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EALTH CARE, EALTH EALTH CARE, IV his position paper regarding the roles of clinical pharmacology in health care, teaching and research was composed and edited version of a recent publication entitled “linical Pharmacology in eaching and Health ) in 2010, Volume 107, pages 531 – 559. wedish Foundation for For O LFor OMS Gjölin-ForsbergFor IUPH), Folke ydney, 1 ummaryHistory of linical Pharmacologist in Patient herapy in Paediatric Patientseriatric Patientslinical Pharmacology and the Pharmaceutical Industryverviewlinical Pharmacology, ........................... 2 ATentral nervous systemFederal ood laboratory practiceP, P, and egulatory OTC Ceaching and 3 involves all aspects of the relationship between drugs and humans. It is a multidisciplinary science of scientic skills including medicine, pharmacology, pharmacy, biomedical science and nursing. are specialists in clinical pharmacology. undertaken several years of postgraduate training pharmacologists have as their primary goal that of improving patient care, directly or indirectly, by developing better medicines and promoting the safer pharmacology in the early part of the 21st century executives and board level directors of primary and secondary care systems and directors in can bring to the delivery of better health care for all THARMACOLOGN PATlinical pharmacology has developed a number of ways in which the clinical care of patients can wherever they may reside. linical care of paediatric the clinical pharmacologist and these special services to help in this task as well as skills such as of new and expensive medicines into the delivery of health care. linical pharmacologists provide, in collaboration with other health care staff such as pharmacists, drug information services to a wide pecialist services may include patients, and health care systems could do more through a knowledge of pharmacology. he concept of personalised medicine is one where TARMACOLOGchapter 9 and addenda I and II). Perhaps the most ummary 4 prescribe, usually in particular areas, attention needs to be paid also to their training in prescribing. ince assessment drives learning, the assessment and the regulatory arrangements available in different countries mean that the approach suggested is a RARMACOLOGesearch is a vital part of the training and everyday linical pharmacological research has always aims to translate new scientic data on drugs into phase I studies, would be advantageous. However, CARMACOLOGhe pharmaceutical industry has been at the GSSENTARMACOLOGpharmacologists are working in hospitals, regulatory agencies or in Health ssessment (HTATAcontributions from clinical pharmacology. rug Policies” to he quality, safety and efcacy of medicines Aindustry.linical pharmacologists are paying increasing attention to the health needs of those peoples who conditions that are endemic in the poorest parts of to meet these needs is rather different from that Ceaching and 5 brought together a group of experts in linical Pharmacology, and to outline how it could help to improve the use of drugs in the delivery of health care (1). In the last four decades use, in the number and diversity of drugs that are s a result newly developed drugs are very although there are welcome exceptions in the provision by Big Pharma of modern drugs at a very low or no cost (eg ivermectin for onchocerciasis). as the cost effectiveness of drug therapy and to the is done about it. In addition the problem of therapies and the higher proportion of elderly patients study of which has now given rise to the discipline taken more seriously. the errors made during the prescribing process in the internet providing easy access to appropriate information and knowledge (6). hese problems are report in the light of lessons that have the last 20 years of the twentieth century, clinical the pharmaceutical industry and the ervice (health care in the U and this is likely to be true in Introduction 2 6 pharmacology in the early part of the 21st century e have gathered a group of distinguished clinical link with industry and governments. e hope that in the ational Use of edicines policy (9). However, this document is particularly aimed at decision makers in a variety of organisations, in of primary and secondary care organisations and directors in the pharmaceutical industry. in clinical pharmacology can bring to the delivery of D Ceaching and 7 involves all aspects of the relationship between drugs and humans. Its breadth includes the discovery and society, and the deliberate misuse of drugs. pharmacology is a multidisciplinary team science of scientic skills including medicine, pharmacology, pharmacy, biomedical science and nursing. specialists in clinical pharmacology. hey have trials, drug evaluations, pharmacoepidemiology, drug toxicology. ome countries have accreditation D 3 Ceaching and 8 History of Ceaching and 9 times and the discovery of drugs such as quinine, (see10) may very well be considered the rst scientic 20th century. It is difcult to nd who rst coined the middle of the century brought pharmacology and clinical know-how about drugs together and axon literature, Harry However, in 1914, a textbook was written by Hans of which was translated as ‘Pharmacology, literature, Paul Bonn, published his monograph in 1932 entitled ethodology of herapeutic Investigation’ and helley and Baur, his contributions escaped the attention of the oodman and he Pharmacological Basis odell, also at ornell, to launch the rst scientic journal in the subject entitled ‘and drug measurements in body uids as tools in clinical pharmacology. in clinical pharmacology offered training to potential asagna, a pupil of Harry Beecher at John Parallel developments occurred in ermany, the Uplace in France (17). IUPH History of 4 10 develop clinical pharmacology. executives rnold Burgen in the U and Helena of clinical pharmacology, led by the late ), Franz about the roles of clinical pharmacology in teaching, research and health care (18). For the rst time, in primary health care was emphasised.Vane, rvid Ceaching and 11 odern drug therapy has unquestionably countries over the last 50 years. onditions such as nd complex surgery, beyond the imagination of our forefathers, can be performed immeasurably with the emergence of safe and need in developing, emerging and developed lzheimer’s disease, Parkinson’s disease or Huntington’s disease. of the second half of the 20th century, research-based pharmaceutical companies were, for practical often with considerable ingenuity – for healthcare to maintain the industry’s infrastructure.People in poorer countries, unable to meet these senses, never been brighter. and combinatorial chemistry, offer unimaginable array of biotechnological techniques offers unique Yet, despite