Basic & Clinical Pharmacology & Toxicology, 2014, 115, 172–178

Doi: 10.1111/bcpt.12278

MiniReview

Development of Clinical Pharmacology as a Medical Speciality in Europe – The Roles of WHO, IUPHAR and EACPT Folke Sj€oqvist Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Hospital, Huddinge, Stockholm, Sweden (Received 23 May 2014; Accepted 26 May 2014) Abstract: This MiniReview shows that both WHO and IUPHAR very early recognized that there is a gap between the availability of academic expert knowledge in pharmacology and its utilization in health care. Many initiatives have been taken to bridge this gap, but still 12 European countries do not recognize clinical pharmacology as a medical speciality because the profession has failed to develop defined functions in patient care. A first priority for EACPT therefore ought to be to promote clinical pharmacology as a medical speciality recognized by the European Union. The pharmacological services listed in Table 7 that focus on drug problems agree well with those that were recently prioritized in the IUPHAR/WHO/CIOMS manifesto to correct a major weakness in the health care of today in order to promote rational use of drugs.

Clinical pharmacology has now existed as a teaching and research discipline for nearly 50 years, but with notable exceptions, it is not yet established in many countries as a medical speciality. This MiniReview describes the attempts of IUPHAR, WHO and EACPT to involve clinical pharmacology in the global efforts to improve the use of medicines towards increased efficacy and safety. The MiniReview emphasizes the situation in Europe. The Role of WHO Farsighted pharmacologists realized that clinical pharmacology had to reach out to the bedside in order to develop and therefore initiated discussions with WHO on this matter. In December 1969, WHO brought together a group of experts to outline a report on the scope, organization and training of clinical pharmacology [1]. The group was led by the late Sir Derrick Dunlop (UK), and with the late professors Louis Lasagna (USA), Franz Gross (Germany) and Leon Goldberg (USA) as members. Participants who are still alive include L. Dettli, Switzerland, C.T. Dollery, UK and F. Sj€oqvist, Sweden. WHO was represented by professor Hans Friebel, Dr. H. Halbach, Dr. T.L. Chrusciel and the temporary adviser professor Desmond Laurence, London. The report concluded that the functions of clinical pharmacology should be: to improve patient care by promoting the safer and more effective use of drugs; Author for correspondence: Folke Sj€oqvist, Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Hospital at Huddinge, S-141 86 Stockholm, Sweden (e-mail [email protected]). This is an invited MiniReview in recognition that Folke Sj€oqvist has been awarded the 2013 BCPT Nordic Prize in Basic & Clinical Pharmacology & Toxicology.

to increase knowledge through research; to pass on knowledge through teaching and, to provide services, such as drug information, drug analysis, the monitoring of drug abuse and advice on the experimental design of clinical drug studies. It was said that all these functions should in fact serve to enhance benefit–cost ratios of drugs. The first function is a prelude to the WHO priority of today ‘Rational Use of Medicines (RUM)’. Another important step in the development of clinical pharmacology took place in Oslo the same year where a WHO Drug Consumption Group was formed [2]. The methodology for international comparisons of the use of drugs was discussed and the WHO Drug Utilization Research Group (DURG) was born. A common drug classification and a common unit for measuring drug consumption (the defined daily dose, DDD) was introduced permitting valid comparisons of prescribing habits within and between countries [3,4]. The transit from classical clinical pharmacological studies such as drug trials and pharmacokinetics to pharmacoepidemiology had then been taken, and it is eloquently described in the WHO publication Drug Utilization Studies edited by Graham Dukes [5]. In 1977, WHO published its first list of essential drugs [6]. For many years, pioneers in clinical pharmacology were the driving forces in the expert committees making these selections, Daniel Azarnoff, Per Knut Lunde, Iwan Darmansjah, D.R. Laurence, Marcus Reidenberg and Gianni Tognoni to mention a few. It is clear, not the least from a review by Tognoni and Lunde [7], that the idea had its origin from academic pharmacology. As an example, national drug lists based on clinical pharmacological evaluations of the therapeutic armamentarium were introduced in Scandinavia already in the mid

