International Nonproprietary Names for Pharmaceutical Substances

WHO DRUG INFORMATION

VOLUME 6 • NUMBER 4 • 1992

PROPOSED INN LIST 68 INTERNATIONAL NONPROPRIETARY NAMES FOR PHARMACEUTICAL SUBSTANCES

WORLD HEALTH ORGANIZATION • GENEVA WHO DRUG INFORMATION

WHO Drug Information provides an overview of topics relating to drug development and regulation that are of current relevance and importance, and includes the lists of proposed and recommended International Nonproprietary Names for Pharmaceutical Substances (INN). Its contents reflect, but do not present, WHO policies and activities and they embrace socioeconomic as well as technical matters.

The objective is to bring issues that are of primary concern to drug regulators and pharmaceutical manufacturers to the attention of a wide audience of health professionals and policy-makers concerned with the rational use of drugs. In effect, the journal seeks to relate regulatory activity to therapeutic practice. It also aims to provide an open forum for debate. Invited contributions will portray a variety of viewpoints on matters of general policy with the aim of stimulating discussion not only in these columns but wherever relevant decisions on this subject have to be taken.

WHO Drug Information is published 4 times a year in English, French and Spanish.

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© World Health Organization 1992

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ISSN 1010-9609 World Health Organization, Geneva

WHO Drug Information Volume 6, 1992: Index

A Didanosine and HIV, (1) 15 Diethylene glycol, (4) 169 ACE inhibitors, (1) 15 Dithranol, (3) 123 fetotoxicity, (2) 56 Doxycycline, (1) 37 dialysis anaphylaxis, (2) 56 Drug control, (3) 131 Acetylsalicylic acid, (4) 149 Drug information centres, (3) 106 Aciclovir, (1) 29, (2) 69 Drug surveillance, (2) 75 Advertising standards, (1) 14 Allopurinol, (2) 45 Aluminium diacetate, (2) 71 E poisoning, haemodialysis, (4) Epinephrine, (2) 73 Anaphylaxis, (3) 110 Erythromycin, (1) 32, (2) 68, (3) 123 Anthraquinone, (4) 168 Essential drugs lists, rare diseases (4) 147 Antibiotic resistance, (4) 160 Etretinate, (3) 124 Anticoagulants, (4) 153 Expensive drugs, cost containment, (3) 106 Antihistamines, (4) 165 Artemether, (1) 6 Ascaris therapy, (3) 98 F Atovaquone, (4) 168 Fenfluramines, (3) 110 Finasteride, (4) 168 Fluoxetine, (3) 110 B Foscamet sodium, (1) 16 Benzathine benzylpenicillin, (1) 30, (2) 67 Benzoyl peroxide, (3) 121 Benzyl benzoate, (2) 72 G Benzylpenicillin, (1) 30, (2) 67 Germander, (2) 57 Beta-adrenoreceptor agonists, (4) 153 Glafenine, (2) 57 asthma, (1) 17, (2) 56 Good Clinical Practice for pharmaceutical Bioavailability, (1) 1 products, (4) 170 Bioequivalence, (1) 1 Group-A streptococci, (2) 55 Biological standardization, (1) 38 Growth hormone, (3) 111 standards, (1) 38 Bufexamac, (2) 56 H Heparins, (4) 151 C Herbal medicines, (3) 103 Calamine lotion, (2) 70, (3) 121 HIV & tuberculosis, (2) 51 Ceftriaxone, (1) 31 Hydrocortisone, topical use, (1) 19 Chloramphenicol, meningitis, (2) 45 (2) 73, (3) 124 multiresistance, (4) 160 Chlorofluorocarbon restriction, (1) 15 I Chlorphenamine, (3) 121 Cinchophen, (2) 57 Immunity, vitamins and trace elements, (4) 161 Ciprofloxacin, (1) 31 Immunization, rubella, (3) 103 Clinical trial protocol, (4) 1855 Importation, illegal, (2) 57 Contraceptive, injectable, (4) 167 Infections, post-operative wound, (2) 53 Isoniazid, tuberculosis, (1) 12 oral, (4) 166 lUDs, (1) 6 Corticosteroids, immunosuppression, (1) 15 varicella, (2) 57 Counterfeiting, workshop (2) 41 L Counterfeits, (1) 3 Lucidine, (4) 168 D M Dapsone, (3) 122 M. leprae vaccine, (1) 7 Declaration of Helsinki, (4) 186 Magnesium, (4) 158 Dialysis anaphylaxis/ACE inhibitors, (2) 56

1 WHO Drug Information Volume 6, Index 1992

Melarsoprol, (2) 47 Meta-analysis, (4) 145 S Metamizole sodium, (1) 16 Salicylic acid, (2) 71 Methoxsalen, (3) 125 Selenium sulfide, (3) 127 Methylrosanilinium chloride, (2) 70 Spectinomycin, (1) 35 Metronidazole, (1) 33 Stereoisomerism, (4) 163 Miconazole, (1) 33 Streptomycin, tuberculosis, (1) 12 Micronutrients, (4) 161 Sulfamethoxazole/trimethoprim, (1) 35 Mumps vaccines, (4) 164 Sumatriptan, (3) 111 Mupirocin, (2) 68 Sunscreens, (3) 128 N T Non-steroidal anti-inflammatories, (4) 160 Tacrine, (2) 58 Noscapine, (1) 16 Tar products, (3) 128 Nystatin, (1) 34 Temafloxacin, (3) 112 Tetracycline, (1) 36, (3) 129 Thiazides, (4) 156 O Thrombolytic therapy, (4) 150 Ofloxacin, leprosy, (3) 99 Tiabendazole, (2) 69 Opioids, pain, (3) 99 Tibolone, (3) 112 Oral rehydration, (2) 46 Triazolam, (3) 112 Trimethoprim, (1) 35 P Tuberculosis & HIV, (2) 51 chemotherapy, (1) 12 Paediatric prescribing, (4) 163 Typhoid vaccines, (1) 9 Pain, opioids, (3) 99 Parental attitudes, (3) 108 Permethrin, (2) 72 V Pertussis vaccination, (1) 52 Vaccination, pertussis, (2) 52 vaccines, (4) 155 Vaccine immunogenicity, (1) 13 Pharmaceutical Inspection Convention, (3) 96 Vaccine, M. leprae, (1) 7 PIC, (3) 96 mumps, (4) 164 Podophyllum resin, (1) 34 pertussis, (4) 155 Postmarketing surveillance, (3) 95 typhoid (1) 9 Pralidoxime salt, (3) 101 Vitamin A, (1) 11 Prednisolone, (3) 126 Vitamin D, (3) 103 Procaine benzylpenicillin, (1) 30 Propofol, (2) 58 Pyrazinamide, tuberculosis, (1) 12 W Weight-reducers, (2) 58 Q Quinine, (1) 9 Z Zalcitabine, (2) 58 R Zidovudine, (2) 48 Rifampicin, tuberculosis, (1) 12 Ritodrine, (3) 104 Rubella immunization, (3) 103

2 Volume 6, Number 4, 1992 World Health Organization, Geneva

WHO DRUG INFORMATION

Contents

General Policy Topics More on paediatric prescribing in new product labelling 163 Meta-analysis 145 Mumps vaccines and meningoencephalitis 164 Personal Perspectives Non-sedating antihistamines and cardiac arrhythmias 165 Essential drugs: for patients or for Standardized instructions for oral populations? 147 contraceptives 166 Injectable contraceptive approved by FDA 167 Reports on Individual Drugs Haemodialysis and chronic aluminium Acetylsalicylic acid in peripheral poisoning 167 arterial disease 149 Flucloxacillin: cholestatic jaundice 167 Acute pulmonary embolism: a place for Herbal products: more potential carcinogens 168 thrombolytic therapy? 150 Human interleukin-2 for renal cancer 168 Venous thromboembolism: heparins - Atovaquone for treatment of Pneumocystis fractionated and unfractionated - in carinii pneumonia 168 prophylaxis and treatment... 151 Finasteride for benign prostatic hyperplasia 168 ...and for how long are anticoagulants Diethylene glycol: yet another tragedy 169 really needed? 153 Beta-adrenoreceptor agonists and asthma deaths 153 Consultative Document Pertussis vaccines: cellular and acellular 155 Proposed WHO Guidelines for Good Clinical Thiazide therapy: who needs potassium Practice (GCP) for trials on pharmaceutical supplements? 156 products 170 Magnesium and acute cardiac infarction 158 Clinical trial protocol 185 Declaration of Helsinki 186 General Information More reports of multiresistant Salmonella typhi 160 Recent Publications Anti-inflammatory drugs: new insights into Infectious disease: an ominous and adverse gastrointestinal effects 160 unpredictable threat 189 Immunity, vitamins and trace elements 161 Proposed International Non• Regulatory Matters proprietary Names: List 68 191 Stereoisomerism and drug development 163

i

WHO Drug Information Vol. 6, No. 4, 1992

General Policy Topics

performance of a new drug to national regulatory Meta-analysis authorities when the individual studies lack the Practising doctors need to know how accumulated statistical power to demonstrate a clinically impor­ knowledge on a given set of therapeutic options is tant therapeutic effect with reasonable certainty (3). best translated into appropriate clinical manage­ Even more questionably, it is used as a means of ment. Meta-analysis provides them with an answer arbitration when the results of the individual trials in quantitative terms. It offers an "ultimate" estimate are discordant. of the comparative risks and benefits associated Proponents of meta-analysis readily concede that it with alternative courses of action. In doing so, it is far from a precise statistical tool. Sceptics provides a norm for the practising doctor to follow. question its very legitimacy as a quantitative Its potential influence on the routine practice of technique (4). The complexity of biological re­ medicine is profound. Yet the term has slipped into sponses and their multifactorial determinants the medical lexicon before being securely defined. demand that searching tests of comparability must Accredited by use, meta-analysis none the less always be applied to data obtained from different remains problematic through lack of ground rules. trials as a precondition of aggregating them for The basic assumption — and it can never be more quasi-statistical purposes (5). than an assumption — is that independent studies These concerns are far from hypothetical. They designed to test the same hypothesis often have been vindicated by hard experience. A approximate so closely in the criteria by which the persuasive example is provided by three markedly subjects are selected and managed that the data obtained may legitimately be combined or integra­ different interpretations of the risks associated with ted for analytical purposes (1). This inevitably passive smoking provided by three independent offends statistical purists who regard controlled meta-analyses (6-8). Plausible explanations for comparison through rigorous elimination of known these differences and some salutory advice about sources of bias as an inviolate tenet of biological indiscriminate aggregation of data have been investigation. In clinical experimentation — both offered in a recent issue of Pharmaceutical Medi• prospective and retrospective — screening criteria cine (9). Disconcertingly, the article simply spells are used positively and precisely to admit compa­ out principles long-established as fundamental to rable subjects to investigation. In meta-analysis the analysis of biological phenomena: univariate comparability is sought — but with less assurance analysis cannot be appropriately applied to the that it will be achieved — by excluding specific exploration of clearly multivariate problems; only studies from a pre-existing pool of independent but data obtained from well-designed and carefully- similar experiments. The appeal of meta-analysis executed studies that satisfy explicit a priori — the use of all relevant available information to inclusion and exclusion criteria should be admitted obtain a unified quantitative answer to a complex for meta-analysis; and data from trials that have clinical problem — is understandably compelling. produced mutually incompatible results can never But, because there is less assurance that like has be safely aggregated for any analytical purpose. been compared with like, it can sometimes be unrealistically naive. Meta-analysis has not attenuated or changed the basic tenets of biological investigation. Nor can it ever generate from a series of inconclusive and When the technique was first applied, it was inconsistent studies a result that is more reliable reasonable to assume that its conceptual and than the sum of the parts. Inconsistencies in analytical basis would become refined with time biological phenomena need to be examined and, and that its limitations would become better defined whenever possible, explained. Understanding will (2). However, now that it is more widely used, it is never be advanced if tiresome unexplained applied with less, rather than more discrimination. It differences in results are simply obscured. Meta­ has become commonplace, for instance, to resort analysis must never supplant either scientific to meta-analysis — in default of planned multi­ enquiry or the classical academic approach to centre studies — to present conclusions on the review writing in medicine.

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References 6. National Research Council. Environmental tobacco smoke: measuring exposure and assessing health effects. 1. Huque, M. Experience with meta-analysis in NDA Washington: National Academy Press, 1986. submissions. Proceedings of the Biopharmaceutical Section of the American Statistical Association, 2: 28-33 7. Spitzer, W., Lawrence, V., Dales, R. et al. Links (1988). between passive smoking and disease: a best-evidence synthesis. Clinical and Investigative Medicine, 13: 17-42 2. Editorial. WHO Drug Information, 2: 171-172 (1988). (1990).

3. Editorial. Meta-analysis. Pharmaceutical Medicine, 6: 8. Janerich, D., Thompson, W., Varda, L. et al. Lung 113-119 (1992). cancer and exposure to tobacco smoke in the household. New England Journal of Medicine, 323: 632-636 (1992). 4. Thompson, S., Pocock, S. Can meta-analysis be trusted? Lancet, 338: 1127-1130 (1991). 9. Eysenk, H. Meta-analysis: sense or non-sense? Pharmaceutical Medicine, 6:113-119 (1992). 5. Spitzer, W. Meta-mega-analysis: unanswered questions about aggregating data. Journal of Clinical Epidemiology, 44: 103-107 (1991).