the promise from the science, the for-prot organizations, as well as by pharmaceutical new active molecules registered by drug regulatory authorities has fallen dramatically. documentation from regulatory authorities (e.g. in s a consequence, drug regulatory place ever greater demands on manufacturers to after marketing. hile this may have some benets for drug safety, these measures are likely to increase the cost of medicines unless they are implemented oreover, healthcare systems populations they seek to serve are under increasing numbers of elderly and very elderly people (many T T 5 12 TA TH Drug regulatory authorities themselves recognise to innovative medicines. Both the Food and regulatory process of innovative medicines that The process of drug discovery, conned for most of the 20th century to the laboratories of become much more pluralistic. In particular, major pharmaceutical companies were unwilling laboratories, they are now prepared to do so with An increasing number of not-for-prot organizations such as the Bill and Foundation (in eattle) and the Hereditary Foundation (in ew York) are supporting drug discovery and development in co-operation with Stheir traditional models of discovery, development healthcare systems themselves, what future products would bring most value for money. C Too few contemporary clinical pharmacologists contributions to health care by undertaking clinical WTA has emerged in the absence of contributions from clinical pharmacology. his needs to change TA Cchildren, the elderly, those with rare diseases and Ceaching and 13 he ways in which clinical pharmacological services patients with new drugs, novel drug combinations, adapted to the molecular characteristics of the disease based drug information will assist physicians and therapies have to be monitored within the healthcare across medical specialties and systematic use of diminish the gap between documented efcacy in controlled clinical trials and observed effectiveness methodology, drug development and involvement healthcare settings irrespective of the resources of the country or of individual health care facilities. Patients used according to medical, social, environmental and about drugs and their use in clinical practice needs ational Use of edicines (their focus on drug evaluation and on the principles hey should train healthcare staff in the principles of drug evaluation and promote the use of guidelines and drug recommendations based on scientic Pharmacologist in Patient 6 14 evaluation among clinicians and pharmacists (26,27). clinical pharmacologists and pharmacists trained in KARMACOLOGAThe form these services take may vary from country to country and facility to facility depending on the of these services are the DTCepartments at hospitals or in primary care. DTCdrug information, in services to DTCwell as in resource-poor settings. he role of critical efcacy, safety and cost-effectiveness for a specic in local health care settings is complementary to of critical drug evaluation include assessment of the quality and completeness of a clinical drug study. can assist healthcare staff to assess the value of a By applying this procedure it is feasible to rate the quality of a drug study with a maximum of 24 points that will help to guide the clinician about the strength of a specic clinical drug study and drug therapy. It will be possible to choose between suggested drug therapies by comparing 15 (b) Drug and Therapeutics Committees (DTC)DTCprimary care physicians in order to provide the same he membership will vary depending on local circumstances and resources relevant medical staff, clinical and other pharmacists DTCwill usually take the form of a local formulary or ”Wise List”coepidemilogical servicesDTCtherapy in clinics and in hospitals (30, 35). Ideally, ogy, pharmacoeconomics and clinical pharmacology. hese services are important for a systematic introfacility and can then be linked to forecasting future (d) Drug information servicestargeted to guide clinicians in evaluating and solving he services provided he latter, addressing problems at a patient level the availability of staff at the particular facility. information services build on systematic literature searches in databases and reference books combined his service should assist DTCservice is also helpful for provision of unbiased is well documented to improve adherence to drug DTC(e) Services in pharmacovigilancecentre for reports of adverse drug reactions (DTCFrance and weden (37). Pharmacovigilance should (f) Continuing medical education 16 pharmacogenetic servicesparticipation of a ivision or Pharmacology. services should always involve service, particularly for elderly patients, is to ensure hapter 8). n example of successful translation of oreover, growing, particularly in the eld of cancer.abuse and other toxicological services. In involved in toxicological services such as diagnosis (i) Direct Patient Servicescare of patients with particular clinical problems pharmacologists are mainly used for their skills in therapeutic polypharmacy. therapies in the treatment of major infectious diseases expertise supported by adequate drug analytical logical) Servicesservices include tools, knowledge databases on -pharmacological services provide hese services are predicted to become of of mobile phones and internet access in lesser extension to the public and to patients (24). multidisciplinary eld will be of great importance professional network can help to provide electronic drug information from different countries. contents of e-pharmacological services are heavily dependent on expertise in critical drug evaluation. herapy in Paediatric Patients Ceaching and 17 development of paediatric clinical pharmacology. decades, training capacity remains very small. onsequently the number of trained paediatric paediatrics and clinical pharmacology. However, regulatory, clinical and industrial).study, regulatory assessment and appropriate use trained nurses, pharmacists, laboratory scientists) paediatric drug development. ccordingly, building D PAEDATRARMACOLOGPaediatric clinical pharmacology is a scientic discipline that involves all aspects of the relationship the continuum between discovery, development, pharmacology is concerned with the response to and the adverse effects of medicines, their use and misuse, and the economics of drug therapy. clinical pharmacology, it involves numerous such as nurses and pharmacists). Paediatric clinical pharmacology is therefore a scientically driven eld appropriate aspects of paediatric drug therapy. SN PAEDATRARMACOLOGpharmacology are diverse and can include patient care, research, teaching, drug development and drug regulation. Paediatric clinical pharmacologists may participate directly in the care of paediatric patients as either primary