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1960s. Provided that such are well communicated, they may have a major impact on prescribers with up to 90% adherence to the recommendations issued [8,9]. This series of WHO technical reports has now published the 17th Model list of Essential Medicines and still clinical pharmacologists play an important role in the selection process. During the next decades, clinical pharmacology developed because of the medical need to establish in scientific terms the benefits of drug therapy relative to its risks. A WHO Working Group on Clinical Pharmacology in Europe was formed in 1983 and its recommendations were summarized in three papers in Eur. J. Clinical Pharmacology during 1988 [10–12]. Clinical pharmacology was described as an indispensable part of the health service and considered to be important both in hospitals and primary health care. Services included patient care directly in general medicine (drug problem-oriented consultations) or more indirectly through pharmacotherapeutic rounds and sessions. The roles in drug information and in formulary committees, clinical trials, drug utilization surveys and monitoring of adverse drug reactions were underlined as well as therapeutic drug monitoring. In 1990, WHO headquarter in Geneva (Drs V. Fattorusso and J. Dunne) organized an informal meeting to discuss the role of clinical pharmacology in public health. The meeting took place 20 years after the initial WHO study group met in Geneva and 5 years after the Nairobi conference on the Rational Use of Drugs. It was agreed that clinical pharmacology had developed from being product-oriented to become patient-orientated and society-orientated. The discrepancy between the need for and the availability of clinical pharmacologists in health care had increased. It was underlined that the roles of clinical pharmacology and the new discipline clinical pharmacy were complementary and that collaboration between the two should be encouraged. Clinical pharmacologists should be involved in the teaching about rational drug use at all levels. The proceedings of this meeting were not published. In 1991, WHO Europe in Copenhagen put together a booklet with the three papers mentioned above dealing with the roles of clinical pharmacology in teaching, research and health care [13]. The WHO team consisted of Graham Dukes, Leo Offerhaus and Inga Lunde. The potential usefulness of the discipline for the rational use of medicines (RUM) in primary health care was emphasized. The booklet contains reports from 21 European countries. A few countries reported that clinical

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pharmacology now was established as an academic discipline at all medical schools (Denmark, Finland, France, Germany, Norway, Sweden, Switzerland and UK), while most countries considered that services in clinical pharmacology in health care were poorly developed or lacking. There are other examples from this time of mutually fruitful collaboration between European clinical pharmacology and WHO such as the international cooperation in drug surveillance summarized in a CIOMS conference 1993 [14] and the booklet Introduction to Drug Utilization Research 2003 [15]. During the coming years, attempts were made to convince WHO about the need to update the recommendations from 1970. Finally, these efforts resulted in a joint publication from WHO, CIOMS and IUPHAR in 2013 [16], which was a modification of an IUPHAR paper from the previous year [17]. A driving force within WHO in this important development was Professor Lembit R€ago. Recently, WHO (Richard Laing) and European drug experts (on the initiative of Lars Gustafsson, Sweden) met to discuss the interface management of pharmacotherapy, particularly the collaboration between hospitals and primary health care [8]. The roles of WHO in the development of clinical pharmacology are summarized in Table 1. The Role of IUPHAR The International Union of Pharmacology (IUPHAR) was founded in 1965 after a decision in IUPS (International Union of Physiological Sciences) to approve that its Section on Pharmacology formed an independent union [18]. In the forthcoming world congresses in pharmacology, due attention was paid to the developments in clinical pharmacology. An important step towards the formation of a Section of Clinical Pharmacology within IUPHAR was taken in May 1973. In a proposal to Arnold Burgen, president of IUPHAR, three clinical pharmacologists (Colin Dollery, UK, Dan Azarnoff, USA and Folke Sj€ oqvist, Sweden) suggested that an interim commission on clinical pharmacology should be formed. It was supposed to map out training sources for clinical pharmacologists in different countries, survey drug usage and response in different parts of the world, the latter including genetic and environmental differences in drug response. It should also evaluate the effectiveness of clinical pharmacology in relation to healthcare delivery and the provision of drug information by means of bias-free education of prescribing