146 WHO Drug Information Vol. 6, No. 4, 1992

Personal Perspectives

sufferers from cystic fibrosis require pancreatic Essential drugs: for patients or for enzymes with their meals because, even before populations? they were born, their pancreas was destroyed. But, because cystic fibrosis is less well known — and John A. Dodge virtually absent from large parts of the world — pancreatic enzymes are not included in national Professor of Child Health, Queen's University, lists of essential drugs even in countries with Belfast, and Chairman, Scientific/Medical populations of predominantly European descent, Advisory Committee, International Cystic such as some in Latin America. Fibrosis (Mucoviscidosis) Association In these countries the calculated numbers of By preparing guidelines and models for lists of patients with cystic fibrosis must run into tens of essential drugs which should be readily available to thousands according to the known gene frequency, those who need them, WHO has performed a even though the proportion of these patients that valuable service to the developing world. The are actually diagnosed may be as low as 10% (3). purpose of such lists is clear: "To extend the Partly because they are not recognized, and partly accessibility of the most necessary drugs to those because adequate treatment is not available, populations whose basic health needs cannot be affected children die at an early age. The disease met by the existing supply system"(1). The onus is consequently has a low prevalence despite a high on each individual country to evaluate and adopt a incidence. As a result, it continues to be regarded list of essential drugs according to its own policy in as a very rare disease by the health authorities and the field of health. the medical profession, and this perception means that, when it does occur, it is frequently unrecog­ Some countries, concerned with abuse of existing nized. Whereas mean life expectancy for cystic regulations by commercial interests, have drawn up fibrosis is now approximately 30 years in the stringent proposals which will undoubtedly benefit industrialized countries of Europe and North the majority of the population and protect them from America, it only reaches 6 years even for the exploitation. Under new legislation in Nigeria, for minority who are diagnosed and treated in Latin example, "any drug which is not on the essential America (4). drugs list cannot be imported, manufactured, sold, exposed for sale or distributed" (2). However, while Families unfortunate enough to have children with the concept and principle of an essential drugs list cystic fibrosis usually avail themselves of all the is excellent, its rigid and exclusive implementation information they can obtain. They are well aware of may highlight the conflict which sometimes arises the treatment available in Europe and North between the needs of society and those of the America, and the corresponding enhancement of individual. The very success and radical nature of life expectancy. Similar treatment is not available in such policies, while being for the general good, may their own countries because the essential drugs be harmful or dangerous to the health of some lists are being applied restrictively. Thus, an patients, whose diseases are sufficiently rare for instrument intended to make necessary drugs their needs to be overlooked in the compilation of available to the majority of patients has the effect of drug lists. For such individuals, specific remedies denying drugs that are essential to the unfortunate or physiological replacement excluded from the list few. may be lifesaving, and may be essential for long- term therapy. Heading the essential drugs required by children with cystic fibrosis are capsules containing pan­ Nobody would question the inclusion of thyroxine in creatic enzymes. They may have to take many of a list of essential drugs, even though severe these with each meal if they are to digest their food hypothyroidism may be rare in a given community, properly. In addition, because they often become because the value of replacement treatment for the infected with organisms such as Pseudomonas affected individuals is common knowledge. Equally, aeruginosa, they frequently require antibiotics not

147 Personal Perspectives WHO Drug Information Vol. 6, No. 4, 1992

widely used for other types of infection. I have with any necessary supporting information. Such a encountered many affected families who are placed list will need to be kept under frequent review and in severe financial hardship because they love their varied according to local needs, not least because children and can only obtain the "forbidden" but antibiotic usage must be controlled in the light of essential enzyme treatment by bribing airline staff changing drug resistance patterns. It is also to smuggle these preparations in, at vastly inflated inevitable, following the identification of the respon­ cost and at the risk of criminal prosecution. But sible gene in 1989, that new forms of treatment for even this strategy is only available to the more the disease will be developed within the next few prosperous families. years.

Cystic fibrosis is only one example of many Where such associations do not exist, the respon­ potentially treatable conditions that are excluded sible clinician must be able to apply to the appropri­ from effective care by the restrictive interpretation ate service for necessary exemptions to be of essential drugs lists. The number of such authorized on behalf of his patients, and not be conditions will grow with better diagnostic aware­ baulked by junior officials with no authority to vary ness. As this happens, there will be a need for the regulations. The essential drugs concept must greater diversity of drugs, and the need to accom­ be interpreted in a way that operates to the benefit modate exceptions to the general rule must be — never to the detriment — of individual patients. widely appreciated by those who legislate for the health of populations. There must be ways to References reconcile the needs of society with those of the individual. Cooperation must be established 1. The use of essential drugs. Report of the WHO Expert between the health services and nongovernmental Committee, Technical Report Series No. 796. World Health Organization, Geneva (1990). agencies representing responsible professional opinion and with patient groups acting to defend 2. Ransome-Kuti, O. Safe drugs for everyone. World minority interests. Health, March-April 1992.

National cystic fibrosis associations, for example, 3. Raskin, S. DNA data suggests the incidence of cystic are able to provide lists of named patients, and to fibrosis in Brazil may be tenfold more than observed. distribute imported drugs to those in need. They American Journal of Human Genetics, 51 (Suppl):1437 can also provide to the public health services a list (1992). of drugs which they believe to be essential for their 4. Macri, C.N., de Gentile A.S. Latin American Registry of patients, as exemplified in the table below, together Cystic Fibrosis: Progress Report 1990, Buenos Aires (1992).

Drugs Used in Cystic Fibrosis

Nutritional Pancreatic extracts (replacement therapy). Multivitamin preparations. Vitamin E.

Antimicrobial therapy Broad spectrum antibiotics, e.g., ampicillin, amoxicillin, amoxicillin/clavulanic acid com­ pounds.

Antistaphylococcal agents, e.g. cloxacillin, flucloxacillin.

Antipseudomonal agents, e.g. carbenicillin, ticarcillin, aminoglycosides such as gentamicin or tobramycin, selected cefalosporins such as ceftazidime.

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Reports on Individual Drugs

Acetylsalicylic acid in peripheral acid reduces the need for peripheral artery surgery in individuals with and without a history of arterial disease claudication (8). Acetylsalicylic acid, even at low dosage, exerts an References antithrombotic effect, apparently because it inhibits 1. Moncada, S., Vane, J. Arachidonic acid metabolites clot formation by irreversibly reducing the capacity and the interactions between platelets and blood-vessel of platelets to aggregate (1). This process of walls. New England Journal of Medicine, 300: 1142-1147 aggregation is believed to be a crucial and perhaps (1979). ultimate step in coronary and peripheral artery occlusion (2). Indeed, acetylsalicylic acid has 2. Verhaega, R., Bounameaux, H. Peripheral arterial already been shown, when administered promptly, occlusion: thromboembolism and antithrombotic therapy. to reduce the mortality associated with acute In: Fuster, V., Verstraete, M. eds. Thrombosis in cardio• cardiac infarction (3). Five years ago it was also vascular disorders. Philadelphia: Saunders, p.436 (1992). shown in a large prospective study that 325 mg, 3. ISIS-2 (Second International Study of Infarct Survival) taken indefinitely on alternate days, significantly Collaborative Group. Randomised trial of intravenous protects against the risk of a first myocardial streptokinase, oral aspirin, both, or neither among 17 187 infarction (4, 5). This study, which involved middle- cases of suspected acute myocardial infarction: ISIS-2. aged doctors in the USA, has now been extended Lancet, 2: 349-360 (1988). in order to assess whether the same dose of acetylsalicylic acid affords protection against 4. The Steering Committee of the Physicians' Health peripheral atherosclerotic disease (6). It is esti­ Study Research Group. Preliminary Report: findings from mated that, by middle age, almost 1% of men in the aspirin component of the ongoing Physicians' Health North America have signs of peripheral arterial Study. New England Journal of Medicine, 318: 262-264 (1988). occlusive disease (7). Each year some 30 000 of these undergo femoral artery bypass procedures 5. The Steering Committee of the Physicians' Health and almost 40 000 limbs are amputated (8). Study Research Group. Final report on the aspirin component of the ongoing Physicians' Health Study. New Within 5 years, 56 of some 22 000 doctors taking England Journal of Medicine, 321: 129-135 (1989). part in the latter study had needed peripheral arterial surgery. Twenty of these had been ran­ 6. Smith, G., Shipley, M., Rose, G. Intermittent domly allocated to take acetylsalicylic acid and 37 claudication, heart disease risk factors, and mortality: the had been taking placebo. The relative risk of Whitehall Study. Circulation, 82: 1925-1931 (1990). undergoing peripheral surgery among those taking acetylsalicylic acid was 0.54 (95% confidence 7. Gillum, R. Peripheral arterial occlusive disease of the intervals 0.30-0.95; p=0.03). extremities in the United States: hospitalization and mortality. American Heart Journal, 120: 1414-1418 (1990). Antiplatelet therapy has previously been shown to reduce the risk of arterial occlusion in comparable 8. Goldhaber, S., Manson, J., Stampfer, M. et al. Low- degree among patients convalescing after periph­ dose aspirin and subsequent peripheral arterial sugery in eral arterial surgery or angioplasty (9,10). It has the Physicians' Health Study. Lancet, 340: 143-145 (1992). been suggested that intra-arterial thrombolytic drugs should be used, in the absence of contra­ 9. Hess, H., Mietaschk, A., Deischsel, G. Drug-induced indications, in virtually all patients with acutely inhibition of platelet function delays progression of ischaemic lower limbs (11). In many countries, peripheral occlusive arterial disease: a prospective however, expense precludes their use. There is double-blind arteriographically controlled trial. Lancet, 1: obvious need, where this constraint exists, to 415-419 (1985). assess the antithrombotic effect of oral acetylsali­ cylic acid in these patients. There is also a need, as 10. Giansante, C, Calabrese, S., Fisicaro, M. et al. the authors of the recent study suggest, to confirm Treatment of intermittent claudication with antiplatelet or refute the possibility that low-dose acetylsalicylic agents. Journal of International Medical Research, 18: 400-407 (1990).

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11. Mc Namara, T., Bomberger, R., Merchant, R. Intra­ different approaches to treatment in these circum­ arterial urokinase as the initial therapy for acutely stances (13). None the less, since more than one in ischemic lower limbs. Circulation, 83 (suppl 1): 106-119 three of these patients may be expected to die in (1991). the short term (6, 14), thrombolytic therapy for critically ill patients has come to be regarded as Acute pulmonary embolism: routine in many hospital centres (13). a place for thrombolytic therapy? Only a multicentre prospective study of international Acute pulmonary embolism remains a serious dimensions is likely to provide the basis for formu­ medical emergency. It is a matter of concern that lating definitive therapeutic guidelines. Given the many cases still remain unrecognized during life high cost of thrombolytic agents, the investment and that clear, internationally-recognized criteria for could be readily justified. Meanwhile, pending the diagnosis and assessment are lacking (3). Women results of such a study, the case for employing have been assumed to be at greater risk as a thrombolytic therapy in acute pulmonary embolism consequence of estrogen use, childbearing and a simply rests unproven. higher frequency of thrombophlebitis, but even this is now contested (2). Each year, over 30 000 References deaths are attributed to the condition in North America alone (1). Prompt anticoagulation with 1. Goldhaber, S., Morpurgo, M. Diagnosis, treatment and heparin and warfarin undoubtedly saves lives, but prevention of pulmonary embolism. Report of the WHO/ International Society and Federation of Cardiology Task even with the best of management, about 10% of Force. Clinical Cardiology, 268: 1727-1733 (1992). treated patients die whilst in hospital (4, 5). 2. Quinn, D., Thompson, B., Terrin, M. et al. A prospective In the mid-1970s there was expectation that investigation of pulmonary embolism in women and men. treatment with urokinase or streptokinase, the first Journal of the American Medical Association, 268: 1689- parenterally-administered antithrombotic agents, 1696 (1992). might hold advantage over heparin in the crucial initial phase of treatment. The results of compara­ 3. Hillum, R. Pulmonary embolism and thrombophlebitis in tive trials were largely disappointing (6-8), but the United States, 1970-1985. American Heart Journal, 114: 1261-1264 (1987). interest was rekindled a few years ago with the introduction of tissue plasminogen activator (tPA) 4. Barritt, D., Jordan, S. Anticoagulant drugs in the and other fibrin-specific thrombolytic agents (9-12). treatment of pulmonary embolism: a controlled trial. Lancet, 1: 1309-1312 (1960). A recent review of published trials in which the response to treatment was monitored using either 5. Dalen, J., Alpert, J. Natural history of pulmonary radiographic or haemodynamic techniques con­ embolism. Progress in Cardiovascular Disease, 17: 259- cludes that there is still insufficient evidence to 270 (1975). determine whether thrombolytic therapy is of clinical benefit either in terms of morbidity or mortality (13). 6. Urokinase pulmonary embolism trial: phase 1 results. Journal of the American Medical Association, 214: 2163- One encouraging finding, based on a sample of 2172 (1970). only 40 patients, is that, seven years after treat­ ment, patients receiving thrombolytic therapy had 7. The urokinase pulmonary embolism trial: a national significantly lower pulmonary vascular resistance cooperative study. Circulation, 47(suppl 2): 1-108 (1973). than patients receiving heparin (14). However, it is not yet certain that this apparent advantage is of 8. Urokinase-streptokinase pulmonary embolism trial: clinical consequence, and it has to be weighed phase 2 results. Journal of the American Medical against one report of a 10-fold excess of minor Association, 229: 1606-1613 (1974). bleeding events during treatment among patients receiving tPA (12). 9. Tissue plasminogen activator for the treatment of acute pulmonary embolism: a comparative study by the PIOPED investigators. Chest, 97: 528-533 (1990). The patients who might be expected to benefit most from thrombolytic treatment are those in shock as a 10. Levine, M., Hirsh, J., Weitz, J. et al. A randomized trial consequence of massive pulmonary obstruction. of a single bolus dosage regimen of recombinant tissue Too little information is provided in the published plasminogen activator in patients with acute pulmonary literature to offer an insight into the relative value of embolism. Chest, 98: 1473-1479 (1990).