care givers or consultants, or may herapy in Paediatric Patients 18 the health care setting or the wealth of the country. the country level, paediatric clinical pharmacologists can provide valuable service in the development edicines Policies that consider the the basic human rights of paediatric patients who often extends to the regulatory assessment of monitoring of the performance of medicines in different clinical settings after regulatory approval (eg through the application of pharmacoepidemiology, pharmacovigilance and pharmacoeconomic principles) It should also be recognised that, globally, more than to 9 million children die every year before their 5th birthday from diseases that are usually amenable represent the hope of 100% of the world for its and services that can be provided by paediatric TN PAEDATRARMACOLOGPaediatric clinical pharmacology is a sub-discipline Finally, it must be emphasised that training in paediatric clinical pharmacology must extend beyond pharmacologists. It is vital that educational curricula components of the principles of paediatric clinical pharmacology. programs and in paediatric medical and surgical he continued development of programs and eriatric Patients Ceaching and 19 he most rapidly expanding age group world-wide reserve, impaired baroreex function, decreased particularly at risk for polypharmacy related adverse treatment of hypertension, coronary artery disease, their research, teaching and clinical service toward importantly to patient safety and well being. For in order to choose the appropriate dosage. benet relationships in older patients are abundant. imilarly, teaching for older patients and pharmacologists is inadequate to meet either the linical pharmacology has an important role to foster disease-based therapeutics. In geriatric medicine, common path to patient disability and death have addition, the concept of competing morbidity such but in the more obvious clinical presentation of another concurrent illness, has advanced clinical for specic drug therapy intervention in the context and implementation of treatment guidelines to eriatric Patients 20 linical pharmacologists and geriatric medicine specialists leads to extreme polypharmacy when multiple tation of multiple therapy guidelines result in conicts, contradictions, and the simultaneous use of drugs that are known to have harmful pharmacokinetic he geriatric clinical pharmacologist brings the appropriate therapeutic dilemmas, or to conduct the research he multidisciplinary health care team is championed by geriatric medicine as the optimal means of providing care for the complex older patient with multiple a key role on this team, working closely with the primary geriatric medicine clinician, the clinical pharmacist, and other members of the team to individualise and modify role of the clinical pharmacologist assumes even greater importance. herapeutic decision-making for older drug therapy must be considered in the context of limited resources and the desire to provide effective and opportunities for the clinical pharmacologist to team Teaching Ceaching and 21 For most physicians, drug therapy is the main tool at he prescribing demands progressively increased because of many important Twhich they are less familiar.Patients are taking more drugs, increasing the MPatients who receive drugs are older and sicker, and Patient throughput is increasing (matched by a TTAof drugs to be quantied more accurately, and this Patients increasingly expect their physicians to Poor access to trained medical staff in developing and tuberculosis in developing and T The marketing activities of pharmaceutical powerful drugs from their rst day of clinical work. pharmacology, at the point of graduation, as the basis he primary determinant of the effectiveness of to changes in pharmacotherapy. support systems and electronic prescribing will help for which they are least well prepared. Importantly, educational interventions such as the ‘prescribing performance. 9Teaching 22 ATE EDCATa new teaching discipline and many medical schools incorporated it into their curricula as a distinct in both basic and clinical pharmacology, the former disease in the country concerned. selected in such a way that their pharmacological properties reect the important pharmacodynamic to a ist (2), a regional list for ‘prescribers have chosen their specialty. Postgraduate and continuing education in clinical prescribed. However, an understanding of the basic principles of should allow physicians to take a logical approach to learning about any of the drugs he principal recommendations for the delivery of in the undergraduate medical curriculum are Ccurriculum, visible to students in all years, either Core learning objectives in should be clearly drugs and attitudes towards pharmacotherapy. T‘student formulary’), similar to the process used policy. Tassessment that indicates whether the main be possible to compensate for a poor performance in this area by a good performance in other items. 23 SLARedical students are often overwhelmed by the ‘student formulary’ that helps to prioritise study and diseases. For each drug or group of drugs, students irrational drug therapy. DVariability in the structure of medical courses will require local solutions for delivery of the courses in ‘is straightforward. elivery is more challenging often with an emphasis on problem-based learning. and through several years of the course. his poses learning opportunities across many modules over opportunities to observe and appraise critically the C LEADERScourse, will be strong and enthusiastic leadership. individual who will oversee delivery and ensure of drugs are highlighted throughout the course. 24 students are helped to tackle the practical issues of weighing the harms and benets of drug therapy, of therapy. LNG SThe successful delivery of the core curriculum may in large groups and small groups, practical classes and opportunities for self-directed learning. knowledge, skills and attitudes outlined in groups, or researched and discussed at intervals learning opportunities and self-assessment in ertainly, it is important that students should omputer-assisted learning packages are relevance in resource-poor countries with chronic lack of educated staff. Innovative teachers should be able to use the academic high-speed networks for ASSESSMENTemphasising the importance of in the course and ensuring that graduates are t to practice. 