Clinical pharmacology: a view from two angles

Trends in Pharmacological Sciences January 1985

Clinical pharmacology: a view from two angles Clinical p h a r m a c o l o g y presents starkly contrasting p r o b l e m s in b o t h the d e v e l o p e d a n d less d e v e l o p e d worlds. In the w e s t e r n world the vast a m o u n t of i n f o r m a t i o n that has accumulated on pharmacokinetics, d r u g availability and side-effects m e a n s that the m o s t efficient a n d dedicated p h a r m a c o l o g i s t is always o p e n to 'errors of o m i s s i o n ' . Third World p r o b l e m s are m o r e f u n d a m e n t a l . In the f o r m e r case, technology offers an easy answer; in the article below, G u n n a r Alvfin describes the d r u g i n f o r m a t i o n service that has b e e n set u p in the D e p a r t m e n t of Clinical P h a r m a c o l o g y in H u d d i n g e U n i v e r s i t y Hospital, S w e d e n w h i c h d e m o n s t r a t e s the usefulness of c o m p u t e r s ,in generating definitive literature searches. Clinical p h a r m a c o l o g i s t s - including visiting fellows from d e v e l o p i n g countries - can use this s y s t e m for training in d r u g i n f o r m a t i o n evaluation. But Third World p r o b l e m s cannot be a n s w e r e d b y s i m p l y offering h i g h technology, Western training to clinical p h a r m a c o l o g i s t s w h o will return to countries w h e r e relevant technology is not available, and w h e r e specific local n e e d s are not met. In a second article, H e n r y Fraser describes the difficulties such p h a r m a c o l o g i s t s face and stresses the n e e d for a p p r o p r i a t e education.

Drug information: a service provided by clinical pharmacologists ONE IMPORTANT feature of both professional and private life today is the emergence of the informational society. Because of the vast amount of data and reviews of accumulated information in various disciplines, the natural tendency is to organize this information in order to make it efficiently retrievable. In many areas, computer systems for organizing and providing facts are being developed. N e w terms such as

Education and research in developing countries IN A 1964 Resolution the World Health Organization stated: 'The effective and safe use of drugs is seriously impeded by a lack of Clinical Pharmacologists.' Twenty years later, in spite of a series of WHO study groups, expert committees and valuable technical reports, the situation remains largely unchanged in many countries, especially in the developing world 1. Why has such a clearly identified need remained unfilled?

artificial intelligence and expert systems have been introduced. Having chosen applied pharmacology, i.e. clinical pharmacology, as your field of medical expertise you will be recognized by your clinical colleagues as the person to consult on drug problems. This may challenge your practical knowledge in pharmacology. Many of us find ourselves spending considerable amounts of time digging up information and composing well founded answers to clinical questions. Since 1974, our department has dealt with such queries in a

Laurence and Bennett 2 may have identified the crucial issue when they wrote: 'No medical school can be e,onsidered complete without a department or sub-department of clinical pharmacology'. For without such a unit neither undergraduate, postgraduate or research training in clinical pharmacology can be developed. Thus WHO recommendations have either gone unnoticed or been left to administrators or pharmacists to implement. As a result most less developed countries (LDCs) have tackled only the problem of drug procurement. The role of clinical pharmacologists has been clearly set out 3,4 and the need is even greater in the LDCs than the developing world, for several reasons. First of all, drugs are developed in metropolitan countries and later marketed among very different populations

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standardized way. Questions are p h o n e d in and the c l i n i c a l pharmacologist in charge, along w i t h a pharmacist, makes a plan for a literature search. T o s i m p l i f y this process, w e first check standard literature sources that are kept on hand.

In about half of the cases MEDLINE searches are subsequently performed. The answer is written and references are included after the available information is reviewed. T w o examples of answers are s h o w n i n the box b e l o w . continued on page 3.

Query n:o 3861, October 5, 1983

Key words: oxymetazoline Query A patient returning from the US has been treated there with 'Dristan Long lasting nasal mist'. What is this and can anything similar be bought here?