Table 1. The role of WHO in developing clinical pharmacology. Year

Important event

1969 1969 1977 1983 1990 1991 1993 2013

WHO study group on Clinical Pharmacology Scope, Organization, Training [1] meets in Geneva WHO Drug Consumption group formed in Oslo [2] The first list of essential drugs published by WHO [6] The WHO Working Group on Clinical Pharmacology in Europe formed [9] Informal consultation in clinical pharmacology and its relevance to public health held in Geneva Clinical Pharmacology. The European Challenge was published [12] Drug Utilization studies, Methods and Uses published by WHO [5] Clinical Pharmacology in health care, teaching and research. WHO/IUPHAR/CIOMS joint publication [16]

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doctors. Already this early proposal emphasized the role of clinical pharmacology in health care. The following year, IUPHAR decided to form a Section of Clinical Pharmacology, which was formally established at the Sixth World Conference in Pharmacology in Helsinki 1975. Colin Dollery became its first chairman. About 300 clinical pharmacologists attended this meeting, bylaws were accepted and an advisory board appointed with members from Germany, Hungary, India, Sweden, UK and USA. Important meetings with the executive board aiming to strengthen the Section were held in Deer Lodge, Montana, 1977, and in London 1978. The suggestion to organize the first World Conference in Clinical Pharmacology and Therapeutics was made in 1977 and received with hesitation among basic pharmacologists but finally held in London in 1980. The major aim was to promote contacts between clinical pharmacologists throughout the world. A visionary meeting for that purpose was held at the Royal Society of Medicine in London on 6 August 1980. Brief reviews of the status of clinical pharmacology were given by 20 experts from Africa, Asia, Australia, Europe and North America and common goals of the discipline were outlined. Many of these pioneers left typed or handwritten notes of their comments in my hands (as organizer of the meeting). My own mentor Lou Lasagna stressed the importance of certification of the clinical pharmacologist and that teaching of clinical pharmacology must be obligatory at all medical schools, conditions that still are not fulfilled in USA. Similarly to his North American colleague, Dick Ogilvie, Canada, reported about the difficulties to recruit clinical pharmacologists in the absence of career posts in the health service. Optimistic reports about the academic developments in Europe were presented by Denis McDevitt, UK and Per Knut Lunde, Norway, regions where clinical pharmacology now is well established as a medical speciality. In retrospect, it is interesting to note the pessimistic predictions of Andrew Schaepdryver, Belgium, Harry Wesseling, the Netherlands, C. Sirtori, Italy, and Pierre Simon, France, countries where clinical pharmacology still has difficulties to reach out in the healthcare system. Developing countries were well represented with reports from India (R.C. Saxena), Africa (K. AdjeponYamoah, Ghana) and Barbados (H. Fraser). At this meeting, it was emphasized that the training of other medical specialists in clinical pharmacology may be equally as important as recruiting clinical pharmacologists in the efforts to rationalize drug treatment. As an example, a great number of internists, psychiatrists and paediatricians have been involved in clinical pharmacological research and now act as ambassadors of the discipline. One session of the meeting was devoted to drug problems in developing countries (drug evaluation, drug promotion) and introduced by Dr. Halfdan Mahler, director general of WHO. Three years experience of the WHO essential drug concept was discussed by P.K. Lunde, Norway, Gianni Tognoni, Italy, and N.D.V. Lionel, Sri Lanka. In 1983, the first two secretaries of the Section of Clinical Pharmacology, Dan Azarnoff and Per Knut Lunde, put together