25 here this is the case, there should be a clear, the knowledge and skills that support rational prescribing. Furthermore, whether assessment performance in prescribing or therapeutics with good performances in other assessments. chance for self assessment at regular intervals during ASS ATE CATonly because of the constant emergence of new broad-based, supervised prescribing through to progressively specialised and less supervised work promoting the importance of principles and knowledge. In the case of specialists in primary important in updating knowledge and skills and education. Perhaps the greatest is to nd the necessary time in already busy clinical schedules. However, this problem is being increasingly challenge is to provide good quality non-promotional ecent years have seen pharmaceutical role in the delivery of unbiased postgraduate 26 Ceaching and 27 1970 (1), the section on research emphasised the However, we should be aware that not all research into drugs falls within the remit of translational medicine. he endeavour of a pharmacologist working in a supercially mentioned in the 1970 document are now the priority. ational use of medicines implies that drugs should be chosen according to efcacy, includes studies that elicit new data about drugs clinical pharmacology is usually interdisciplinary and pharmacokinetics and pharmacodynamics, an area in the molecular mechanisms but also in designing combined with experimental studies or enhanced elimination capacity. 10R of 28 CATfew subjects being tested. hese Phase I studies are industry or in specialised clinical trial units. to meta-analysis or systematic reviews of several documenting the efcacy of drugs. methods for the evaluation of clinical interventions is now mastered by clinical intervention difference is the detection of relatively frequent evaluation of biomarkers as measures of drug action THis an optimal therapeutic effect or an increased risk of be the case, for instance with some central nervous research into clinical routine samples has been of patients at risk: the elderly, children and patients revolutionary developments in biotechnology and century mainly aims at understanding the role of genetic variation in the capacity or function of 29 receptors and their relationship to the clinical effects offer genotyping services, in addition to principles of the laboratory methods that are used, perform them. In experimental studies on pharmacogenetics, the main responsibility of the relevant problem, design the study that will help LANCE to placebo or comparable to or even better than properties or readily explained in the context thereof. However, at marketing, serious or even lethal but very rare pharmacology of the drug and that occur in, say, 1 out of 10,000 patients or even less commonly, may unknown potential drug toxicity. DSATtesting of interventions to enhance the quality of these processes. It is common to quantify drug is the typical maintenance dose of the drug in an OLOGdetecting harmful effects on the foetus) or impossible will require very large numbers of patients. pharmacoepidemiology, which may be dened as epidemiology. 30 and that presents problems with confounding and is compared with drug use in a sample of new development in clinical pharmacology. For pharmacology. CS pharmaceutical products, services and programmes as well as other healthcare interventions. of life, epidemiology, decision sciences and health services research in the examination of drugs. linical pharmacologists are important in the eld the average patient. he main role of a clinical quality and suitability of clinical trials data for the existing treatments. It is necessary to arrive at an objective quantitative evaluation of ‘benet’ or Ceaching and 31 has expanded very signicantly since the original decades, drugs produced or extracted from biological antibodies and recombinant vaccines) such as insulin, somatotropin, interferon, granulocyte-stimulating factor, erythropoiesis-stimulating factors like epoetin F-alpha) and oday, 20–30% of urrently, about 400 wing to their production process pattern of potential adverse effects compared with effects deserve special attention (63).ost biologics are very large, complex molecules to the formation of protein isoforms, alteration of glycosylation patterns and/or changes in the tertiary is not called ‘generic’ but ‘biosimilar’ or ‘follow-on those needed previously. LARS – PROATthe original manufacturer’s product. has stipulated that a regulatory framework should to ensure that biosimilars are safe and effective. oreover, biosimilars have to undergo post-ccordingly, has taken a case-by-on biologics (64). In particular, the manufacturer of a 11EBiologics and Biosimilars 32 dossier, including data on the manufacturing process, of the new erythropoiesis-stimulating agent in enerally, it is permitted to extrapolate results on from renal anaemia to the symptomatic treatment of chemotherapy-associated anaemia. However, this may vary between agencies and from time to time. with epoetin alpha, an isolated erythroblastopenia (pure red cell aplasia) has occurred as a consequence erythropoietin (65). In general, the immunogenic production process, and also on the mode of efcacy, without causing severe adverse reactions. must be observed over at least 12 months in order to assess possible immunogenicity and the prole the immunogenic potential of a biosimilar, post-risk management plans are obligatory for biosimilars.o illustrate the differences of approval for biosimilars and Binocrit (ustria) were approved Che extensive requirements of regulatory drugs. It is therefore expected that biosimilars may In summary, the assessment of the harm benet physicians, manufacturers and regulatory authorities needs of drug innovation on the one hand and patient provided the necessary training in molecular and cell Ceaching and 33 OVthe discovery, development and marketing of new organisations varying from ‘big pharma’ global to smaller, usually disease-focused, specialised on generic, over-the-counter (OTC) or complementary broad perspective of all aspects of drug discovery pharmacodynamics to pharmacoepidemiology, ore importantly, of the drug target, disease pathophysiology, context efcient manner.lobally, pharmaceutical companies operate in a regulatory, social and political inuences constantly increases rapidly, chemistry, high-throughput screening, rational ‘blockbuster’ drugs are also apparent as patents development and a number of high-prole safety-resulted in an increased regulatory focus on risk management during the drug development process. marketing approaches used in the industry are being t the discovery level, there is recognition that he separate silos of discovery, increasingly integrated vertically into development teams that include functions from early discovery ompanies are emphasising translational research with related services and diagnostics to identify for drug development and marketing. he focus towards development of medicines that produce real Pharmaceutical Industry 34 high benets coupled with high value and cost. espite the problems facing the industry, the 21st century owing to ageing populations and the through mergers and acquisitions and this trend is set to continue. Paradoxically, they may become less homogeneous, with niche market, biotechnology RARMACOLOGskills and attitudes required are discussed below.Traditional roles:industry customarily has been involved at the early with preclinical, translational medicine  biomarker, Follow-up on Pforms used during early and late development, pharmaceutical industry (69-71). ate clinical development – Phase III conrmatory industry contribute to greater or lesser extents in a egulatory – preparation of submissions, interactions with regulatory authorities and regulatory strategy planning. 