Answer and Conclusion This product directly corresponds to the Swedish drug Nezeril nasal spray. Both contain the ec-adrenergic agent oxymetazolin (0.05%). Dristan is an over-the-counter drug in the US1. Pharmacokinetic information on the 'long lasting' effects is not available2. We assume that the two products have about the same clinical effects. Signature of investigator

References 1 Martindale. The extra pharmacopoeia. 1982; 28th ed 2 Drugline no 2516 Literature search by BO Query n:o 3900, October 24, 1983 Key words: primidone, kinetics, dose-response relationship, epilepsy, petit mal,

electroencephalography Query A patient suffering from petit mal epilepsy, currently has no seizures but exhibits pathological EEG activity. This patient wants to obtain a driver's licence. The question is whether the abnormal EEG activity can be normalized by anticonvulsant drugs. Plasma primidone concentration was found to be 65 ~mol 1-1. How should this be interpreted?

Answer My|epsin or primidone is an antiepileptic lacking current documentation and is not included in present local drug recommendations1. The clinical effects of this drug are difficult to assess, as both the parent compound and the two metabolites formed (phenobarbital and phenylethylmalonamide) have pharmacological effects. It is thus not possible to give a meaningful interpretation of the actual primidone concentration, except that it is within the same range as has been previously observed in monitored patients2. One should consider suppressing the pathological EEG activity by using ethosuximide or valproic acid. The authorities might approve an application for a driver's licence after a special neurophysiological investigation has been performed in a patient exhibiting petit mal EEG activity but no s e i z u r e s 3.

Conclusion Primidone is an antiepileptic with insufficient documentation to allow rational interpretation of plasma concentrations, because of two active metabolites being formed. Abnormal activity characteristic of petit mal epilepsy in the EEG can be corrected using antiepileptics used to control petit mal seizures. Signature of investigator

References 1 Stockholm City Council Drug Recommendations 1983-1984 2 Antiepileptic Drugs (eds) Woodbury, D. M., Penry, J. R., Schmidt, R. P. Raven Press, New York. 1972 3 Personal consultation with neurophysiologist

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with different nutritional a n d other e n v i r o n m e n t a l influences. Drug promotion bears little relation to local health needs, which may go largely u n m e t in poor countries. W h e n drugs are available they may be inappropriately used because therapeutics teaching in the LDCs often follows the patterns of metropolitan countries without benefit of more relevant teaching materials or analysis of local needs. Finally alternative approaches to treatment, including traditional medicines and n o n drug methods, may need to be evaluated. Therefore the LDCs greatly need clinical pharmacologists with skills and interest in teaching therapeutics, carrying out relevant research, m o n i t o r i n g drug use and developing national formularies and drug policies. Training programmes must provide a working knowledge of all these areas. Since the specialty interfaces with so m a n y disciplines at so m a n y levels, teaching and c o m m u n i c a t i o n skills are particularly important. Such a comprehensive training programme is hardly available anywhere, yet it is clearly the ideal. In an attempt to give some impetus to the promotion of clinical pharmacology in the LDCs the International U n i o n of Pharmacology and the Clinical Section of the British Pharmacological Society organized a workshop in London last year involving clinical pharmacologists from both Europe and developing countries. This workshop focused on three areas undergraduate teaching, postgraduate teaching and research training, and made a n u m b e r of important recommendations. Undergraduate teaching in the LDCs must not continue to be modelled on that of developed countries. Indeed, in one sense it is modelled on the past, w h e n pharmacology was taught entirely as a basic science course, b y nonclinicians, and was not a popular course with medical students s. Doctors in LDCs will invariably work with a limited drug formulary and the cost-effectiveness of therapy is of prime importance. Local disease patterns, n o n - d r u g treatment and risk/benefit analysis must be emphasized throughout training. This can only be done continued on page 3.