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the first global list of persons active in the discipline. Contact persons were identified in 60 countries and many on that list later became national leaders in clinical pharmacology. Subsequent world conferences in clinical pharmacology were held in Washington (1983), Stockholm (1986), HeidelbergMannheim (1989), Yokohama (1992), Buenos Aires (1996), Florence (2000), Brisbane (2004) and Quebec City (2008). The section of clinical pharmacology continuously increased its activities and was promoted to a Division within IUPHAR in 1996 with Folke Sj€ oqvist as the first chairman and three representatives in the executive committee of IUPHAR. In 2003, a proposal from the Clinical Division to broaden the name of IUPHAR to the International Union of Basic and Clinical Pharmacology was accepted after rather lengthy discussions, but the idea was supported by some renowned pharmacologists including two former presidents of IUPHAR, B€ orje Uvn€as, Sweden, and Colin Dollery, UK, and two Nobel Laureates, Sir John Vane and Sir James Black. The decision was ratified at the IUPHAR congress in Beijing 2006. As a result, it was decided to ask Kim Brøsen to arrange the first joint world congress in basic and clinical pharmacology in Copenhagen in 2010. The development of clinical pharmacology as a scientific discipline during the first 75 years was reviewed by Colin Dollery in 2006 [19]. He pointed out that European clinical pharmacology had originated either from internal medicine or basic pharmacology but that the two schools now had reached considerable convergence. At the congress in Copenhagen, IUPHAR had composed a 50-year anniversary issue of its journal Pharmacology International, where the CP division summarized its efforts to improve the use of drugs worldwide [20]. It was mentioned that between 1977 and 1983, several board members had participated and in some cases chaired the early expert committees on the selection of essential drugs. Moreover, CPT world conferences from the beginning of 1980 had devoted sessions to the rational use of medicines. In this issue, the clinical division also presented its activities towards better use of medicines in children [21]. During 2010, IUPHAR published its position paper entitled ‘Clinical Pharmacology in Research, Teaching and Health Care’ [15]. It emphasized that research in clinical pharmacology often is a multidisciplinary effort involving collaboration with other academic disciplines such as biochemistry, genetics, statistics, epidemiology and other pharmaceutical sciences. However, in clinical services aimed to improve the use of drugs in patients, the clinical pharmacologist has to stand on his/her own feet relying on a full-fledged medical training. The position paper outlines the research domains in clinical pharmacology and the fundamentals in teaching of the discipline. A model core curriculum is included for clinical pharmacology, therapeutics and prescribing for medical students building on the experiences in Scotland by Simon Maxwell [22]. The near relationship between pharmacological knowledge and drug prescription is emphasized. Some years previously, an embryo for a global curriculum was developed [23,24].

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In another addendum, a model curriculum for medical specialization in clinical pharmacology is outlined with references to curricula in European and non-European countries. Training to reach competence in the clinical pharmacology services listed in Table 2 is emphasized. Key clinical pharmacological services suggested by IUPHAR are listed in Table 2, but not in any particular order as their importance may vary between countries. The list shows the limitless possibilities for the medical speciality clinical pharmacology to play an important role in patient care. The major IUPHAR decisions about clinical pharmacology are summarized in Table 3. Joint Efforts of WHO, CIOMS and IUPHAR The position paper from IUPHAR regarding clinical pharmacology [17] was well received internationally and evoked the interest of both WHO and CIOMS (The Council for International Organizations of Medical Sciences). Both organizations decided to reedit the document to a joint publication with IUPHAR emphasizing the roles of the discipline in health care even more [16]. This manifesto clearly distinguishes between its roles as an interdisciplinary science and as a medical speciality with responsibility to improve the utilization of medicines in health care. Leading pharmacological journals have supported the manifest [25,26].

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For the first time, the discipline has an internationally agreed dynamic definition as follows: Clinical pharmacology is the scientific discipline that involves all aspects of the relationship between drugs and human beings. Its breadth includes the development of new drugs, the application of drugs as therapeutic agents, the beneficial and adverse effects of drugs in individuals and society and the deliberate misuse of drugs. Clinical pharmacology is a science that may be of significant interest to a variety of professions including physicians, pharmacists, nurses and scientists in many different disciplines. The term ‘clinical pharmacologist’ is also used in a professional sense to refer to those physicians who are specialists in clinical pharmacology. They have usually undertaken several years of postgraduate training focusing on important aspects of clinical pharmacology including clinical trials theory, drug evaluations, pharmacoepidemiology, pharmacoeconomics, pharmacogenetics, pharmacovigilance and clinical drug toxicology. Such clinical pharmacologists have as their primary goals that of improving patient care, directly or indirectly, by promoting the safer and more effective use of drugs. The Role of EACPT The growth of clinical pharmacology in Europe was stimulated by an initiative taken by Pierre Bechtel, Besancon, which