35 dvisory – arranging and managing scientic and clinical advisory boards, interactions with key patent lawyers and responding to queries from retain as in-house know-how or put in the public development paths – quicker development gives overall discovery, development and marketing. Industry roles and needs. Pharmaceutical companies usually have distinct scientific and pharmacologists will normally start in the scientic stream, but are well placed because of their broad background to contribute linical pharmacologists are needed in roles including managing a project or product functional area such as clinical pharmacology, benet epidemiology. for higher management roles with involvement in the company’s overall discovery, development and he clinical pharmacologist in industry normally has basic training as a physician with specialist training in clinical pharmacology. or externally, for necessary industry-specic skills such egulatory requirements – international, regional and country-specic.egulatory compliance – xPs, electronic and hard eadership and decision-making in complex industry, a broad understanding of the business issues and models in the industry, the differences between industry sectors, and how product value • thical and societal perspectives and broad industry issues – attitudes and ethical practices in a company or industry sector, medical versus marketing department 36 he goal of drug development is to convert and a sustainable business model for the company. to inuence industry practices along appropriate ethical, societal and medical lines, even though this Ceaching and 37 suitable and valuable in a number of government-drug approval, post-marketing surveillance, drug all these three dimensions are complementary and to protect its citizens through support and promotion take all necessary measures to make sure that clinical which medicines (or other healthcare interventions) enough grounds to ensure safety. It also involves the follows scientic principles that can justify both the his forms the ethical dimension of the role of Following the two world wars, several initiatives eclaration of Helsinki in1964. In particular, the socioeconomic circumstances, laws and regulations, he most important of the publications of investigators, the guidelines, to which several clinical pharmacologists have contributed, have for the design, conduct, performance, monitoring, auditing, recording, analysis and reporting of clinical 13Gfor 38 ECS TTEES AND LATOR BODcommittees in detail. For example, the particularly valuable as members of ethics review medicines are used to treat their citizens. are based on assessment of the quality, safety and Usually, these and other medicines-related regulatory functions are carried out by specialised regulatory authorities ( Food Policy Perspective on afety, clear mission statement, which includes the national regulatory authority goals, is necessary to safety, efcacy and quality of medicines, and their urope and has very far reaching responsibilities, has a broader mission statement supervision of medicines, for the benet of public prescription medicines through a single based pharmaceutical industry; andresearch and development programmes, to perform inspections for ensuring fundamental laboratory practice’ (P) collectively) provisions 39 developmental concerns. It is very important that data and to understand what, at the time of the about each drug under review. also have units focusing on clinical pharmacology. For Pharmacology. owadays, safety surveillance and pharmacovigilance are also the responsibility of the CCAL PARMACOLOGpublic procurement, developing national treatment his work may also involve edicines Policy. It is important that such support but also where there is a good prospect of he monitoring of the performance of drugs in real life after regulatory approval, including cost-TAqualied specialists. However, all these activities of HTAany of the assessments are very much administration of drugs by new technologies. history gives evidence that not all the research necessary for developing and promoting public sector initiatives and funding. hus, governments may also be involved in delivering nancial support judgements about the scientic value of proposals of drug therapy. value for research in pharmacovigilance (78). and safety. 40 government’s efforts to create a research-friendly environment in its country should be composed make government ofces well informed about the necessary scientic background, and thus help their wing to the relative lack of new therapies and pressure from patient groups and industry, However, effective methods for pharmacovigilance the topic of pharmacoepidemiology. harms of long-term pharmacotherapy. imilarly, pharmacoeconomics attempts to give a nancial cost and value to everyday drug use which may become the necessary infrastructure in terms of governmental institutions and necessary resource allocations to inter-related and interdependent. he clinical pharmacologist is a specialist who, working at government level, serves the public effective medicines are authorised for use, as well as facilitating cost-effective prescribing and improving he training of clinical pharmacologists meet the needs of various government services in expertise of clinical pharmacologists. However, few have given the necessary priority to the development of the discipline of clinical pharmacology, and many Ceaching and 41 yurvedic and Unani medicine, homeopathy, naturopathy and other administered western world where modern prescription and over-eport on linical Pharmacology (1), the use of traditional (‘complementary’, ‘alternative’) many of which have now created national regulatory bodies to set standards for their quality and safety.developing countries has improved, it is still However, the involvement of clinical pharmacologists From a clinical pharmacologist’s perspective there mineral, is not necessarily standardised and quality may vary between suppliers and seasons. hinese preparations (82). any of the oreover, the taking of traditional and conventional ll physicians need to be aware and knowledgeable