis, biochemistry and screening programnes, toxicology, and clinical { 17- crials. Unless such support is forthcoming, Ehe Group considered EhaE induscrial interest would remain limited and unlikely to be of the scope and magnitude necessary Eo make significant advancesl (c) concluded thaE the OC projecE must t.3ke fuII advantage of exisEing R & D prograrmes in the field, in particular Ehat of che UNDP/World Bank/WHO Special Progranrne for Research and Training in Tropical Diseases (TDR). TDR has done exteasive tnrork to lay the basis for air expanded and focussed programme on Ehe chemotherapy of onchocerciasis. &nong this is support for the development of facili.cies Eo screen chemicals for filaricidal activity, and for clinical- Eeseing of proroising compounds. As a result of TDRrs scimulating and coordinating role, which provides nearly Us $ 1 million annually for research on onchocerciasis chemoEherapy, over 8000 chemicals originating in che drug induscry have now passed chrough Ehe various sc reening procedures established; (d) decided E.hat in order to encourage the involvemenE of indusrrial firms in rheproject, economic returns outside t.he human healr,h fietd which result from chemicalsdeveloped with financial support of rhe projecE should accrue co the company involvedl (e) reconunended chat in order to achieve the critical mass of sciencisEs necessary for the achievement of progress and at the same time encourage competicion and avoid puEEing.aLl resources into a single approach, two interdisciplinary groups, each made up of six professionals (biologists and chemisEs), and relaced technicians, should be set up as soon as compeEent people can be identified; (f) noted Ehat a research proposal had been received from Ciba-Geigy LEd., Basel, Switzerland, which deals wirh the preclinical developmenE of Ehee macrofilaricidal drugs which have successfully passed the animat screening procedures. Another proposal has been received from the liellcome Foundation, Beckenham, Kenc, tIK, for support of an integraEed prograrrne of parasitological, biochemical and chemical research aimed aE developmenE of a safe and effective macrofilaricide; (g) noEed also that imporEant qrork has been done by scaff of Janssen pharmaceuEica, Beerse, Belgium, on Ehe chemotherapeutic value of mebendazole and relaEed compounds against filarial infections. A new formulaEion of mebendazole, which produces significantly increased levels of che drug in the blood, has been produced recenElyl (h) approved the following disposirion of funds for 19g2: I - Toxicology of selected Ciba-Geigy compounds - Synthesis and biochemistry studies at the Wellcome Foundation - Clinical studies on rnebendazole - levamisoleformulations of Janssen PharmaceuEica Strengthening c linical capabilities Idencification of regulaEory requiremenEs for registration of onchocerciasis .... Travel and other cosEs of progranrme us$ 500 000 410 000 25 000 25 000 25 000 50 000 =- \ adminisErat ion 1 035 000 / I 18 Funds not expended and Ehe remainder of Ehe US $ should be reEained for pursuiE of promising leads. 1.15 million budgeEed for 1982 (i) proposed a managemenE sEructure for the OC project which includes the following: ( the project will be financed by OCp, advice of che Director, TDR; who will act on che scientific and technical a Steering CommitEee on the Chemotherapy of onchocerciasis will be escablishedjointly by TDR and OCP to direct all work in the field conducced by the rwo Programmes. The Steering Conrmittee will have a fulI-time secrecary who is extremely knowledgeable in the field of industrial drug research and is highly results-oriented; proposals for Ehe plan of acEion and prograrmne budget will be approved for scientific and technical conEent by DirecEor TDR and for financial context byDirectors of OCP and TDR; a Scientific and Technical Revier"r CommiEtee, composed of members from theSciencific and Technical Advisory CommitEee of TDR and the Experr. AdvisoryComnittee of OCP, will be set up to review research proposals for sciencific andtechnical policy; (jl reconunended the following(based on 1982 US dollars): amounts be budgeted for each of the next five years us $ (000) (i)(ii)(iii) ( iv)(v)(vi) 1 200 200 700 800 300 250 SupporE for two interdisciplinary