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11. Böttiger, B., Böhrer, H. Thrombolysis for pulmonary differ somewhat in their anticoagulant properties embolism. Lancet, 340: 852 (1992). and even, perhaps, in their clinical effects. In general, they are comparable in their antithrombotic 12. Goldhaber, S., Kessler, C, Heit, J. et al. TPA versus activity to unfractionated heparin (8). They differ urokinase in acute pulmonary embolism: a randomized from the latter, however, in that they are relatively controlled trial. Circulation, 84 (suppl. II): 357 (1991) weak inhibitors of platelet function (9), and they are 13. Anderson, D., Levine, M. et al. Thrombolytic therapy virtually without effect on activated partial thrombo­ for the treatment of acute pulmonary embolism. Canadian plastin time and other widely used heparin-sensitive Medical Association Journal, 146: 1317-1324 (1992). clotting assays (10, 11).

14. Sharma, G., Folland, E., Mclntyre, K. et al. Longterm In the prophylactic setting, despite early indications hemodynamic benefit of thrombolytic therapy in pulmo­ that they might reduce the risk of haemorrhage (12, nary embolic disease. Journal of the American College of 13), there is no conclusive evidence to show that Cardiologists, 15: 65A (1990). fractionated preparations hold advantage over less 15. Tibutt, D., Davies, J., Anderson, J. et al. Comparison expensive unfractionated heparins (8, 14). None by controlled clinical trial of streptokinase and heparin in the less, it remains possible that they may hold treatment of life-threatening pulmonary embolism. British advantage in the treatment of established, uncom­ Medical Journal, 1: 343-347 (1974). plicated deep-vein thrombosis (13).

Because fractionated heparins are both more Venous thromboembolism: extensively bioavailable and more persistent in their effect than unfractionated heparin preparations heparins — fractionated and (15-18), it is practicable to administer them sub¬ unfractionated — in prophylaxis cutaneously in therapeutic dosage. This is an important advantage, since therapeutic doses of and treatment.... unfractionated heparin have to be infused intra­ venously at rates determined by repeated monitor­ Approaches to prevention and treatment of acute ing of the activated partial-thromboplastin time. deep vein thrombosis have changed little since heparin and oral anticoagulants were introduced Early experience in many centres — based largely over 40 years ago. Thrombolytic agents, which are on venographic data rather than clinical outcome — discussed above, are of equivocal value and has suggested that twice daily subcutaneous uncompetitively costly in this setting. Antiplatelet injection of fractionated preparations is as effective agents, including acetylsalicylic acid —which has as continuous intravenous infusion of unfrac­ gained importance in the management of thrombus tionated preparations in dispersing venous throm­ in the coronary and cerebral arteries — have far bus (14, 19). Direct clinical confirmation of this less effect on thrombus in the low pressure venous equivalence has now been obtained in a random­ and atrial systems where deposition of fibrin rather ized multicentre study involving 400 US patients than platelet activation is the prime causative factor (13). New episodes of venous thromboembolism (1). occurred within 3 months in 6 of 213 patients who received a fractionated preparation, at an average It has been estimated that some 25% of patients dose of some 12 000 International Factor Xa undergoing major surgery, and perhaps 50% of Inhibitory Units subcutaneously once daily for 6 those requiring major orthopaedic procedures, days, and in 15 of 219 patients who received develop venous thrombosis (2). Subcutaneous unfractionated heparin intravenously for the same heparin — 5000 IU injected two or three times daily period at a daily dose of 30 000 to 40 000 units throughout the perioperative period — reduces this daily. risk by as much as 70% (3-5). However, many surgeons remain reticent to resort to a prophylactic An unexpected but encouraging result was that measure that is associated with a substantial risk of major bleeding, which occurred in 11 patients major haemorrhage (5). receiving infusions of unfractionated heparin, was reported in only one patient taking the fractionated When low-molecular-weight fractions of heparin preparation. Whether or not this reflects a dosage were first developed it was hoped that this risk of effect rather than an intrinsic difference between bleeding might be reduced (6, 7). The various fractionated and unfractionated heparins (20), the preparations that are now available commercially

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clinical importance of the finding is uncontested. 9. Salzman, E., Rosenberg, R., Smith, M. et al. Effect of For reasons that remain unestablished, however, heparin and heparin fractions on platelet aggregation. this initial advantage was ultimately lost because Journal of Clinical Investigation, 65: 64-73 (1980). bleeding episodes during the subsequent extended 10. Andersson, L., Barrowcliffe, T., Holmer, E. et al. period of warfarin therapy were more frequent Anticoagulant properties of heparin fractionated by affinity among the patients who had received the fraction­ chromatography on matrixbound antithrombin III and by ated preparation. gel filtration. Thrombolysis Research, 9: 575-583 (1976).

The possibility remains that, for patients with 11. ten Cate, H., Lamping, R., Henny, C. et al. Automated established deep vein thrombosis, subcutaneous amidolytic method for determining heparin, a heparinoid, administration of fractionated heparins may prove and a low-Mr heparin fragment, based on their anti-Xa to be not only simpler but also safer than intra­ activity. Clinical Chemistry, 30: 860-864 (1984). venous infusion of unfractionated heparin. If this is so, it may become feasible for the first time to treat 12. Levine, M., Hirsh, J., Gent, M. et al. Prevention of deep vein thropmbosis after elective hip surgery: a some cases of uncomplicated deep vein thrombosis randomized trial comparing low-molecular-weight heparin in an outpatient setting. Opportunities for reducing with standard unfractionated heparin. Annals of Internal health care costs while at the same time enhancing Medicine, 114: 545-551 (1991). patient safety arise infrequently. The therapeutic application of fractionated heparins clearly merits 13. Hull, R., Raskob, G., Pineo, G. et al. Subcutaneous continued investigation. low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal vein References thrombosis, New England Journal of Medicine, 326: 975- 982 (1992). 1. Stein, B., Fuster, V., Halperin, J., Chesebro, J. Antithrombotic therapy in cardiac disease: an emerging 14. Salzman, E. Low-molecular-weight heparin and other approach based on pathogenesis and risk. Circulation, 80: new antithrombotic drugs. New England Journal of 1501-1513 (1989). Medicine, 326: 1017-1019 (1992).

2. National Institute of Health Consensus Development 15. Bergqvist, D., Hedner, U., Sjorin, E., Holmer, E. Conference. Journal of the American Medical Association, Anticoagulant effects of two types of low-molecular-weight 256:744-749 (1986). heparin administered subcutaneously. Thrombolysis Research, 32: 381-391 (1983). 3. Colditz, G., Tuden, R., Oster, G. Rates of venous thrombosis after general surgery: combined results of 16. Bara, L., Billaud, E., Gramond, G. Comparative randomized trials. Lancet, 2: 143-146 (1986). pharmacokinetics of a low-molecular-weight heparin (PK 10 169) and unfractionated heparin after intravenous and 4. Clagett, G., Reiss, J., Prevention of venous thrombo­ subcutaneous administration. Thrombolysis Research, 39: embolism in general surgical patients. Annals of Surgery, 631-636 (1985). 208:227-240 (1988). 17. Bratt, G., Tomebohm, E., Widlund, L, Lockner, D. 5. Collins, R., Scrimgeour, A., Yusuf, S, Peto, R. Reduc­ Low-molecular-weight heparin (KABI 2165, Fragmin): tion in fatal pulmonary embolism and venous thrombosis pharmokinetics after intravenous and subcutaneous by perioperative administration of subcutaneous heparin. administration in human volunteers. Thombolysis New England Journal of Medicine, 318: 1162-1173 Research, 42: 613-620 (1986). (1988). 18. Frydman, A., Bara, L, Le Roux, Y. et al. The anti­ 6. Salzman, E. Low-molecular-weight heparin: is small thrombotic activity and pharmacokinetics of enoxaprine, a beautiful? New England Journal of Medicine, 315: 957- low-molecular-weight heparin, in humans given single 959 (1986). subcutaneous doses of 20 to 80 mg. Journal of Clinical Pharmacology, 28: 609-618 (1988). 7. Verstraete, M. Pharmacotherapeutic aspects of unfractionated and low-molecular-weight heparin. Drugs, 19. Hirsh, J., Levine, M. Low-molecular-weight heparin. 40:498-530 (1990). Blood, 79: 1-17 (1992).

8. Nurmohamed, M., Rosendaal, F., Büller, H. et al. Low- 20. Thomas, D. Low-molecular-weight heparin, New molecular-weight heparin versus standard heparin in England Journal of Medicine, 327: 817-818 (1992). general and orthopaedic surgery: a meta-analysis. Lancet, 340: 152-156 (1992).

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4. Fennerty, A., Dolben, J., Thomas, P. et al. A com­ ....and for how long are parison of 3 and 6 weeks anticoagulation in the treatment anticoagulants really needed? of venous thromboembolism. Clinical and Laboratory Haematology, 9:17-21 (1987). It was first shown over 30 years ago that use of 5. Moser, K. Venous thromboembolism. American anticoagulants can reduce mortality associated with Reviews of Respiratory Disease, 141: 235-277 (1988). thromboembolism (1). Ever since, controversy has persisted over the time for which it is necessary to 6. Fennerty, A., Campbell, I., Routledge, P. Anticoagu­ inhibit coagulation in patients with deep vein lants in venous thromboembolism. British Medical Journal, thrombosis. Various estimates, ranging from 3 297: 1285-1288 (1988). weeks to 6 months, have been proposed on the basis of small prospective, controlled studies (2-5). 7. Editorial. Management of venous thromboembolism. However, a recent meta-analysis of these results Lancet, 1:275-277 (1988). has suggested that rates of recurrence and 8. Research Committee of the British Thoracic Society. haemorrhage are independent of the period of Optimum duration of anticoagulation for deep-vein treatment (6). thrombosis and pulmonary embolism. Lancet, 340: 873- 876 (1992). Only large multicentre prospective studies could resolve this uncertainty (7). The challenge has now been broached in a British trial in which the effects Beta-adrenoreceptor agonists of warfarin therapy continued for either 4 weeks or 12 weeks were compared in a sample of 756 and asthma deaths patients with venous thromboembolism, after initial For several years controversy has persisted over administration of heparin (8). Only some 15% of the the use of beta-adrenoreceptor agonist agents in patients had recently undergone surgery and, asthma. During the mid-1970s these drugs rather among these, the incidence of treatment failure and than corticosteroids were widely advocated for recurrence in both groups was about 2.5%. Among long-term maintenance therapy. However, a the remaining 85% of patients, however, the risk of decade later, a retrospective analysis undertaken in an unsatisfactory outcome was some fivefold New Zealand showed that increased use of beta- greater and the longer period of treatment held adrenoreceptor agonists had been accompanied by clear advantage. a rising trend in the number of deaths attributed to the disease (1). The first of several case-control The paucity of controlled, objective evidence on the studies inspired by this finding (1-5) showed that benefits and risks of anticoagulant therapy is the relative risk of death or near death was greatest surprising. On the basis of this one study it seems among patients using fenoterol (1). However, that 4 weeks of anticoagulation is adequate for further analyses — and a review of the literature (6, patients with acute postoperative venous thrombo­ 7) — revealed the existence of similar associations embolism. Other patients who develop deep vein with use of oral and nebulized salbutamol, high thrombosis or pulmonary embolism, and particularly doses of isoproterenol, theophylline, and oral those in whom no underlying cause or risk factor is corticosteroids (5). identified, should remain on warfarin for at least 3 months. One possible interpretation of these studies is that References patients who are most severely incapacitated make the greatest use of drugs (8-12). Indeed, this is an 1. Barritt, D., Jordan, S. Anticoagulant drugs in the inevitable corollary of orthodox asthma manage­ treatment of pulmonary embolism: a controlled trial. ment protocols (13). The argument is still pro­ Lancer, 1: 1309-1312 (1960). pounded, however, that fenoterol is intrinsically more hazardous than salbutamol and other beta- 2. O'Sullivan, E. Duration of anticoagulant therapy in adrenoreceptor agonists and that it should no venous thromboembolism. Medical Journal of Australia, 2: longer be used (14, 15). 1104-1107 (1972).

3. Holmgreen, Anderson, G., Fagrell, B. et al. 1 month v 6 Whereas basic differences have been described in months therapy with oral anticoagulants after symptomatic the actions of fenoterol and salbutamol at beta- deep vein thrombosis. Acta Medica Scandinavica, 218: adrenergic receptors (16), the epidemiological data 279-284 (1985). are most simply explained by assuming that dosage

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differences alone account for the apparent differ­ 3. Sears, M., Taylor, D., Print, C, et al. Regular inhaled ence in the strength of the association between beta-agonist treatment in bronchial asthma. Lancet, 336: these two beta-adrenoreceptor agonists and death 1391-1396 (1990). from asthma (14, 17, 18). This has motivated the manufacturer of fenoterol to introduce a 100 mcg/ 4. Grainger, J., Woodman, K., Pearce, N., et al. Pre­ dose formulation wherever it was not formerly scribed fenoterol and death from asthma in New Zealand, 1981-1987: a further case-control study. Thorax, 46: 105- available. 111 (1991).