Table 2. Service functions for clinical pharmacologists in health care (from 16). Critical drug evaluation of new and old drugs Participation in Drug and Therapeutics Committees (DTC:s) Pharmacoepidemiological services from providing statistics on drug utilization to pharmacoepidemiological surveys Drug information services aimed to evaluate drug problems in individual or groups of patients Services in pharmacovigilance, responsibility for ADR reporting Continuing medical education Therapeutic drug monitoring (TDM) and pharmacogenetic services (phenotyping and genotyping of drug metabolizing enzymes, transport proteins and receptors) Measurement of drug concentrations for the diagnosis and prevention of drug abuse Other toxicological services Direct patient services for the evaluation of drug-related problems such as therapeutic failures, ADR:s, drug interactions and inappropriate polypharmacy Electronic Pharmacological (e-Pharmacological) services such as evidence-based databases for rational drug prescribing

Table 3. Development of clinical pharmacology in IUPHAR. Year

Important decisions

1965 1973 1975 1977 1980 1983 1996 2003 2006 2010 2010

The International Union of Pharmacology (IUPHAR) is founded Decision to form a Section of Clinical Pharmacology within IUPHAR Section of Clinical Pharmacology established at the IUPHAR congress in Helsinki Suggestion to organize the First World Congress in Clinical Pharmacology First World Congress in Clinical Pharmacology in London (chaired by prof. Collin Dollery) First global list of clinical pharmacological societies, sections and contact persons Division of Clinical Pharmacology formed in IUPHAR Proposal to change the name of IUPHAR to International Union of Basic and Clinical Pharmacology The proposal above is ratified in Beijing First joint World Conference in Basic and Clinical Pharmacology in Copenhagen (prof. Kim Brøsen) Position paper ‘Clinical Pharmacology in Research, Teaching and Health Care’ published [15]

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led to a European collaboration to define criteria for the choice and definition of healthy volunteers and patients in studies on drug development. This included the exploration of genetic and environmental factors explaining interindividual differences in drug disposition [27]. The project was accepted as a COST concerted action in late 1985, and in 1989 [27], 11 countries were involved (Denmark, Finland, France, Federal Republic of Germany, Ireland, Norway, Spain, Sweden, Switzerland and the United Kingdom). In 1998, Bechtel and Gunnar Alvan summarized the 12 years of fruitful collaboration [28]. The WHO Regional Publication from 1991 [13] revealed several shortcomings in the development of clinical pharmacology in Europe with surprising differences between countries. The report led to the insight that there was a need for a Europe-wide organization whose primary aim should be to promote the overall development of the discipline in the region. The idea was enhanced by the political developments in Europe with colleagues in East and West Europe coming closer to each other. The proposal to create a European association was first discussed in Frankfurt and Paris 1991 and further developed at the IUPHAR congress in Yokohama in July 1992 where representatives from France, Germany, Italy, Norway, Spain, Sweden and UK participated. At the follow-up meeting in Paris the same year, organized by George Cheymol, the aims of the association were outlined. EACPT was then founded in Verona in March 1993. At this meeting organized by Giampaolo Velo, statues and aims of EACPT were agreed upon and later given legal credibility in European law through legal officers in Germany [29]. Other pioneers at these early meetings included P. Bechtel and P. Jaillon (France), H. Dengler, J. Kuhlmann and N. Rietbrock (Germany), J.R. Laporte (Spain), P.K.M. Lunde (Norway), M. Orme (UK) and F. Sj€ oqvist (Sweden). The history of EACPT during the first 10 years has been documented by Jochen Kuhlmann, Wuppertal, in an unpublished booklet ‘10 years EACPT 1993–2003’. Since then, the policy of EACPT has been to recruit colleagues from all European countries to joint efforts aiming to improve the use of drugs in health care. The chairpersons have been chosen from different countries, in chronological order Sweden (F. Sj€oqvist), Italy (G. Velo), UK (M. Orme), Germany, (I. Cascorbi) and now Spain (G. Calvo-Rojas). The intention is to increase the input from Eastern European countries. In the early 1990s, IUPHAR had already taken initiatives to improve the contacts between Eastern and Western European clinical pharmacologists. An exchange programme between UK and Sweden with three Eastern European countries, Bulgaria, Hungary and Estonia, was financed and organized in April 1993. This programme has had great importance for the recruitment of Eastern European clinical pharmacologists to EACPT. A fundamental idea with the founding of EACPT was to make the discipline much more visible in health care. This is evident from several of the aims in the statutes: promoting the utilization of clinical pharmacological services in healthcare delivery.