herbal remedies. Patients often use traditional physician. In fact, it is up to the physician to be proactive by inquiring about the use of traditional non-disclosure included patients’ anticipation of 14TTraditional 42 complete ignorance of the potential risk of using It is clear from these observations that the training THATE here is a need for instruction about traditional THATE ARMACOLOGthe community for quality, safety and efcacy, using Service:that the clinical pharmacologist is competent to of patients using traditional medicines. However, to have a broader inuence on prescribing by traditional library contains many systematic reviews of efcacy aware of, use and promote these resources. Ceaching and 43 was in a large part due to the realisation of basic removed from the practice of medicine, but also due to the desire of prominent clinicians specialising and improve the quality of drug therapy. drugs are used be it internal medicine, paediatrics, psychiatry, anaesthesiology, geriatric medicine or oncology. perform collaborative research and to disseminate information about the principles of drug evaluation improving drug therapy. numbers, contribution and collaboration among his is particularly the case for multi-disciplinary information services. In pharmacoepidemiology epidemiologists is necessary., collaboration with drug analytical experts trained in chemistry or pharmacy. 15CD 44 Ceaching and 45 Historically, clinical pharmacology developed it is not a separate medical specialty, clinical pharmacology should be recognised as a scientic anaesthesiology or psychiatry. Irrespective of which model is used, the optimal district) hospitals and primary health care also need experts in clinical pharmacology. uch expertise can described below. ARMACOLOGTALuch departments have sufcient staff for the manifold interests of clinical pharmacology in research, teaching and clinical service. will comprise both clinical pharmacologists and other multidisciplinary staff such as pharmacists for the treatment of patients. he advantage of of the hospital making it easier for them to relate rare when the disciplines work on their own. Finally, as nurses, computer experts, statisticians, laboratory technicians and secretaries to full its role properly. 16Ofor 46 DIVIARMACOLOGservices required is signicantly smaller than as listed services. In either case, the long-term aim should be to grow so that a full range of services, relevant to the needs of the community, can be provided. DIVIARMACOLOGARMACOLOGwith (or has developed from) a department of basic pharmacology. arrangement have been discussed above. DELOARMACOLOGZATany clinical pharmacology organisations start to the healthcare needs of their communities, they develop new skills and require different staff groups. health care to patients, e.g. by looking after qually, there are clinical pharmacology organisations approach to drug therapy. Ceaching and 47 in 1970 (1), the medical world has changed dramatically. developments in molecular biology have generated However, more than 50% of countries that replied survey in 2003 had no policies in place to the excessive use of antibiotics which is a major factor rst-line antibiotics for dysentery, pneumococcal pneumonia and hospital-acquired infections (38). ssembly, recognising these strengthen multidisciplinary national bodies for edicines Policy. came to a focus in the ‘uidelines for the rug Policies’ published in own policies in varying stages of implementation. he quality, safety and efcacy of medicinesindustry’ (quotation from the edicines Policy, 2000). Quality of medicines is threatened by counterfeiting, these is a contemporary problem, especially in the quality, safety and efcacy of a new medicine evaluate clinical trials performed in many different population also requires an understanding of local epidemiology (if only to establish whether or not the country ‘needs’ this particular medicine – based racial variations in, for example, the metabolism of Increasingly, pharmaceutical companies are 17TPharmacology in 48 he trial results feed into the regulatory system at the point of pre-marketing assessment. learly, this provides an opportunity to obtain country-specic protocols, who manages the necessary initial research responsibility for the clinical supervision of patients. surveillance will permit the timely detection of less common adverse effects not detected in the limited pre-marketing data. For many developing countries, limited resources mean that most new medicines variations from country to country. In whichever guide decisions in the home country but also to EQUITACCESShe individual’s right to the ‘best possible standard to essential medicines. For the poorest populations, of annual per capita income adjusted for within-country cost of living, expressed in ‘international dollars’ (so-called ‘‘Purchasing Power Parities’’) was $41,674 for the United tates in 2005, $3487 for inuence the outcome, the starting point is always evaluation of the clinical trials data from which alongside cost in the cost-effectiveness calculation. specically. In countries where the cost of medicines his may be the same as the country’s ‘ist’, and this is the case in many low and middle income countries. However, subsidy of examination of not only the quality, safety and efcacy of medicines but also measures of cost-effectiveness and affordability. 49 locally is a potent way of ensuring that limited RATHaving medicines of high quality that are accessible to all does not guarantee that they will be used in the best possible way. and health objectives met by ensuring the highest and relating it to clinical indication in a community, ommonly, utilisation has to be measured In many countries, this task has fallen to pharmacists However, when the results are being interpreted, country, hospital or community serve as the reference implementation of interventions to mitigate problems guidelines is one of the interventions that has a large o have the necessary authority, the guidelines and transport problems for particular formulations of such as the isolated island communities of the Pacic to maintain currency. linical pharmacologists Ideally, guidelines should be prepared rst and the essential medicines list produced from their updating and review. 