What conclusions can now be drawn from this 5. Spitzer, W., Suissa, S., Emst, P. et al. The use of beta- debate? Advice recently set out in a letter to the agonists and the risk of death and near death from New England Journal of Medicine translates the asthma. New England Journal of Medicine, 326: 501-506 epidemiological knowledge into sound clinical (1992). practice (19). It advises doctors to reassure asthmatic patients that beta agonists are safe and 6. van Metre, T. Adverse effects of inhalation of excessive amounts of nebulized isoproterenol in status asthmaticus. even life-saving in the short term, and that they can Journal of Allergy, 43: 101-113 (1969). be taken during acute attacks. Only when they are used continuously do they apparently pose a risk 7. Trautlein, J., Allegra, J., Field, J., Gillin, M. Paradoxic which is still being investigated. Any patient who bronchospasm after inhalation of isoproterenol. Chest, 70: needs to refill a prescription for a beta- 711-714 (1976). adrenoreceptor agonist aerosol more frequently than every two months should also receive anti­ 8. Garrett, J. Turner, P. The severity of asthma in relation inflammatory treatment with an inhaled corticoste­ to beta agonist prescribing. New Zealand Medical Journal, roid or sodium cromoglicate. 104:39-40 (1991). 9. Rea, H., Mulder, J., Fenwick, J. et al. Prescribing for Patients with newly diagnosed asthma should be asthma and severity markers. New Zealand Medical carefully assessed before primary treatment is Journal, 103: 491 (1990). started. They may be provided with one canister of a beta-adrenoreceptor agonist for use only when 10. Wilson, J. Selective prescribing of fenoterol and symptoms occur or when the peak expiratory flow salbutamol in New Zealand in general practice. Post rate falls below a threshold value. Marketing Surveillance, 5: 105-118 (1991).

Patients already inhaling beta-adrenoreceptor 11. Petri, H., Urquhart, J., Herings, R., Bakker, A. agonists in large quantities should be advised that Characteristics of patients prescribed three different inhalational (β2-agonists: an example of the channeling the habit may aggravate their condition. They phenomenon. Post Marketing Surveillance, 5: 57-66 should be encouraged to reduce their use by (1991). setting the threshold for inhalation at a lower peak expiratory flow rate (some 50% of the best value). 12. Gottlieb, D., Celli, B. Beta-agonists and deaths from Use of inhaled steroids should be adjusted to the asthma. New England Journal of Medicine, 327: 355 lowest maintenance dose that induces an accept­ (1992). able response. Only rarely is it necessary either to prescribe supplementary bronchodilators — such 13. National Asthma Education Program. Guidelines for as ipratropium bromide or theophylline — for daily the diagnosis and management of asthma. Bethesda, MD. use, or to bring patients into hospital to reassure Department of Health and Human Services, (Publication No. 91-3042): 71-86 (1991). them that they can safely stop or reduce the use of beta-adrenoreceptor agonists. 14. Burrows, B., Lebowitz, M. The beta-agonist dilemma. New England Journal of Medicine, 326: 560-561 (1992). References 15. Pearce, N., Crane, J., Burgess, C. et al. Beta agonists 1. Crane, J., Pearce, N., Flatt, A., et al. Prescribed and death from asthma. New England Journal of fenoterol and death from asthma in New Zealand, 1981- Medicine, 327: 355-356 (1992). 1983: case control study. Lancet, 1: 917-922 (1989). 16. Löfdahl, C, Svedmyr, N. Beta agonists — friends or 2. Pearce, N., Grainger, J., Atkinson, M. et al. Case- foes? European Respiratory Journal, 4: 1161-1165 control study of prescribed fenoterol and death from (1991). asthma in New Zealand, 1977-1981. Thorax, 45: 170-175 (1990).

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17. Ernst, P., Suissa, S., Boivin, J. et al. Beta agonists Estimates of the efficacy of these vaccines are and death from asthma. New England Journal of highly dependent upon the case definition for Medicine, 327: 356 (1992). pertussis (8). A protection rate against severe illness of some 95% was recently recorded in the 18. Staudinger, H., Haas, J. Beta agonists and deaths USA among some 300 pre-school children fully from asthma. New England Journal of Medicine, 327: 355 (1992). immunized with whole-cell vaccines who were subsequently exposed to pertussis infection within 19. Woolcock, A., Sears, M., Barnes, P. Beta agonists and their households (20). Re-analysis of some death from asthma. New England Journal of Medicine, apparently disappointing data on the efficacy of two 327:354 (1992). acellular vaccines (21) indicates that a similar degree of protection against severe illness may be conferred by the newer vaccines (22-24). Only Pertussis vaccines: cellular prospective randomized studies can yield reliable and acellular comparative data, and it is doubtful that the results would justify the considerable effort and expense Relatively recent concerns that whole-cell pertussis involved. vaccines used for the past 50 years may have caused occasional cases of encephalopathy, It might be more profitable to search for advanta­ sometimes resulting in permanent neurological geous properties among the newer vaccines (8). damage and death (1, 2), have inspired the There is need for a vaccine that induces longer development of alternative "acellular" vaccines (3). lasting immunity, and for one that is sufficiently immunogenic to offer protection in the first few These products contain various antigenic compo­ months of life (25). Since the adult population nents of Bordetella pertussis including, most remains an important reservoir of infection, there is commonly, pertussis toxin, filamentous also a place for a less reactogenic vaccine that haemagglutinin (an outer membrane protein), and could be used safely to boost immunity in later life other agglutinins. They are less likely to cause the (26). Without tangible incentives, however, and local reactions, fever and febrile convulsions without reasonable expectation of success, there is associated with whole-cell vaccines (3-6). There is little likelihood that the necessary investment of also some evidence that, when administered to time and effort will be dedicated to such ends. older children, they are comparable in efficacy to whole-cell vaccines (9, 10). However, evidence of References their protective efficacy in infants still rests largely 1. Kulenkampff, M., Schwartzman, J., Wilson, J. Neuro­ on studies of immunogenicity and reactivity (6-8). logical complications of pertussis inoculation. Archives of Diseases of Childhood, 49: 46-49 (1974). Studies of their protective efficacy in the primary immunization of younger children are still in 2. Department of Health and Social Security. Report of the progress. However, in Japan, acellular vaccines are Committee on Safety of Medicines and Joint Committee already employed routinely to immunize children on Vaccination and Immunisation. London, (1981). over two years of age, and one product has 3. Edwards, K., Karzon, D. Pertussis vaccines. Pediatric recently been approved in the USA for booster Clinics of North America, 37: 549-566 (1990). doses in children aged 15 months and over (11). 4. Ad Hoc Group for the Study of Pertussis Vaccine. For several reasons this new generation of Placebo-controlled trial of two acellular pertussis vaccines pertussis vaccines requires meticulous assess­ in Sweden: protective efficacy and adverse events. Lancet, 1:955-960 (1988). ment. Firstly, the new products commonly cost at least twice as much as the whole-cell vaccines. 5. Blumberg, D., Mink, C, Cherry, J. et al. Comparison of Secondly, the evidence associating whole-cell an acellular pertussis-component diphtheria-tetanus- pertussis vaccines with severe neurological pertussis (DTP) vaccine with a whole cell pertussis damage is now widely contested (12-19). Indeed, if component DTP vaccine in 17- to 24-month-old children, a risk exists at all, it is so small as to be virtually with measurement of 69-kilodalton outer membrane unmeasurable (8). Thirdly, although no direct protein antibody. Journal of Pediatrics, 117: 46-51 (1990). comparisons of efficacy have yet been made, it is 6. Edwards, K., Lawrence, E., Wright, P. Diphtheria, possible that the more reactogenic whole-cell tetanus and pertussis vaccine: a comparison of the vaccines may offer greater protection against immune response and adverse reactions to conventional severe illness than the newer products. and acellular pertussis components. American Journal of Diseases of Children, 140: 867-871 (1986).

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7. Blumberg, D., Mink, C, Cherry, J., et al. Comparison of 20. Onorato, I., Wassilac, S., Meade, B. Efficacy of whole acellular and whole-cell pertussis-component diphtheria- cell pertussis vaccine in preschool children in the United tetanus-pertussis vaccines in infants. Journal of Pediat¬ States. Journal of the American Medical Association, 267: rics, 119: 194-204 (1991). 2745-2749 (1992).

8. Shapiro, E. Pertussis vaccines: seeking a better 21. Ad Hoc Group for the Study of Pertussis Vaccines. mousetrap. Journal of the American Medical Association, Placebo controlled trial of two acellular pertussis vaccines 267: 2788-2790 (1992). in Sweden: protective efficacy and adverse events. Lancet, 1:955-960 (1988). 9. Kato, T., Goshima, T., Nakajima, N. et al. Protection against pertussis by acellular pertussis vaccines (Takeda, 22. Olin, P., Storsaeter, J., Romanus, V. The efficacy of Japan): household contact studies in Kawasaki City, acellular pertussis vaccine. Journal of the American Japan. Acta Paediatrica Japan, 31: 698-701 (1989). Medical Association, 261: 560 (1989).

10. Mortimore, E., Kimura, M., Cherry, J. et al. Protective 23. Storsaeter, J., Hallander, H., Farrington, C. et al. efficacy of the Takeda acellular pertussis vaccine Secondary analyses of the efficacy of two acellular combined with diphtheria and tetanus toxoids following pertussis vaccines in a Swedish phase III trial. Vaccine, 8: household exposure of Japanese children. American 457-461 (1990). Journal of Diseases of Children, 144: 899-904 (1990). 24. Blackwelder, W., Storsaeter, J., Olin, P., Hallander, H. 11. Immunization Practices Advisory Committee. Acellular pertussis vaccine: efficacy and evaluation of Pertussis vaccination: acellular pertussis vaccine for clinical case definitions. American Journal of Diseases of reinforcing and booster dose use — supplementary ACIP Children, 145: 1285-1289 (1991). statement. Morbidity and Mortality Weekly Report, 41:1- 10 (1992). 25. van Savage, J., Decker, M., Edwards, K. et al. Natural history of pertussis antibody in the infant and effect on 12. Cherry, J., Brunell, P., Golden, G., Karzon, D. Report vaccine response. Journal of infectious Diseases. 161: of the task force on pertussis and pertussis immunization 487-492 (1990). — 1988. Pediatrics, 81 (suppl): 933-984 (1988). 26. Mortimer, E. Pertussis and its prevention: a family 13. Griffith, A. Permanent brain damage and pertussis affair. Journal of Infectious Diseases, 161: 473-479 vaccination: is the end of the saga in sight? Vaccine, 7: (1990). 199-210 (1989). 14. Fulginiti, V. A pertussis vaccine myth dies. American Thiazide therapy: who needs Journal of Diseases of Children, 144: 860-861 (1990). potassium supplements? 15. Golden, G. Pertussis vaccine and injury to the brain. Journal of Pediatrics, 116: 854-861 (1990). After 30 years of use, thiazide diuretics still provide an appropriate point of departure for most patients 16. Griffin, M., Ray, W., Mortimor, E. et al. Risk of in a stepped programme of antihypertensive seizures and encephalopathy after immunization with the therapy (1). In 1985, however, demonstration within diphtheria-tetanus-pertussis vaccine. Journal of the a large multicentre study of an apparent association American Medical Association, 263: 1641-1645 (1990). between use of thiazides and an increased inci­ dence of sudden death, raised concerns about the 17. Child Neurology Society. Ad hoc Committee for the Child Neurology Society: consensus statement on propensity of these drugs to induce dangerous pertussis immunization and the central nervous system. electrolyte disturbances (2). Annals of Neurology, 29: 458-460 (1991). It is usually assumed that thiazides predispose to 18. Wentz, K., Marcuse, E. Diphtheria-tetanus-pertussis ventricular arrhythmias by reducing serum potas­ vaccine and serious neurologic illness: an updated review sium concentrations (3-6), but the evidence of the epidemiologic evidence. Pediatrics, 87: 287-297 supporting this hypothesis is equivocal. Some (1991). studies have demonstrated a correlation (3, 7-9), 19. Howson, C, Fineberg, H. Adverse effects following while others have not (10-12). In these circum­ pertussis and rubella vaccines: summary of a report of the stances other risk factors, including decreased Institute of Medicine. Journal of the American Medical serum magnesium concentrations (3-5) and Association, 267: 392-396 (1992). decreased intracellular concentrations of both potassium and magnesium (8) have been pro­ posed.

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Economic as well as therapeutic advantage is to be 2. Multiple Risk Factor Intervention Trial Research Group. gained from characterizing which patients are at Baseline rest electrocardiographic abnormalities, antihypertensive treatment, and mortality in the Multiple risk and the nature of their underlying electrolyte Risk Factor Intervention Trial. American Journal of disturbance. Some doctors prescribe a potassium Cardiology. 55:1-15 (1985). supplement or a potassium-sparing diuretic only for patients who become distinctly hypokalemic. Even 3. Hollifield, J. Potassium and magnesium abnormalities: though the cost of these supplementary medicines diuretics and arrhythmias in hypertension. American can exceed that of the primary therapy, many Journal of Medicine, 77: 28-32 (1984). others prescribe them routinely for every hypertensive patient receiving a thiazide diuretic 4. Hollifield, J. Electrolyte disarray and cardiovascular (11-14). disease. American Journal of Cardiology, 63: 21B-26B (1989).