groups of scientiscs Basic biochemistry Chemical synthesis/screening Toxicology assessmenE of screened chemicals Clinical studies, Phase I & II SecreEariat, administraEion, travel and meetings 3450 Success of the earlier phases of the project will significanrly influence Ehe amounts needed under (iv) and (v) above. Amounrs above US $ 3.45 miLlion should be released for expenditure in any given year only afEer approval of the Conrmittee of Sponsoring Agencies of OCP and che Standing Conunittee of TDR. Surplus funds should be held in reserve for release to support promising leads; (k) ,concLuded thaE one of the two interdisciplinary groups of scientisEs should be located aE ehe Wellcome Foundat.ion, which should be given support for at least a three-year period, beginning in 1982, for an integrated synthesis/biochemistry/ screening programme. Every effort should be made co find and develop a second group asquickly as possible. 1 \ I, ANNEX I ONCHOCERCIASIS CHEMOTHERAPY FUND (OCF) I{ORKING GROUP I'IEMBERSHIP Dr Garnet Davey Aragon Lodge Star Lane Morcombe lake56ffiT61'on Uniced Kingdom (Formerly Research Director, pharmaceutical Division, ICI) Dr B.O.L. Duke Chief, Filarial Infecrions Parasitic Diseases Programme World Health Organization Geneva Sffidrland Mr J.D.M. Marr Liaison Officer onchocerciasis control Progranrme in the volca River Basin area World Health Organization Geneva 5ffir1and Dr A.B. Morrison (Chairman) AssisEant Deputy Minister Department of National Health & Welfare Ot cawa Canada Dr David trleisblat 11 185 Hawthorne Route I Galesburg Michigan 49053 United States of Americat (Formerly Director of PharmaceuEical Research, che Upjohn Company) / Annex IIfrl(-)z s -iH rd & v) >FlH<(/) .JJ rdH<azH <t4 ctE .1 Fr or (J J o&Ap. H FrP( rrlov14& s F{Oo> HFIUOH<(/) (adH(JIH< O.oE Z F4 60dAa& tr OJ <JEr (!.ddo F{(HA tl <h .aE(ao(,) E o.d..t&trtr{J(,ttlJ(JOO0,F<Oo0rtr =*l OE 0,CJHOdO@zzc) G l{ oO{-ko.U .l xoo,OTtrEt- o tr o U o(! o E o o t{q, E(! oHOHO J(,aalr <Fl O(-)<F{E HH Az&a oHFCDtr@Fl<(!G(.) FEqApoEO d(u oo .dE rrO > r.d(.)O! <o(ulotdEc <EAE(!(uA.c r.o-o cJ) C) HFEfrl c/)ZHHFItzoOrQ(-) <4, t4 = r.:dz EcaA u c >(!>,&14OuFr d.d.d A (,)FH u >r.d E Odplrld (0 OE.JtrUq) p.G o trt FfFIO <<Fl0d=otsl H CJ zz<ET<Eo4 p. & z tl H Fl rd&A C9 ^!FIO o P <J!oEo, €HC) q IZH <nA<x aO.hFI FH tl F(J l-{& Fr H tq (, zq)HHz&t\tEtOsfdfqQ&rtrOA aq7 Ha td E-z a a trl Hap F a OHF{E(/)Id <E ca(J H ra (,} > ho(J o0..{tdooo >Fld oHooo. u)<)EtoZFa uldXOdFOo.GZ?. C IHUO'Flg)> <.d OEE O l-{z<rr (Jp&A Fl aH c) tl&Itlfr ho Fz 14EAoJ ld tda rd F ) I t t ( ir A. DuEies I ANNEX III JOB DESCRIPTION SECRETARY, ONCHOCERCTASTS CHEIToTHERAPY STEERING COMMITTEE To establish, develop and coordinaEe a complex multidisciplinary international prograflrme to find and develop a drug against onchocerciasis, including biochemical sEudies, chemical synthesis and screening progranunes, toxicology assessment and clinical trials. The incumbenE wilt be responsible for managing approximately US $l mitlion of resources each year, involving research co.riraits-with leading scientists and institutions. Under Ehe general technical direction of the Director of TDR, to coordinar.e activicies of the OC projecc with relevanE activiEies of the TDR prograrune, incl-uding those of the Steering Cormnittee on Filariasis. To actively communicate and cooperate with experts in the drug indusEry, academia and research institutions, and representatives of naEional governments as required. To communicate regularly with the Chairman and members of the Scientific and Technical Review Committee of the OC project. 5. To represenc the OC project aE scientific meetings and congresses. B. Skil1s and Personal Characteristics Extensive experience of the drug development process, obtained Ehrough holding a major position in che research hased drug indusEry for many years. A very high level of proven scientific judgement, including judgemenE of scientific EalenE; and of Proven expertise in management of complex drug developmenE projecEs. 4 3 A high degree of personal integrity; the abilicy to keep confidences and to be trusced to do so. Ability to r^rork well with people of diversedisciplines. backgrounds, naEionalities and C. Education t 2 I' 3 4 i I 2 a ?-. Ph.D or M.D.