50 In many developing countries, there is a dearth of provided by pharmaceutical companies with, not unexpectedly, a promotional bias. play a major role in the editorial processes and as patient-focused information. Increasingly, medicines information is being produced for consumers, written (see also chapter 9 and doctors prescribe less well than they might (6,38). medicines, or new uses for old ones, are introduced.hose business is the education of consumers? Peer education is a powerful technique and several studies not be the primary educator but often becomes from medical to everyday language. THARMACOLOGLOC HEALTknowledge, improving prescribing or the consumer’s use of medicines (99). However, while it appears intuitive, there is virtually no evidence to link adherence play the crucial role in patient recovery. further, emerging role is treatment for up to 80% of the world’s population. estern clinical pharmacology, provide surprises. For example, it is arguable that the 51 have recently set up a regulatory framework for traditional  complementary medicines. also the difcult problem of assessing the efcacy of the past, and which are produced by an industry that for the necessary clinical trials work and thus many problems remain to be solved. However, research been members of the national advisory committees populations that they assume the same importance as other factors that inuence public health has led control studies (100) and health database linkage only feasible in countries that have the necessary Cthe efcacy of medicines in patients and the equally However, the list of ingredients in a contemporary full for a single individual. In reality, and especially in resource-poor countries, clinical pharmacologists will make the biggest contribution, working as part of a team, whether in the hospital, the community be rather different and much broader than envisaged 52 CHARMACOLOGinvolves all aspects of the relationship between drugs and humans and involves the delivery of about drugs. It is a multidisciplinary science that scientic skills including medicine, pharmacology, pharmacy, biomedical science and nursing. who are specialists in clinical pharmacology. trials, drug evaluations, pharmaco-epidemiology, pharmacoeconomics, pharmacogenetics, pharma-covigilance and clinical drug toxicology. he primary of patient care, directly or indirectly, by promoting CHARMACOLOGlinical Pharmacology is a relatively new medical century. However it has its roots in a much older tradition of ‘materia medica’ century when the discipline was seen to verview Ceaching and 53 CHLOE PLACE OARMACOLOG CHARMACOLOGN PATtherapy in what is often termed the ational Use a range of services is offered to clinical colleagues information services (often in collaboration with pecial skills are available in drug utilisation, pharmacoepidemiology, and pharmacovigilance. In in therapeutic drug monitoring services. hese are often combined with pharmacogenetic services verview 54 CHPAEDATRC PATdevelopment for a number of reasons but particularly treatable diseases in under-developed countries. CHATRC PATfunction which affects the excretion of drugs and their Pharmacology. CHARMACOLOGll clinical pharmacologists havea considerable new prescribers are more likely to prescribe less Postgraduate teaching of varying needs around the world in the postgraduate CHARMACOLOGpatients and patient populationsesearch in drug at the time of the 1970 their efcacy, adverse drug reactions and cost as multidisciplinary. 55 CHARMACOLOGOLOGCS AND LARSpharmacology. In contrast to common drugs, synthesis, biologics are made in a living system, a special regulatory framework in order to ensure require post-marketing monitoring similar to that for regulatory authorities and requires expertise across CHARMACOLOGthe pharmaceutical and biotechnology industry pharmacology. clinical pharmacology. CHSSENTARMACOLOGovernments need to develop systems to serve the the needs of various government services in order in making decisions in public health. In particular, of clinical pharmacologists, although few have given the necessary priority to the development of the CHARMACOLOGin the under-developed world. It is clear that use 56 CHOLLAORATlinical pharmacology is a multidisciplinary activity different professional groups is critical. ome of the pharmacology include medicine, pharmacology, pharmacy, biomedical science, nursing, social and behavioural sciences, dentistry, economy, epidemiology, genetics, toxicology, mathematics and CHSATARMACOLOGlinical pharmacology services can be delivered services to be delivered from a department or division needs of primary care are also important particularly where these services are delivered outside the CHENTRAL PLACE ARMACOLOGLOC HEALTand resources available in such countries necessitate a different approach to developing the rational use the need to be able to monitor therapy and prevent in a contemporary clinical pharmacologist’s work or discipline. In reality, and especially in resource poor countries, clinical pharmacologists make the biggest needs is rather different, and much broader, than R Ceaching and 57 linical Pharmacology. rug Policies. population based study. Br J edicines. http://www.who.int/medicines/ollery linical Pharmacology, the rst jöqvist F. n historical perspective on the ditor Pedro P. Paul tatus and Future , editor. and biochemical genetics. J J TTTThe origins of clinical pharmacology in France].linical Pharmacology. Food and opportunity on the critical path to new medicinal ervices, 2004. gency. round for the Future. R19 58 riple therapy. http://www.economist.com/people/displaystory.cfm?story_id=11919385F. vorn J. ichler H, Breckenridge , Flamion efcacy-efciency gap: a regulator’s perspective odman B, , Berg to enhance prescribing efciency in jöqvist F, Bergman U, , LOrug and therapeutics committees: a concept to select, communicate and achieve drugs in ambulatory care in alley, rooks J. rug epidemiology and clinical rimshaw J. From best evidence to best ervices. jöqvist F. psychotropic drugs. ordisk Psykiatrisk vorn J. Principles of educational outreach ( “academic detailing”) to improve clinical rganisation, Harvard Harvard Pilgrim Health. Primary 59 ountries: Fact Book and 2006.orld Health F. wedish society and a new service function in clinical pharmacology. LTjöborg B, Bäckström rvidsson Böttiger Y, – a drug-drug interaction database designed , Breitkreutz J, hoonara I, Hoppu Paediatric Paed Perinatal LO. Principles of Pediatric Pharmacology. ew York., Howarth P, et al. raining in Paediatric orld Population ew York,2001. www.lderly. In linical Pharmacology, 2nd edition, bernethy, York, 2007, in the elderly. Fried P, ottdiener et al. Frailty in older adults: ao Y, ing drug burden index to dene the functional burden of medications in , Fried P, Boult AWlinical practice guidelines and quality of 60 gostini JV. Potential patients with multiple conditions. ngl J , Vincent of prescribing errors in hospital inpatients: a prospective study. , Pezzullo Jrch Pharmakol eaching of medical pharmacology: J. Undergraduate preparation for prescribing: the views of 2413 medical students and recent graduates. Br J a dynamic interactive electronic drug formulary for medical students. Br J lin Pharmacol . ‘ac.uk/pubs/contents/304df931-2ddc-4a54-rabowski