A prospective comparative trial has recently been 5. Martin, B., Milligan, K. Diuretic associated hypo¬ completed which offers an objective basis for magnesemia in the elderly. Archives of Internal Medicine, assessing the need for electrolyte supplements 147:1768-1771 (1987). (15). Concentrations of potassium and magnesium were monitored both in plasma and cells of more 6. Schapner, H., Freis, E., Friedman, R. et al. Potassium than 200 hypertensive patients with abnormalities restoration in hypertensive patients made hypokalemic by of the electrocardiogram. All were treated with hydrochlorothiazide. Archives of Internal Medicine, 149: hydrochlorothiazide 50 mg daily, and each was 2677-2681 (1989). assigned at random to receive placebo or supple­ 7. Hollifield, J., Slaton, P. Thiazide diuretics, hypokalemia ments of either potassium 40 mmol/day, potassium and cardiac arrhythmias. Acta Medica Scandinavica, 40 mmol/day and magnesium 400 mg/day, or 647 (suppl): 67-73 (1981). triamterene 100 mg/day. 8. Abraham, A., Rosenman, D., Meshulam, D. et al. After 2 months of hydrochlorothiazide therapy, Serum, lymphocyte, and erythrocyte potassium, mag­ there was no significant change in mean intra­ nesium, and calcium concentrations and their relation to cellular potassium and magnesium concentrations tachyarrhythmias in patients with acute myocardial within mononuclear cells. Mean serum potassium infarction. American Journal of Medicine, 81: 983-988 concentrations had fallen, on average, in similar (1986). degree in all the treatment groups. However, serum 9. Cohen, J., Neaton, J., Prineas, R., Daniels, K. Diuretics, potassium concentrations fell below 3.0 mmol/l only serum potassium and ventricular arrhythmias in the among 6 of 60 patients who received no potassium Multiple Risk Factor Intervention Trial. American Journal supplement and, of these, 5 had a high frequency of Cardiology, 60: 548-554 (1987). of ventricular ectopic activity. Several previous studies have similarly suggested that ventricular 10. Papademietriou, V., Fletcher, R., Khatri, I., Preis, E. arrhythmias are liable to occur below this threshold Diuretic-induced hypokalemia in uncomplicated systemic serum potassium concentration (3, 12, 16). More hypertension: effect of plasma potassium correction on prolonged thiazide therapy or use of higher daily cardiac arrhythmias. American Journal of Cardiology, 52: doses may, of course, induce hypokalaemia in a 1017-1022 (1983). higher proportion of patients. The authors of this study remain confident, however, that careful 11. Papademietriou, V., Price, M., Notargiacomo, A. et al. Effect of diuretic therapy on ventricular arrhythmias in monitoring of serum potassium concentrations, hypertensive patients with or without left ventricular particularly during the first few months of diuretic hypertrophy. American Heart Journal, 110: 595-599 therapy, with a view to treating the minority of (1985). patients who become hypokalaemic, is a less expensive therapeutic option than routine prescrib­ 12. Papademietriou, V., Burris, J., Notargiacomo, A. et al. ing of potassium supplements. Thiazide therapy is not a cause of arrhythmia in patients with systemic hypertension. Archives of Internal Medicine. 148: 1272-1276 (1988). References 13. Poole-Wilson, P. Diuretics, hypokalemias and 1. Joint National Committee on Detection, Evaluation, and arrhythmias in hypertensive patients: still an unresolved Treatment of High Blood Pressure. The 1988 Report. problem. Journal of Hypertension, 5 (suppl 3): S51-S55 Archives of Internal Medicine, 148: 1023-1038 (1988). (1987).

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14. Kaplan, N. How bad are diuretic-induced hypokalemia heart block, or in the proportion of patients to and hypercholesterolemia? Archives of Internal Medicine, receive antiarrhythmic drugs, direct current 149:2649 (1989). cardioversion, or temporary pacing. Nor was there 15. Siegel, D., Hulley, S., Black, D. et al. Diuretics, serum any indication that either of the outcomes was and intracellular electrolyte levels, and ventricular influenced by administration of thrombolytic agents arrhythmias in hypertensive men. Journal of the American or acetylsalicylic acid, or by previous treatment with Medical Association, 267: 1083-1089 (1992). beta adrenergic blocking agents, calcium antago­ nists, or diuretics. 16. Holland, O., Nixon, J., Kuhnert, L. Diuretic-induced ventricular ectopic activity. American Journal of Medicine, The authors conclude that magnesium is most likely 70:762-768 (1981). to have a direct protective action on the myocar­ dium, but they accept that several of the subgroup analyses are of low statistical power. Further information on the regimen used in this trial will Magnesium and acute cardiac shortly become available with the completion of infarction another large prospective study (20) and data on the long-term outcome of patients admitted to the Several small prospective clinical studies have recently published study are still being collected. suggested that intravenous infusion of magnesium salts reduces mortality in acute myocardial It is highly unlikely, when these results become infarction, but none has had sufficient statistical available, that they will fundamentally modify the power to be conclusive (1-4). The effect appears to advice that the authors of this paper now offer: result from a pharmacological action of magnesium "Magnesium infusion is a simple and safe treatment salts rather than correction of a deficit (5). Magne­ which can be generally used for suspected acute sium might simply act physiologically in these myocardial infarction. The point estimate of benefit circumstances as a calcium channel blocking agent is a reduction over the first 4 weeks of about 25 (5); it might dilate the coronary arteries (6, 7), or deaths per 1000 patients treated. No contra­ exert an antiarrhythmic (8-12) or antiplatelet action indications have been identified, though in the (13, 14), or it might directly protect the myocardium presence of moderate to severe renal failure, (15-17). adjustment of the maintenance infusion will be necessary to avoid accumulation of magnesium". Pooled analysis of the results of these trials (1-4, 8-10) has suggested that infusion of magnesium References sufficient to raise serum concentrations by 30- 1. Smith, L. Heagerty, A., Bing, R., Barnett, D. Intravenous 100% may halve the risk of death when adminis­ infusion of magnesium sulphate after acute myocardial tered early after onset of infarction (18). However, infarction: effects on arrhythmias and mortality. Interna• the confidence interval is wide, while timing and tional Journal of Cardiology, 12: 175-180 (1986). dosage varied widely (30-90 mmol of magnesium sulfate or chloride given over 24-48 hours). 2. Rasmussen, H., Suenson, M., McNair, P. Magnesium infusion reduces the incidence of arrythmia in acute myo­ cardial infartion. A double-blind placebo-controlled study. Since these results were published a large, Clinical Cardiology, 10: 251 -256 (1987). randomized, double-blind placebo-controlled study involving 2316 patients with suspected myocardial 3. Shechter, M., Hod, H., Marks, N. et al. Beneficial effect infaction who were admitted to the coronary care of magnesium sulfate in acute myocardial infarction. unit of a large regional hospital in the United American Journal of Cardiology, 66: 271 -274 (1990). Kingdom has been completed (19). On admission each patient received either intravenous mag­ 4. Woods, K., Fletcher, S., Smith, L. Intravenous nesium sulfate (8 mmol over 5 minutes followed by magnesium in suspected acute myocardial infarction. 65 mmol over 24 hours) or physiological saline. At British Medical Journal, 304: 119 (1992). 28 days both expected mortality and left ventricular failure had been reduced by about 25% among the 5. Woods, K. Possible pharmacological actions of magnesium in acute myocardial infarction. British Journal patients who had received magnesium (95% of Clinical Pharmacology, 32: 3-10 (1991). confidence intervals: 1-43%, and 7-39%, respec­ tively). 7.8% of patients receiving magnesium and 6. Kimura, T., Yasue, H., Sakaino, N. et al. Effects of 10.3% of those receiving placebo had died. The two magnesium on the tone of isolated human coronary groups did not differ significantly in the incidence of arteries. Circulation, 79:1118-1124 (1989).

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7. Vigorito, C, Giordano, A., Ferraro, P. et al. Hemody­ 14. Adams, J., Mitchell, J. The effect of agents which namic effects of magnesium sulfate on the normal human modify platelet behaviour and of magnesium ions on heart. American Journal of Cardiology, 67: 1435-1437 thrombus formation in vivo. Thrombosis and Haemostasis, (1991). 42:603-610 (1979).

8. Abraham, A., Rosenmann, D., Kramer, M. et al. 15. Hearse, D., Stewart, D., Braimbridge, M. Myocardial Magnesium in the prevention of lethal arrythmias in acute protection during ischaemic cardiac arrest: the importance myocardial infarction. Archives of Internal Medicine, 147: of magnesium in cardioplegic solutions. Journal of 753-755 (1987). Thoracic and Cardiovascular Surgery, 75: 877-885 (1978).

9. Rasmussen, H., Gronbaek, M., Cintin, C. et al. One- 16. Ferrari, R., Albertini, A., Curello, S. et al. Myocardial year death rate in 270 patients with suspected acute recovery during post-ischaemic reperfusion: effects of myocardial infarction, initially treated with intravenous nifedipine, calcium and magnesium. Journal of Molecular magnesium or placebo. Clinical Cardiology, 11: 377-381 and Cellular Cardiology, 18: 487-498 (1986). (1988). 17. Borchgrevink, P., Bergan A., Bakoy, O., Jynge, P. 10. Kulick, D., Hong, R., Ryzen, E. et al. Electrophysio­ Magnesium and reperfusion of ischemic rat heart as logical effects of intravenous magnesium in patients with assessed by 31P-NMR. American Journal of Physiology, normal conduction systems and no clinical evidence of 256: H195-204 (1989). significant cardiac disease. American Heart Journal, 115: 367-373 (1988). 18. Teo, K., Yusuf, S., Collins, R., Held, P., Peto, R. Effects of intravenous magnesium in suspected acute 11. Ceremuzynski, L, Jurgiel, R., Kulakowski, P., myocardial infarction: overview of randomized trials. Gebalska, J. Threatening arrhythmias in acute myocardial British Medical Journal, 303:1499-1503 (1991). infarction are prevented by intravenous magnesium sulphate. American Heart Journal, 118: 1333-1334 (1989) 19. Woods, K., Fletcher, S., Roffe, C, Haider, Y. Intravenous magnesium sulphate in suspected acute 12. Rogiers, P., Vermeier, W., Kesteloot, H., Stroobandt, myocardial infarction: results of the second Leicester R. Effect of the infusion of magnesium sulfate during atrial Intravenous Magnesium Intervention Trial (LIMIT-2). pacing on ECG intervals, serum electrolytes and blood Lancet, 339: 1553-1558 (1992). pressure. American Heart Journal, 117:1278-1283 (1989). 20. Editorial. Magnesium for acute myocardial infarction? 13. Watson, K., Moldow, C, Ogbum, P., Jacob, S. Lancet, 338: 667-668 (1991). Magnesium sulfate: rationale for its use in pre-eclampsia. Proceedings of the National Academy of Sciences of the USA, 83: 1075-1078 (1986).

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General Information

5. Wallace, M., Yousif, A, Spread of multiresistant More reports of multiresistant Salmonella typhi. Lancet, 336: 1065-1066 (1990). Salmonella typhi 6. Eykyn, S., Williams, H. Treatment of multiresistant Chloramphenicol still remains the most effective Salmonella typhi with oral ciprofloxacin. Lancet, 2: 1407- drug for treating typhoid fever in many parts of the 1408 (1987). world but reports from several countries indicate 7. Soe, G., Overturf, G. Treatment of typhoid fever and that multiresistant forms of Salmonella typhi are other systemic salmonelloses with cefotaxime, ceftri­ spreading from their apparent foci of origin in the axone, cefoperazone and other newer cephalosporins. Indian subcontinent. Plasmid-mediated resistance Reviews of Infectious Diseases, 9: 719-736 (1987). to a wide range of antibiotics including chloram­ phenicol, ampicillin, trimethoprim and sulfa­ methoxazole has now been recorded in North America (1-3), Europe (4), and the eastern Anti-inflammatory drugs: new Mediterranean region (5). Most of these accounts insights into adverse refer to the detection of carriers exclusively among travellers and expatriates, but the most recent — gastrointestinal effects from Ontario, Canada — describes the isolation of It is now beyond reasonable dispute that use of multiresistant strains not only from travellers nonsteroidal anti-inflammatory drugs is associated returning from India and Bangladesh but from their with an increased risk of gastric ulceration. The contacts within Canada (3). evidence derives from both epidemiologic and endoscopic investigations (1), and from prospective Plasmids coding for resistance to the widely used as well as retrospective studies (2-8). Acute gastric antityphoid drugs, chloramphenicol, ampicillin, and erosions may occur within weeks of starting trimethoprim/sulfamethoxazole pose a formidable treatment (5) and there is evidence of a dose- therapeutic challenge. Each of the isolates obtained related risk (7). in Canada was susceptible to the fluoroquinolones — norfloxacin and ciprofloxacin — and to the third Less has been published about possible adverse generation cefalosporins, cefalothin, cefmandole, effects of these drugs on the small intestinal cefotaxime, and cefoxitin. The potential of fluoro­ mucosa. However, not only have ulceration and quinolones to disturb growth of cartilage in experi­ perforation been associated with several com­ mental animals still excludes their use in children pounds (8-12), but reports of diffuse inflammatory (6). In these circumstances third-generation changes (13, 14) and increased mucosal perme­ cefalosporins offer the only secure option (7). ability among patients on long-term nonsteroidal anti-inflammatory drug therapy (15-17) have References suggested that enteropathy resulting in weight loss 1. Grant, R., DiMambro, L. Antimicrobial resistance and and iron deficiency anaemia (18, 19) may well be a resistance plasmids in Salmonella from Ontario, Canada. common complication of treatment. Indeed, Canadian Journal of Microbiology, 23: 1266-1273 (1977). inflammatory changes identified both by leukocytic infiltration of the ileum (13) and enteroscopic 2. Tauxe, R., Puhr, N., Wells, J. et al. Antimicrobial examination (20) have been estimated to occur in resistance of Salmonella isolates in the USA: the some two-thirds of all patients on long-term importance of international travellers. Journal of Infectious therapy. Diseases, 162: 1107-1111 (1990).