TIPS - January 1985

3 D R U G INFORMATION CENTRE 1982

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than referring the patient for additional diagnostic or treatment procedures. We hope that this service promotes rational medicine as outlined recently in an editorial entitled E n d o f cIinicaI f r e e d o m 1. Participation in a drug information enterprise also provides excellent educational possibilities for trainees. In our department, a number of visiting fellows from developing countries take part, thereby gaining experience in evaluation of information in the drug field 2. This will hopefully be of use in their future positions, as the lack of expertise in drug control agencies of developing countries is most severe. Senior members of the staff find the activity a stimulus to keep up with recent developments within the rapidly expanding field of pharmacotherapy. It is an opportunity for the clinical pharmacologist to be active in the health care system and thus pay his tribute to society. Without solid practical applications of clinical pharmacology, the future is all but decided for this speciality. One important aspect of implementing such a service is the interaction within a department of clinical pharmacology. The department must have a certain size and scope to provide the necessary facilities for evaluating all kinds of clinical pharmacological questions. For example drug analysis expertise is of great value. Questions received through the drug

by practising physicians with some training in clinical pharmacology and with the aid of teaching materials which reflect these differences. Trainees in clinical pharmacology in the Third World are few and far between. Clearly for the foreseeable future we will be dependent on a few metropolitan centres for training. Such cooperation requires considerable co-ordination and agreement on the kind of training required. A major problem recognized in the past has been 'overtraining' in a very narrow research field, dependent on costly, sophisticated equipment and technical skills not available on return home, rather than a high level of competence in the more practical skills of greatest value in local research and health care. Training should be comprehensive and should include a sound working knowledge of pharmacokinetics and therapeutic drug monitoring, design and operation of clinical trials, drug utilization and adverse reaction monitoring, monitoring of drug overdose, drug policies and development of formularies and so on. A specific clinical sub-specialty experience, for example hypertension or epilepsy, is of great value in subsequently establishing the usefulness of the clinical pharmacologist to his colleagues. Another recognized problem is the selection of candidates for training. A single trainee lost to a metropolitan country may set back any such programme in his country by a decade. On the other hand an unsuitable trainee may never have the dynamism or determination to initiate change on his return home. Co-operation between the home country and the host supervisor could establish one or more collaborative projects to be carried out in the home country during the training period. This would sensitize local colleagues to the kinds of skills the clinical pharmacologist has to offer and make it easier to get research and other programmes off the ground. But most important, the trainee must have a guaranteed university or government career post to return to. It is suggested that in addition to providing comprehensive training

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Drugs/ pregnancy E

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Therapy and choice of drugs

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Fig. 1. Distribution of topics for the inquiries. continued from page 2.

The entire staff of the clinical pharmacology department takes part in the drug information service as an integral part of duty and training. The drug information unit is staffed b y one secretary and two pharmacists specially trained in literature retrieval and assessment. This activity is particularly well suited for collaboration between the medical and pharmaceutical professions. All answers are scrutinized and countersigned by a senior clinical pharmacologist in cases where the primary investigator is junior. All answers written each week are reviewed at a round table discussion by the entire staff before being mailed. In urgent cases, preliminary answers are delivered promptly over the phone. The pattern of the inquiries is shown in Fig. 1. Questions concerning adverse effects including teratogenicity and the advisability of breast-feeding while on a specific drug regimen comprise roughly half of those submitted. The number of questions handled per year is about 500. There are no simple ways to assess the cost-effectiveness of this service. However, this fascinating aspect of medical intervention has to be evaluated at a time when there is pressure to stabilize or reduce health care budgets. In single cases, it is possible that evaluating the literature may be a much cheaper and more reasonable solution to a clinical problem

T I P S - January 1985

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information centre have also led to d e t a i l e d clinical studies, including the d e v e l o p m e n t of nely assay methods. The final function of our service is to b u i l d u p a data b a n k from the documents 3. W e have called our data b a n k "DRUGLINE' to denote similarity to the search m e t h o d ology of MEDLINE w h i c h w e utilize extensively. This was p o s s i b l e t h r o u g h collaboration w i t h the medical i n f o r m a t i o n d e p a r t m e n t of the K a r o l i n s k a Institute, w h i c h runs a MEDLINE/MEDLARS centre for Scandinavia. The questions are thus retrieved in exactly the same w a y as w i t h MEDLINE and no major extra routines have to be l e a r n e d b y the user. The data b a n k