H. Follow-on biologics: data exclusivity and the balance between innovation and competition. chellekens H, eufkens Hafety-related regulatory actions for biologicals Frank cell aplasia and epoetin therapy. . Biosimilars: policy, clinical and regulatory considerations. as simple as cost alone. J biosimilars: what really matters is patient safety. ewis P. discovery and development. Br J lin Pharmacol Vane J, pharmaceutical industry. Br J the pharmaceutical industry Br J 61 eb site: http://www.cioms.ch/publications/frame_P) nnex apps.who.int/medicinedocs/en/q (last accessed International conference of harmonization (IH) eb site: www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html Policy Perspective on afety, http://www.who.int/medicines/publications/eb site: http://www.ettigan P. Quality use of medicines , Friedman electronic health records: a feasibility study. J. Paving the ritical Path: How can linical Pharmacology help achieve the Vision? , Boissel JP; How to anticipate , Petein ). ed eVane rnet I, Peters Faurer HH, alter-ack I et al High prevalence of unknown lin 62 , Fosket Jisclosing complementary and alternative medicine use in the medical breast cancer. J Fam Prac 1999;48:453-8.orld Health rganisation 1999 orld Health rganisation 2007. org/reviews/en (last accessed pril 11 2012).supplements for physicians to know about. http://books.google.co.za/books?id=8igAACAAcurriculum-for-us-medical-schools.htm (last edicine, hinese University of Hong ong. http://www.icm.cuhk.edu.hk/icm/en/index.htmedicines edicinal Plant http://www.plantzafrica.com/pril , he global threat of counterfeit drugs: why industry and governments must communicate database of http://www.who-umc.org/DECLARATHogerzeil HV, asanovas JV, www.worldbank.org/data/icp., Hogerzeil HV, and in developing countries. Health Policy Plan 63 , Ulfelder H, Poskanzer Fraser H Routledge P. Folb PI. Mucklow J. Postgraduate education in clinical lin Rcurriculum for clinical pharmacology and Gpharmacology education in primary care 64 E Ceaching and 65 ADDRESSProf Folke linical Pharmacology, afety, meritus Professor, Flinders University of linical Pharmacology, Institute of Public Health, University ofinslows Vej 19, linical Pharmacology, Universityermany.linical Pharmacology, epartment of Paediatrics and linical Pharmacology, Universityection of Pediatric Pharmacology of IUPHmeritus Professor, Universiy of E20 66 linical Pharmacology, York ew York, Prof Folke meritus Professor, linical Pharmacology,meritus Professor, linical Pharmacology, alvary Prof Petra linical Pharmacology, Heliosermany.epartment of Pharmacology, University of the Free P. section of Pediatric Pharmacology are:nabwani (Botswana), Facundo regory Ceaching and 67 understanding, skills and attitudes relevant to the to prescribe safely and effectively at the point of hese core objectives are generic and they apply. circumstances. For each drug, graduates should be as a ‘student formulary’. CNDERSTANDATTRATmolecular, cellular, tissue and organ level the receptor as a target of drug action and related and half-life and their clinical relevanceroute, dose, frequency, and duration of drug Factors that determine inter-individual variation in the frequency of adverse reactions in primary and secondary care linical Pharmacology, 68 the mechanisms by which drugs interact Prescribing for special patient groups with altered physiology, pharmacokinetic handling and women who are pregnant, breast-feeding, or of categorisation of drugs as over-the-counter the responsibilities associated with prescribing the approval process and major regulatory authorities in the relevant country S Controls: crossover, separate control group, untreated, other therapy, placebo The author’s conclusion: adequate, questionable, servicesafety, efcacy and cost-effectiveness 69 the mechanism of action, the indications for use, Retrieval of drug information for prescribers and Aaking a drug historymaking an assessment of adherence to a prescribing oxygen (ow rate, delivery) and preparing and administering drugs by an infusion delivery e.g. inhaled, topical, insulinelderly, children, pregnancy and breast-feeding, 70 history of allergic reactionusing core knowledge of pharmacokinetics to identifying which therapeutic effect to observeational Formularies accessing Poisons Information ervicesassessing the reliability of varying sources of Core Attitudesassessing the potential harms and benets of 71 recognising that doctors should monitor the effects 72 Ceaching and 73 at large. he former may include the direct care of his pattern will vary from country to country. providing information about drug therapy, working rug and herapeutics committees from local (hospital formulary) to regional, national, and AIknowledge and skills needed to carry out this way. It is deliberately set to be broadly based and ASSPhysicians are usually admitted to a clinical work as a practising doctor under supervision in one However admission requirements will vary necessary, for practical reasons, to reduce the scope of clinical pharmacology. ther entry requirements in the form of preparatory/orientation training for OER INTERESTSarrangement with the directors of both programs or Syllabus Overviewis normally a 3 year activity but can vary from 2 – 5 years depending on the country concerned. Formal instruction for the trainee to acquire closely with basic pharmacology. Clinical experience caring for patients with drug Rmore broadly. In some countries 22AMS 74 Alevel. It is often of great benet for the trainee to and to experience work in such a laboratory Cboth experimental and observational ,eg Informed voluntary consent and ethics of iv. Dv. A Additional sources of variation among people in their dose-response, such as age, gender, pregnancy, liver and renal disease, drug D D D The process of drug discovery, development and xiv. Axv. D OClinical experience caring for patients with drug he trainee should get substantial clinical experience consulting about or caring for patients with serious or Ideally, experience with infants and children as Research experience that enhances knowledge of he trainee should be encouraged to identify, improved, with benet to future drug therapy. write the protocol, and obtain any necessary ethics his work will be done under supervision and the thesis (or equivalent) in clinical pharmacology.geographic area in which these patients live, is part of the practice of clinical pharmacology. 75 R clinical pharmacology training program must committed staff, a sufcient number of patients clinical services including the ability to measure research facilities for the resident to carry out a Further details of training programmes can be found C20, CS Clinical Pharmacology in Health Care, Teaching Clinical Pharmacology in Health Care, Teaching