3. Hamett, N., McLeod, S., AuYong, Y. et al. Emergence A lower, but none the less highly significant in Ontario, Canada, of multiresistant Salmonella typhi from incidence of intestinal ulceration has recently been south Asia. Lancet, 340: 177 (1992). recorded at autopsy among patients receiving these drugs (21). Three of the patients in this series had 4. Rowe, B., Ward, L, Threllfall, E. Spread of died of peritonitis from perforated "nonspecific small multiresistant Salmonella typhi. Lancet, 336:1065-1066 intestinal ulcers". The authors propose that non- (1990).

160 WHO Drug Information Vol. 6, No. 4, 1992 General Information

steroidal anti-inflammatory drugs may be respon­ 13. Bjamason, I., Zanelli, G., Smith, T. et al. Nonsteroidal sible for a large proportion of hitherto unexplained antiinflammatory drug-induced intestinal inflammation in humans. Gastroenterology, 93:480-489 (1987). ulcers of the small intestine. 14. Bjamason, I., Zanelli, G., Prouse, P. et al. Blood and References protein loss via small-intestinal inflammation induced by non-steroidal anti-inflammatory drugs. Lancet, 2: 711-714 1. Soll, A. Nonsteroidal anti-inflammatory drugs and peptic (1987). ulcer disease. Annals of Internal Medicine, 114: 307-319 (1992). 15. Bjamason, I., Williams, P., So, A. et al. Intestinal permeability and inflammation in rheumatoid arthritis: 2. Langman, M., Morgan, L, Worrall, A. Use of anti­ effects of non-steroidal anti-inflammatory drugs. Lancet, 1: inflammatory drugs by patients admitted with small or 1171-1174 (1984). large bowel perforations and haemorrhage. British Medical Journal, 290: 347-349 (1985). 16. Bjamason, I., Williams, P., Smethurst, P. et al. Effect of non-steroidal anti-inflammatory drugs and prostaglan­ 3. Somerville, K., Faulkner, G., Langman, M. Non­ dins on the permeability of the human small intestine. Gut, steroidal anti-inflammatory drugs and bleeding peptic 27: 1292-1297 (1986). ulcer. Lancet, 1: 462-464 (1986). 17. Jenkins, R., Rooney, P., Jones, D. et al. Increased 4. Armstrong, C, Blower, A. Non-steroidal anti-inflamma­ intestinal permeability in patients with rheumatoid arthritis: tory drugs and life-threatening complications of peptic a side effect of oral nonsteroidal anti-inflammatory drug ulceration. Gut, 28: 527-532 (1987). therapy? British Journal of Rheumatology, 26: 103-107 (1987). 5. Graham, D., Agrawal, N., Roth, S. Prevention of NSAID-induced gastric ulcer with misoprostol: multicentre, 18. Collins, A., du Toit, J. Upper gastrointestinal findings double-blind, placebo-controlled trial, Lancet, 2:1277- and faecal occult blood in patients with rheumatic 1280 (1988). diseases taking nonsteroidal anti-inflammatory drugs. British Journal of Rheumatology, 26: 295-298 (1987). 6. Beardon, P., Brown, S., McDevitt, D. Gastrointestinal events in patients prescribed non-steroidal anti-inflamma­ 19. Upadhyay, R., Torley, H., McKinlay, A. et al. Iron tory drugs: a controlled study using record linkage in deficiency anaemia in patients with rheumatic disease Tayside. Quarterly Journal of Medicine, 71: 497-505 receiving non-steroidal anti-inflammatory drugs: the role of (1989). upper gastrointestinal lesions. Annals of Rheumatic Diseases. 49: 359-362 (1990). 7. Griffin, M., Piper, J., Daugherty, J. et al. Nonsteroidal anti-inflammatory drug use and increased risk for peptic 20. Morris, A., Madhok, R., Sturrock, R. et al. ulcer disease in elderly persons. Annals of Internal Enteroscopic diagnosis of small bowel ulceration in Medicine, 114: 257-263 (1991). patients receiving non-steroidal anti-inflammatory drugs. Lancet, 337:520 (1991). 8. Holvoet, J., Terriere, L, van Hee, W. et al. Relation of upper gastrointestinal bleeding to non-steroidal anti­ inflammatory drugs and aspirin: a case-control study. Gut, 21. Allison, M., Howatson, A., Torrance, C. et al. Gastro­ 32:730-734 (1991). intestinal damage associated with the use of nonsteroidal antiinflammatory drugs. New England Journal of Medicine, 9. Day, T. Intestinal perforation associated with osmotic 327: 749-754 (1992). slow-release indomethacin capsules. British Medical Journal, 287: 1671-1672 (1983). Immunity, vitamins and trace 10. Madhoc, R., MacKenzie, J., Lee, F. et al. Small bowel elements ulceration in patients receiving non-steroidal anti­ inflammatory drugs for rheumatoid arthritis. Quarterly The importance of correcting vitamin A deficiency Journal of Medicine, 58: 53-58 (1986). among children in developing countries as a defence against potentially lethal acute infections 11. Deakin, M. Small bowel perforation associated with an has been decisively confirmed in recent years. In a excessive dose of slow-release diclofenac sodium. British Medical Journal, 297: 488-489 (1988). broader context, nutritional status has long been recognized as an important determinant of immune 12. Saw, K., Quick, C, Higgins, A. Ileocaecal perforation competence. Protein-energy malnutrition impairs and bleeding — are non-steroidal anti-inflammmatory several aspects of cell-mediated immunity (1), and drugs (NSAIDs) responsible? Journal of the Royal Society various studies have been undertaken to show that of Medicine, 83: 114-115 (1990). restoration of specific vitamins and trace elements

161 General Information WHO Drug Information Vol. 6, No. 4, 1992

to physiological levels may ameliorate specific study merits confirmation, not least because of the deficiencies in the immune response (2-6). Until unexpectedly high incidence of intercurrent recently, however, no formal comparative study had infections among the control subjects. Should this been conducted to explore whether correction of be done, the addition of a third group in whom these nutritional deficits confers tangible clinical micronutrient deficiencies are corrected by dietary benefit. adjustment alone would add an instructive addi­ tional dimension to the study. The clinical correlates of improved micronutrient status have now been investigated within a group of References some 100 independent, apparently healthy, elderly Canadian volunteers who received at random either 1. Chandra, R.K. 1990 McCollum Award Lecture. Nutrition placebo or a daily oral dietary supplement contain­ and immunity: lessons from the past and new insights into ing: vitamin A 400 retinol equivalents, beta- the future. American Journal of Clinical Nutrition, 53: carotene 16 mg, thiamine 2.2 mg, riboflavin 1.5 mg, 1087-1102 (1991). nicotinic acid 16 mg, pyridoxime hydrochloride 3.0 mg, folate 400 µg, cyanocobolamin 4.0 µg, ascorbic 2. Penn, N., Purkins, L, Kelleher, J. et al. The effect of acid 80 mg, colecalciferol 4 mg, vitamin E 44 mg, dietary supplementation with vitamins A, C and E on cell- mediated immunity function in elderly long-stay patients: a iron 16 mg, zinc 14 mg, copper 1.4 mg, selenium randomized controlled trial. Age and Aging, 20: 169-174 20 µg, iodine 0.2 mg, calcium 200 mg, and magne­ (1991). sium 100 mg (7). 3. Duchateau, J., Delepesse, G., Vrijens, R., Collet, H. On average, subjects receiving dietary supplements Beneficial effects of oral zinc supplementation on the for 1 year had taken antibiotics for half the number immune response of old people. American Journal of of days as those receiving placebo. These differ­ Medicine, 70: 1001-1004 (1981). ences were highly significant (mean [SD]: 23 [5] vs 48 [7] days per year). Subjects who had received 4. Meydani, S., Barklund, M., Liu, S. et al. Vitamin E supplementation enhances cell-mediated immunity in supplements were also reported to have signifi­ healthy elderly subjects. American Journal of Clinical cantly higher numbers of certain T-cell subsets and Nutrition, 52: 557-563 (1990). natural killer cells, higher antibody responses, enhanced proliferation response to mitogen, and 5. Payette, H., Rola-Pleszcynski, M., Ghandirian, P. increased interleukin-2 production. The improve­ Nutritional factors in relation to cellular regulatory immune ment in these immunological responses was most variables in a free-living elderly population. American evident among subjects who were shown to be Journal of Clinical Nutrition, 52: 927-932 (1990). deficient initially in one or more micronutrients and who responded well to supplementation. 6. Chavance, M., Hebeth, B., Foumier, C. et al. Vitamin status, immunity and infection in an elderly population. European Journal of Clinical Nutrition, 43: 827-835 With the exception of vitamin E and betacarotene, (1989). which were included at somewhat higher doses, the supplements did not exceed recommended dietary 7. Chandra, R. Effect of vitamin and trace-element allowances. In these amounts they could readily supplementation on immune responses and infection in have been provided in a normal balanced diet. The elderly subjects. Lancet, 340: 1124-1127 (1992).

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Regulatory Matters

Stereoisomerism and drug range (as is the case with thalidomide, levamisole and carnitine). development The US Food and Drug Administration has con­ Many synthetically manufactured compounds exist cluded that few untoward consequences have in different stereometric forms (or enantiomers) — resulted from the widespread use of racemates in molecules that are identical in atomic constitution pharmaceutical preparations. None the less, and bonding but that differ in the spatial arrange­ because many single enantiomers can now be ment of their atoms around one or more asymmet­ produced on a commercial scale either by asym­ ric (or chiral) centres. metric syntheses or chiral separation procedures, the agency is inviting comments on a policy Geometric (or cis/trans) isomers and diastereo- statement concerned with the development of new isomers (isomers of compounds with more than one stereoisomeric drugs. This sets out the case for chiral centre that are not mirror images of one characterizing and studying the chemical and another) are both chemically and pharmacologically biological properties of the individual enantiomers distinct. They are also, in general, readily separable of racemic mixtures early in the process of product and they are treated as different compounds in development in order to provide a basis for select­ pharmaceutical development programmes. ing either the mixture or one of its components for further investigation. Implementation of such a Mirror image enantiomers, in contrast, differ policy would have potential impact on virtually every physically only in their optical rotatory properties aspect of the drug development programme. New and, except in a biological system (or chiral requirements would range from the need to devise environment) in which only one of the enantiomers techniques to identify and quantify all enantiomers is recognized, they are chemically identical. Until early in the development process, to an obligation recently, it was impracticable to separate optical to assure and monitor the stereoisomeric composi­ enantiomers on a commercial scale. Such com­ tion of the finished product throughout its shelf-life. pounds were consequently generally developed for therapeutic use as 1:1 racemates without studying The FDA does not address the budgetary implica­ or characterizing the properties of each enantiomer, tions of the policy. Its scientific rigour cannot be even though it was recognized that the two com­ denied, but a searching cost-benefit analysis of its ponents might have different pharmacokinetic implementation, no matter how speculative, would properties and qualitatively or quantitatively lend realistic perspective to the plans. different pharmacological or toxicological effects. Source: FDA's Policy Statement for the Development of In those instances in which the two components of New Stereoisomeric Drugs. Available from: CDER a racemate have been studied separately, differ­ Executive Secretariat Staff, Center for Drug Evaluation ences in pharmacokinetic properties have frequently and Research (HFD-8), Food and Drug Administration, been found. In general, these are unlikely to have 5600 Fishers Lane, Rockville, MD 20857, USA. therapeutic implication, but they inevitably create uncertainty about the interpretation of blood level assays that fail to distinguish between the two More on paediatric prescribing in components. Differences in therapeutic effects are unpredictable. Sometimes they are negligible; new product labelling sometimes one of the enantiomers is biologically United States of America — It has become almost inactive (as is the case with propranolol); some­ a norm for the data sheet supplied with a newly- times the two have different pharmacological introduced drug containing a new molecular entity properties (d-sotalol is antidysrhythmic, while I- to state that safety and efficacy in children has not sotalol is a beta-adrenergic blocking agent); and, been established. One survey conducted by the most importantly in a clinical context, one enanti­ American Academy of Pediatrics in 1990 estimated omer may be toxic within the therapeutic dosage that 80% of such drugs introduced in the USA