MiniReview improving and harmonizing the teaching of the rational use of drugs at both undergraduate levels. contributing with clinical pharmacological expertise to policy decisions regarding drug regulation in Europe. arranging scientific meetings, workshops and courses in clinical pharmacology and therapeutics in Europe. utilizing the skills of clinical pharmacology and therapeutics in counteracting misuse of prescription drugs and other chemical substances. promoting problem-oriented and patient-oriented drug information for physicians and other health professionals. increasing the input of clinical pharmacological skills in the clinical evaluation of drugs. promoting high professional standards in drug prescribing. promoting high ethical standards in clinical drug research. enabling individual countries to benefit from the diversification of clinical pharmacology and therapeutics in Europe. encouraging collaboration with other agencies interested in clinical pharmacology and therapeutics (e.g. WHO, IUPHAR, EEC).

The first European Congress in clinical pharmacology was held in Paris in 1995 with George Cheymol as president. Subsequent congresses have been arranged every second year. A combined IUPHAR/EACPT congress was organized by Giampaolo Velo in Florence in 2000 (Table 4). This idea to have joint congresses in basic and clinical pharmacology arose anew in 2010. EACPT initiated a new inventory of the discipline in 1999 by publishing A Guide to Training in Clinical Pharmacology in Europe edited by Kim Brøsen, Odense [30]. About 100 training programmes in 28 countries were described. A map of the academic units of clinical pharmacology in each country was presented together with a brief review of the status of the discipline. A much more positive pattern of the progress of clinical pharmacology emerged compared to 1991. The overall impression was that clinical pharmacology had reached out to most medical schools in Europe fulfilling its obligations in teaching and research, while the roles in health care still were vaguely defined in some countries. The most recent attempt to compare the developments of clinical pharmacology in different European countries was made in 2011–2012 by Orme and Sj€ oqvist [31]. A questionnaire was sent to the senior delegate of each of the 31 member countries on the Council of EACPT containing key questions about the present standing of the discipline. Based on the results of the completed survey forms (100% response rate), clinical pharmacology is recognized as an academic discipline in teaching and research in 28 of the 31 countries but as a medical speciality in only 22 countries. In 50% of the countries where clinical pharmacology is recognized as a medical speciality, this recognition has occurred more than 30 years ago. The training of clinical pharmacologists in terms of years after internship varies between the countries. In 8 countries, the training is predominantly in internal medicine with shorter periods in pharmacology. In 11 countries, the training is predominantly in clinical pharmacology, and in 6, there is dual training [31].

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Table 4. Important milestones in the development of EACPT (European Association for Clinical Pharmacology and Therapeutics). Year 1991–1993 1995 1999 2001 1997–2015

2013

Important decisions Creation of EACPT First EACPT congress in Paris (George Cheymol) A Guide to Training in Clinical Pharmacology in Europe, edited by Kim Brøsen, Denmark [25] Summer schools in Clinical Pharmacology being arranged biannually, the first one in Antalya, Turkey. Biannual EACPT congresses, location and president: Berlin 1997 (Ivar Roots) Jerusalem 1999, (Micha Levy) Florence 2000 (Giampaolo Velo) Odense 2001 (Kim Brøsen) Istanbul 2003 (Cankat Tulunay) Poznan 2005 (Alexander Mroziekiewicz) Amsterdam 2007 (Jan Schellens) Edinburgh 2009 (David Webb) Budapest 2011 (Adam Vas) Geneva 2013 (Marie Besson and Caroline Samer) Madrid 2015 (Gonzalo Calvo-Rojas) Questionnaire study about clinical pharmacology in 21 European countries [26]

Table 5. Total number of positions in clinical pharmacology in 31 European countries (from ref. [26]). Total number of positions

Number of countries

Development of clinical pharmacology as a medical speciality in Europe - the roles of WHO, IUPHAR and EACPT.

This MiniReview shows that both WHO and IUPHAR very early recognized that there is a gap between the availability of academic expert knowledge in phar...
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