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over two or three years to specialist level training m o d u l e s should be p r o v i d e d for general p h y s i c i a n s "with an interest in' clinical pharmacology. For example, intensive short courses could prov i d e the general p h y s i c i a n w i t h a s o u n d orientation t o w a r d s clinical p h a r m a c o l o g y and m a n y of the least technical b u t most useful areas for application in his o w n hospital. Similarly short courses in specific subjects, for example d r u g trials m e t h o d o l o g y , statistics, drug utilization studies or therapeutic d r u g monitoring, on s e c o n d m e n t s for six weeks to six m o n t h s for ' h a n d s - o n ' experience, w o u l d b e a feasible a p p r o a c h for more s e n i o r p h y s i c i a n s a n d less costly for the g o v e r n m e n t or medical school

is available to MEDLINE users after a special agreement is signed. This agreement delineates the proper use of D R U G L I N E and states that the user shall not r e p u b lish the answers or use t h e m for m a r k e t i n g , etc. It is understood that a d o c u m e n t reflects the professional o p i n i o n of the investigator at the time w h e n the question was h a n d l e d . It is u p to the user to decide to w h a t extent the document is a p p l i c a b l e to the p r o b l e m at hand. A major limitation to extensive use of the material is that it is p r e d o m i n a n t l y in Swedish. However, we have advanced p l a n s to create a version in English. W e feel that this activity is an i n d i s p e n s a b l e part of a clinical-

p h a r m a c o l o g i s t ' s service in h e a l t h care. Pharmacotherapeutic questions m u s t be evaluated continuously a n d n e w information s h o u l d b e p r o v i d e d w i t h o u t d e l a y for the promotion of h i g h q u a l i t y a n d capacity of medical therapy.

than full specialist training. It w o u l d be a h i g h l y cost-effective w a y of d e v e l o p i n g a team of people w i t h skills in the m a n y different areas of clinical pharmacology. Finally, regional w o r k s h o p s such as the Drug Trials Workshops at several centres in I n d i a in 1984 and p l a n n e d for the C a r i b b e a n in Barbados in 1986 should increase and i m p r o v e the m e t h o d o l o g y of other p h y s i c i a n s interested in s t u d y i n g drugs. There can be no d o u b t that the need for clinical pharmacologists. in d e v e l o p i n g countries is urgent. The thrust of W H O towards health care for all b y the year 2 000 will be severely w e a k e n e d if g o v e r n m e n t s and medical schools do not recognize the value, in terms of both i m p r o v e d health care a n d cost-

effectiveness, of training clinical pharmacologists.

GUNNAR ALVAN

References 1 Hampton, J. R. (1983) Br. Med. J. 287,12371238 2 World Health Organization Technical Report Series N:o 446, 1970 3 Alvfin G., Ohman, B. and Sj6qvist, F. (1983) Lancet ii, 1410-1412

Department of Clinical Pharmacology, Huddinge University Hospital, S-141 86 Huddinge, Sweden.

HENRY S. FRASER

Faculty of Medicine, University of the West Indies, Queen Elizabeth Hospital, Bridgetown, Barbados.

References 1 Fraser, H. S. (1981) Br. J. Clin. Pharmacol. 11, 457459 2 Laurence, D. R. and Bennett, P. (1980) in Clinical Pharmacology, The English Language Book Society and Churchill Livingstone, London 3 Chaudhury, R.R. (1980) J. Indian Med. Assoc. 74, 1 4

4 WHO(1970)ClinicalPharmacology: Scope, Organization, training, Technical Report Series, 403 5 Ali, D. S. and Fernandes, H. J. X. (1972)

Evaluation of Medical Education from the Student's Point of View, in Aspects of Medical Education in Developing Countries, Public Health Papers No. 47, World Health Organization, Geneva