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between 1984 and 1989 were unaccompanied by zation provides good protection against the any information on paediatric use. disease, but it sometimes induces a transient meningoencephalitic reaction (1-3). Many of these new products are of potential value in paediatric practice. Too often, none the less, the Within the United Kingdom, combined measles, manufacturer is deterred from investigating this mumps, rubella vaccines were introduced in 1988, potential by assuming that indications for paediatric and the most widely used have contained the use must be based on separate well-controlled Urabe AM9 strain of mumps virus — Pluserix- randomized studies in children. Inevitably, accord­ MMR® (SmithKline Beecham) and Immrava® ing to the Food and Drug Administration, most (Pasteur-Merieux). Less widely used was a product doctors are reticent to prescribe newly released containing the Jeryl Lynn strain of virus — MMR II® drugs for children, and those that do are likely to (Merck, Sharpe and Dohme). Cases of meningo­ use them inappropriately. encephalitis associated with vaccination had generally been assumed to occur in Britain with an The FDA, in clarifying related policy, has empha­ incidence of about 1: 4 million doses (4). However, sized that it is prepared to waive the requirement much higher incidences had been reported from for rigorously controlled clinical studies in children Japan (5, 6), and a detailed survey recently when other data can satisfy regulatory require­ undertaken by one area health authority in the UK ments. Data from pharmacokinetic studies in that involved laboratory confirmation of cases has children will often be needed to determine appropri­ recently indicated that the incidence of vaccine- ate paediatric dosage. But in some cases extrapo­ induced meningitis is far higher with Urabe than lation based on soundly designed studies in adults with Jeryl Lynn strains, and may approach 1: 4000 may suffice provided there are no grounds — doses (7). having regard to pharmacodynamic studies, safety reports and premarketing or postmarketing studies The latter estimate is based on detection of mumps — for believing that the product may perform in a virus and lymphocytosis in samples of cerebro­ different manner in children. spinal fluid obtained from 8 children who developed signs of meningoencephalitis 17 to 21 days after The FDA routinely reviews novel new-drug applica­ immunization. Admission to hospital was consid­ tions with a view to determining whether studies in ered to be warranted in each case, but none of the children need to be conducted before marketing children was severely ill and, as yet, no long-term approval, whether they can reasonably be deferred sequelae have been reported. Eighty per cent of to the postmarketing period, or whether they need 22 817 children immunized during the period under to be conducted at all. It now proposes to amend review received the Urabe strain, and viruses labelling regulations to require inclusion of state­ resembling this strain were demonstrated within ments about specific identified risks to children each of 5 isolates that were typed. A retrospective supplemented, when necessary, by specific survey of all cases of lymphocytic meningitis warnings against use by children, advice regarding admitted to hospital within the region over the unsafe dosages, and unsafe methods of adminis­ previous 3 years has since confirmed the existence tration. of a strong association with immunization with the Urabe strain 17 to 34 days previously. Source: Food and Drug Administration. Talk Paper, T92- 48, October 30 1992. In the light of these findings, the UK Department of Health decided to withdraw from use combined vaccines containing the Urabe strain of virus with Mumps vaccines and immediate effect. In an open letter to British doctors (8) it has explained that "the risk benefit ratio meningoencephalitis remains strongly in favour of immunization of all Meningoencephalitis complicates about one in 400 children with any MMR vaccine. However, MMR II cases of natural mumps infections. It is sometimes is preferred where this is available because of the severe, it occasionally results in permanent much lower risk of vaccine-associated meningitis". neurological sequelae, and it is associated with an It is understood that no action has been taken to estimated mortality of 1.6 per 10 000 cases. withdraw the licence of any vaccine containing Vaccines containing attenuated strains of mumps attenuated mumps virus currently available within virus have been available for many years. Immuni­ the UK.

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The reaction of national authorities in Europe to the 7. Colville, A., Pugh, S. Mumps meningitis and measles, UK decision has been varied. Whereas some have mumps, and rubella vaccine. Lancet, 340: 786 (1992). withdrawn vaccines containing the Urabe strain, others continue to use these products in their 8. Caiman, K. Open letter to all doctors in England: immunization programmes. It is understood that changes in supply of vaccine. Department of Health, 14 September 1992. SmithKline Beecham will maintain supplies of these vaccines in order to assure maintenance of vaccination programmes when no other supplies are available. Non-sedating antihistamines and cardiac arrhythmias Already, shortages of products containing the Jeryl Lynn strains of virus have been reported from the United States of America — The manufacturers of UK, even though Merck Sharpe and Dohme has two non-sedating antihistamines, terfenadine increased production of MMR II from 20 000 to 100 (Seldane®, Marion Merrell Dow) and astemizole 000 doses per week. MMR vaccine is also manu­ (Hismanal®, Janssen) have included new warnings factured in Switzerland by the Swiss Serum and in the labelling for these products to indicate that Vaccine Institute which uses the Rubini strain, and electrocardiographic changes, including prolonga­ by manufacturers in Japan which use the Hoshino tion of the QT interval, cardiac arrest, torsades de or Torii strains, both of which are claimed to be pointes and other ventricular arrhythmias may similar to the Urabe strain. It is unlikely, however, occur when the maximum recommended drug that these manufacturers will be able to meet plasma concentrations are exceeded (1). A warning increased demand for supplies. to this effect was first included in the labelling for terfenadine in August 1990. It has now been It is important that the data generated within the UK strengthened because further adverse reactions should in no circumstances be interpreted as have been reported and because drug interaction justifying the suspension of existing immunization studies have provided additional relevant informa­ programmes. The incidence and severity of tion. meningitis following natural infection greatly exceeds that associated with any protective vaccine Doctors are advised to caution patients that they currently known to be available in international should not exceed the recommended dose for commerce. terfenadine of 60 mg twice daily, and to ensure that they do not prescribe this drug for patients who References either have significant hepatic impairment or who are taking ketoconazole or the macrolide anti­ 1. Gray, J., Bums, S. Mumps meningitis following biotics, erythromycin and troleandomycin. Rising measles, mumps, and rubella immunization. Lancet, 1: 98 plasma concentrations resulting from retarded (1989). metabolism of terfenadine are presumed to have 2. Murray, M., Lewis, M. Mumps meningitis after measles, induced serious cardiac reactions in these patients. mumps and rubella vaccination. Lancet, 1: 877 (1989). The adverse events associated with astemizole 3. Forsey, T., Minor, P. Mumps viruses and mumps, have usually occurred after substantial overdosage, measles, and rubella vaccine. British Medical Journal, but arrhythmias have occasionally been reported in 299: 1340 (1989). patients who have taken only 2-3 times the recommended maximum dose of 10 mg daily. 4. Maguire, H., Begg, N., Handford, S. Meningoencepha­ Reports have recently been received of 2 patients litis associated with MMR vaccine. Community Diseases who developed arrhythmias when they took Report, 1: R60-61 (1991). astemizole with erythromycin and ketoconazole (2). Blood concentrations have been found to be greatly 5. Sugiura, A., Yamada, A. Aseptic meningitis as a increased in patients taking ketoconazole and also, complication of mumps vaccination. Pediatric Infectious Diseases Journal, 10: 209-213 (1991). it has been presumed, its close congener, itraconazole. Since astemizole is extensively 6. Fuginaga, Motegi, Y., Tamura, H., Kuroume, T. A metabolized in the liver, doctors are advised not to prefecture-wide survey of mumps meningitis associated prescribe the drug for patients with significant with measles, mumps, and rubella vaccine. Pediatric hepatic impairment and to caution all patients that Infectious Diseases Journal, 10: 204-209 (1991). they should in no circumstances exceed the stated dose.

165 Regulatory Matters WHO Drug Information Vol. 6, No. 4, 1992

In several instances, syncopal episodes have been Source: Committee on Safety of Medicines, Current reported to precede the development of severe Problems, No. 35, November 1992. arrhythmias. Doctors have consequently been advised to warn patients taking either of these drugs that they should immediately discontinue Standardized instructions for oral treatment and seek medical advice in the event that they experience such symptoms. contraceptives

Sources United States of America — The Food and Drug Administration has prepared standard, simplified 1. FDA Medical Bulletin: 22, 1992. instructions to be included in package inserts for all brands of combined estrogen and progestogen oral 2. HHS News, P92-30, October 1992. contraceptives (1). The instructions currently provided, which differ from brand to brand, have United Kingdom — Terfenadine and astemizole frequently caused confusion and sometimes, are exempted from prescription control within the through misunderstanding, risk of unwanted UK. However, because of their apparent potential to pregnancy. The new advice is based on published induce ventricular arrhythmias, the Committee on research findings (2-7) and particular attention has Safety of Medicines has asked the manufacturers been accorded to directions for first use of such of preparations containing either of these ingredi­ products and for re-establishing contraceptive ents to revise the labelling and to issue information protection after a lapse of one or more days. leaflets warning patients to consult their doctor before using the product if they are receiving advice or treatment for other conditions. The standardized instructions provide only two starting options: either to start on day 1 of the next menstrual cycle or on the following Sunday. Users By October 1992, the Committee had received 13 are advised that the "Day 1" start is more effective reports of possible arrhythmias induced by since no back-up contraceptive methods are terfenadine and 7 reports implicating astemizole. required during the first week of treatment. Six of these patients died and several were known to have exceeded the recommended dose. In Any user who is uncertain how to proceed after reviewing information generated in the USA and the missing one or more pills, is advised to resume UK the Committee has concluded that all these taking pills as originally scheduled, to employ a events are likely to have been associated with one back-up method of contraception, and if necessary of the following risk factors: to seek professional advice. — exceeding the recommended maximum daily References dose: — concurrent administration of other drugs with a 1. FDA Medical Bulletin: Volume 22, September 1992. potential to induce arrhythmias, including 2. Frazer, I., Jansen, R. Why do inadvertent pregnancies antiarrhythmics, neuroleptics, tricyclic anti­ occur in oral contraceptive users? Effectiveness of oral depressants, diuretics (and other drugs that can contraceptive regimens and interfering factors. Contra• induce electrolyte imbalances). ception, 27: 531-551 (1983).

— pre-existing prolongation of the QT interval; 3. Guillbaud, J. The forgotten pill — and the paramount — clinically-significant hepatic disease; and importance of the pill-free week. British Journal of Family Planning, 12: 35-43 (1987). — concurrent administration of drugs that are potent inhibitors of the metabolism of terfenadine 4. Killik, S., Bancroft, K., Oelbaum, S. et al. Extending the and astemizole in the liver. These include duration of the pill-free interval during combined oral erythromycin or ketoconazole, and possibly other contraception. Advances in Contraception, 6: 33-40 (1990). macrolide antibiotics and imidazole anti-fungal agents. 5. Landgren, B., Diczfalusy, F. Hormonal consequences of missing the pill during the first three consecutive artificial Doctors have been requested to advise patients not cycles. Contraception, 29: 437-446 (1984). to take terfenadine or astemizole if any of these risk factors apply.

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6. Molloy, B., Loulson, K., Lee, J. et al. Missed pill Disease Control discovered that a large proportion conception: Fact or fiction? British Medical Journal, 290: of patients treated in the same centre had raised 1474-1475 (1985). serum aluminum levels, and that the recent deaths of 3 of the patients were attributable to aluminium 7. Smith, S., Kirkman, R., Arce, B. et al. The effect of deliberate omission of trinordinal or microgynon on the toxicity which results in anaemia, impaired bone hypothalamo-pituitary-ovarian axis. Contraception, 34: metabolism, transient or permanent neurological 513-522 (1986). symptoms and death (2). Injectable contraceptive The danger results from the corrosive action of the acidified portion of bicarbonate-based dialysis approved by FDA solutions — which are now used in the majority of dialysis facilities in the United States — on alumi­ United States of America — The Food and Drug nium contained in components of the delivery Administration has recently approved depot system. medroxyprogesterone acetate, 150 mg in single dose vials (Depo Provera®, Upjohn), as an inject­ Centers have been advised on the precautions able contraceptive. The product, which was needed to ensure that leaching of trace elements developed during the late 1960s, has long been into the dialysate does not occur (3, 4). available for this purpose in many other countries, and for almost 10 years it has been included in References WHO's Model List of Essential Drugs. It was at the 1. FDA Safety Alert: Aluminium and other trace element centre of controversy for several years while the contamination in dialysis facilities. FDA, HFZ-240, results of carcinogenicity studies in beagle bitches, Rockville, MD 20857 (1992). which are no longer considered relevant to contra­ ceptive use in women, remained in dispute. Multi­ 2. Luehmann, D., Keshaviah, P., Ward, R. et al. A manual national studies conducted in both developed and on water treatment for hemodialysis. FDA 89-4234, HHS, developing countries have since indicated that the Rockville, MD 20857 (1989). risk of cancer, including breast cancer, associated with use of the product is minimal or absent. 3. Association for the Advancement of Medical Instrumen­ tation. American national standard for hemodialysis systems (AAMI:RD-5-1981), Arlington, VA (1982). To sustain the contraceptive effect, injections need to be given regularly at three-month intervals. 4. Vlchek, D., Burrows-Hudson, S., Pressly, N. Quality Efficacy approaches 99% and the most common assurance guidelines for hemodialysis devices. FDA 91 - adverse effects are menstrual irregularities and 4161, HHS, Rockville, MD 20857 (1991). weight gain. Pregnancy should be positively excluded before the first injection is administered because low birth weight has been associated with intrauterine exposure to the drug. Other contra­ Flucloxacillin: cholestatic jaundice indications include acute hepatic disease, unex­ United Kingdom — Since flucloxacillin was first plained vaginal bleeding, breast cancer, and marketed in the United Kingdom more than 20 venous thromboembolism. Less frequent adverse years ago, doctors have reported a total of 31 reactions include headache, nervousness, abdomi­ cases of hepatic dysfunction associated with its nal pain, dizziness, weakness and fatigue. Investi­ use. However, a recent post-marketing study gations are ongoing into the possibility that long- undertaken within the UK indicates that flucloxacillin term use contributes to osteoporosis. may induce cholestatic jaundice with a frequency of 1:13 000 - 22 000 patients treated. A similar study Source: HHS News, US Department of Health and Human Services, October 29, 1992. undertaken in Australia suggests that patients over the age of 55 years, and those treated for more than 2 weeks are particularly susceptible. Haemodialysis and chronic Two of the cases reported in the UK terminated in aluminium poisoning the death of the patient, but in each case other hepatotoxic drugs had been prescribed. Cholestatic United States of America — Following investiga­ hepatitis was confirmed histologically in 5 cases tion of a case of chronic aluminium poisoning in a and inadvertent rechallenge was positive in 3 patient on haemodialysis (1) the Centers for

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instances. The Committee on Safety of Medicines References has advised doctors that the condition is serious, 1. FDA Medical Bulletin, Volume 22, September 1992. extensively under-reported and probably underdiagnosed. 2. Winklehake, J., Gauny, S. Human recombinant Source: Committee on Safety of Medicines. Current interleukin-2 as an experimental therapeutic. Pharma• Problems, No. 35, November 1992. cological Reviews, 42: 1-28 (1990). 3. Konrad, M., Hemstreet, G., Hersh, E. et al. Pharma­ cokinetics of recombinant interleukin-2 in humans. Cancer Herbal products: more potential Research, 50: 2009-2017 (1990). carcinogens Germany — The Federal Health Office has Atovaquone for treatment of announced an intention to withdraw from the market all herbal products containing derivatives of Pneumocystis carinii pneumonia Rubiae tinctorum radix, including lucidine and other derivatives of anthraquinone. Canada/United States of America — The US Food and Drug Administration and the Canadian Lucidine is partially converted in vivo to 1-hydroxy- Health Protection Branch have jointly reviewed and anthraquinone which has been shown in animal approved for marketing a new antimicrobial experiments to induce tumour formation in the substance, atovaquone (Mepron®, Burroughs intestinal and gastric mucosa and in the liver. Wellcome) for treating mild to moderate Pneumocystis pneumonia in patients who are Source: Communication from the Federal Health Office, intolerant of the standard therapy, trimethoprim/ Berlin, 29 April 1992. sulfamethoxazole. Human interleukin-2 for In a multicentre comparative study, sustained improvement was recorded in about two-thirds of renal cancer patients receiving each treatment. One quarter of the patients receiving trimethoprim/sulfa­ United States of America — The Food and Drug methoxazole — and one tenth of those receiving Administration has approved aldesleukin, ® atovaquone — were intolerant of treatment, (Proleukin ,Chiron), a form of human interleukin-2 whereas the proportion of patients who either died produced by recombinant DNA techniques, to treat or did not respond to treatment was significantly metastatic renal cell carcinoma in adult patients greater among those receiving atovaquone. (1-3). Of 225 patients treated, regression of the tumour occurred in 15% and no evidence of cancer Source: US Food and Drug Administration. Talk Paper, remained in 4%. The median period of response T92-61, 27 November 1992. was 23 months. It is estimated that 4% of the patients died during clinical trials as a result of a wide spectrum of drug- Finasteride for benign associated adverse events. Notable among these reactions was a state of hypotension and reduced prostatic hyperplasia organ perfusion resulting from "capillary leak United States of America — The Food and Drug syndrome". Other frequent and serious reactions Administration has announced that it has approved included cardiac dysrhythmias, angina pectoris, the first drug intended for the treatment of patients myocardial infarction, respiratory failure, anaemia, with symptoms of benign prostatic hyperplasia. In thrombocytopenia, gastrointestinal bleeding, renal premarketing trials, urinary flow increased sig­ failure requiring dialysis, neurological and mental nificantly and other symptoms regressed in about changes, and infections. half the patients taking finasteride (Merck and Co) 5 mg daily over 12 months. Prostate size as mea­ The FDA emphasizes that treatment should be sured by ultrasound was reduced in most of the administered only to hospitalized patients under the patients treated. It is estimated that treatment supervision of a specialist oncologist and in an needs to be continued for 6-12 months before a institution in which specialized intensive care clinical response can be expected. facilities are also available.

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Seven of a total of 543 patients discontinued A common factor in these events is evidence that treatment prematurely. The most common adverse diethylene glycol rather than propylene glycol was effects were loss of libido, impotence and disorders used as a solvent during the manufacture of these of ejaculation. Caution is advised in treating products. Diethylene glycol, which is used widely in patients with hepatic dysfunction since the drug is industry as a solvent and an antifreeze, is acutely extensively metabolized in the liver. toxic to the kidneys and liver. It has been respon­ sible for at least two earlier serious tragedies, one The product information emphasizes that prostatic in the United States of America in 1938, and one in stricture, infection, cancer, hypotonic bladder and India in 1986, both resulting in the deaths of many other neurogenic disorders should be excluded infants. before treatment is started. It also notes that finasteride also reduces plasma concentrations of In the light of this information all national regulatory prostate-specific antigens which are sometimes authorities have been advised to consider conse­ measured as a screening test for prostatic cancer. quential action. Where there is any doubt about the implementation of Good Manufacturing Practices Source: FDA Medical Bulletin, Volume 22, September within the manufacturing facilities, they have been 1992. reminded of the need to:

1. Obtain all possible information on suppliers and Diethylene glycol: channels of distribution of propylene glycol — both yet another tragedy locally manufactured and imported. Within the past three years the World Health 2. Review inspection reports of manufacturers of all Organization has been notified of three apparently registered products that contain propylene glycol as dissociated events in which many children are a declared ingredient. reported to have died after having taken locally formulated medicinal syrups. The products 3. Check relevant documentation and/or chemical implicated were: analyses of products/materials as appropriate.

• paracetamol syrup (Nigeria, September 1989); WHO has appealed to all national authorities to share any information that might assist in any way • a tonic preparation — Propoleo®; Laboratories in preventing such tragedies. Huilen — (Argentina, August 1992); and

• several local formulations of paracetamol syrup (Bangladesh, November 1992).

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Consultative Document

These proposed guidelines remain subject to consultation. Comments, which are invited from all interested parties, should be referred by 15 March 1993 to: The Division of Drug Management & Policies World Health Organization, 1211 Geneva 27, Switzerland

Proposed WHO Guidelines for Good The guidelines are addressed not only to investiga­ tors, but also to ethics review committees, pharma­ Clinical Practice (GCP) for trials on ceutical manufacturers and other sponsors of pharmaceutical products research and drug regulatory authorities. By providing a basis both for the scientific and ethical integrity of research involving human subjects and INTRODUCTION for generating valid observations and sound The purpose of these WHO Guidelines for Good documentation of the findings, these Guidelines not Clinical Practice (GCP) for trials on pharmaceutical only serve the interests of the parties actively products is to set globally applicable standards for involved in the research process, they protect the the conduct of biomedical research on human rights and safety of subjects, including patients, and subjects. They are based on provisions already promulgated in a number of highly-developed they ensure that the investigations are directed to countries including Australia, Canada, EC Coun­ the advancement of public health objectives. tries, Japan, Nordic Countries and the United The Guidelines are applicable specifically to studies States. These guidelines inevitably vary somewhat undertaken in the cause of commercial drug in content and emphasis, but all are consonant with development both prior to and subsequent to regard to the prerequisites to be satisfied and the product registration. None the less, many of the principles to be applied as a basis for assuring the elements are of wider relevance to biomedical ethical and scientific integrity of clinical trials. research. They should also provide a resource for Indeed, they have provided a formal basis for editors to determine the acceptability of reported mutual recognition of clinical data generated within research for publication and, specifically, of any the interested countries. study that could influence the use or the terms of registration of a pharmaceutical product. Not least, Every care has been taken, in developing the WHO they provide an educational tool that should Guidelines as a practicable administrative tool for become familiar to everyone engaged in biomedical the broader constituency of WHO's Member States, research and to every newly-trained doctor. to assure their compatibility with existing national and other provisions. It is hoped, on the basis of DEFINITION OF TERMS further consultation, to seek formal acceptance of the WHO Guidelines by Member States as a Definitions given below apply specifically to the contribution to harmonizing standards internation­ terms used in this guide. They may have different ally and to facilitating movement of pharmaceutical meanings in other contexts. products in international commerce. No question Adverse Event arises, however, of challenging or usurping existing Any untoward medical occurrence that may present national regulations or requirements. The objective itself during treatment with a pharmaceutical is to provide a complementary standard with product but which does not necessarily have a international validity. causal relationship with this treatment.

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Adverse Reaction b) Phase II A response to a pharmaceutical product which is The purpose of these therapeutic pilot studies is to noxious and unintended and which occurs at doses demonstrate activity and to assess short-term normally used in man for prophylaxis, diagnosis, or safety of the active ingredient in patients suffering therapy of disease, or for the modification of from a disease or condition for which the active physiological function. In clinical trials, injuries ingredient is intended. The trials are performed in a caused by overdosing, abuse/dependence and limited number of subjects and are often, at a later interactions with any other product should be stage, of a comparative (e.g., placebo-controlled) considered as an adverse reaction. design. This phase also aims at the determination of appropriate dose ranges/regimens and (if Audit possible) clarification of dose/response relation­ A systematic examination, carried out indepen­ ships in order to provide an optimal background for dently of those directly involved in the trial, to the design of extensive therapeutic trials. determine whether the conduct of a trial complies with the agreed protocol and whether the data c) Phase III reported are consistent with the records on site, Trials in larger (and possibly varied) patient groups e.g., whether data reported or recorded in the case with the purpose of determining the short- and long- report forms (CRF) are consonant with those found term safety/efficacy balance of formulation(s) of the in hospital files and other original recordings. active ingredient, as well as to assess its overall and relative therapeutic value. The pattern and Case Report Form (CRF) profile of any frequent adverse reactions must be A document designed to record data on each trial investigated and special features of the product subject during the course of the trial, as defined by must be explored (e.g., clinically-relevant drug the protocol. The data should be collected by interactions, factors leading to differences in effect procedures which guarantee preservation, retention such as age, etc.). The design of trials should and retrieval of information and allow easy access preferably be randomized double-blind, but other for verification and audit. designs may be acceptable, e.g., long-term safety studies. Generally, the circumstances of the trials Clinical Trial should be as close as possible to normal conditions Any systematic study on pharmaceutical products of use. in human subjects whether in patients or non- patient volunteers in order to discover or verify the d) Phase IV effects of and/or identify any adverse reaction to Studies performed after marketing of the pharma­ investigational products, and/or to study absorption, ceutical product. Trials in phase IV are carried out distribution, metabolism and excretion of the on the basis of the product characteristics on which products with the object of ascertaining their the marketing authorization was granted and are efficacy and safety. normally in the form of post-marketing surveillance, assessment of therapeutic value or treatment Clinical trials are generally classified into Phases I strategies. Although methods may differ, phase IV to IV. It is not possible to draw distinct lines studies should use the same scientific and ethical between the phases, and diverging opinions about standards as applied in premarketing studies. After details and methodology exist. Brief description of a product has been placed on the market, clinical the individual phases, based on their purposes as trials designed to explore new indications, new related to clinical development of pharmaceutical methods of administration or new combinations, products, are given below: etc. are normally considered as trials for new pharmaceutical products. a) Phase I These are the first trials of a new active ingredient Contract or new formulations in man, often carried out in A document, dated and signed by the investigator/ healthy volunteers. Their purpose is to establish a institution and the sponsor that sets out any preliminary evaluation of safety, and a first outline agreements on financial matters and delegation/ of the pharmacokinetic/pharmacodynamic profile of distribution of responsibilities. The protocol may the active ingredient in humans. also serve as a contract when it contains such information.

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Contract Research Organization (CRO) Inspection A scientific organization (commercial, academic or An officially-conducted examination (i.e., review of other) to which a sponsor may transfer some of its the conduct of the trial, including quality assurance, tasks and obligations. Any such transfer should be personnel involved, any delegation of authority and defined in writing. audit) by relevant authorities at the site of investiga­ tion and/or at the site of the sponsor in order to Ethics Committee verify adherence to Good Clinical Practice as set An independent body (a review board or a commit­ out in this document. tee, institutional, regional or national), constituted of medical professionals and non-medical members, Investigational Product whose responsibility is to verify that the safety, Any pharmaceutical product (see definition) or integrity and human rights of the subjects participat­ placebo being tested or used as reference in a ing in a particular trial are protected and to consider clinical trial. the general ethics of the trial, thereby providing Investigator public reassurance. A person responsible for the trial and for the rights, health and welfare of the subjects in the trial. The Final Report investigator must be an appropriately qualified A comprehensive description of the trial after its person legally allowed to practice medicine/ completion including a description of experimental dentistry. (including statistical) methods and materials, a presentation and evaluation of the results, statistical Investigator's Brochure analyses and a critical, ethics, statistical and clinical A collection of data for the investigator consisting of appraisal. all the relevant information on the investigational product(s) known prior to the onset of a clinical trial Good Clinical Practice including chemical and pharmaceutical data and Good Clinical Practice is a standard for clinical toxicological, pharmacokinetic and pharmaco­ studies which encompasses the design, conduct, dynamic data in animals as well as in man and the termination, audit, analyses, reporting and docu­ results of earlier clinical trials. There should be mentation of the studies and which ensures that the adequate data to justify the nature, scale and studies are scientifically and ethically sound and duration of the proposed trial and to evaluate the that the clinical properties of the diagnostic/ potential safety and need for special precautions. If therapeutic/prophylactic product under investigation new data are generated, the information must be are properly documented. updated. Good Manufacturing Practice (GMP) That part of pharmaceutical quality assurance Monitor which ensures that products are consistently A person appointed by the sponsor, and respon­ produced and controlled in conformity with quality sible to the sponsor, for the monitoring and report­ standards appropriate for their intended use and as ing of progress of the trial and for verification of required by the product specification. Any refer­ data. ence to GMP in this document should be under­ Patient Files stood as a reference to the current WHO GMP Hospital files, consultation records or special Guidelines. subject file allowing the authenticity of the informa­ tion presented in case record forms to be verified Informed Consent and, where necessary, allowing them to be com­ A subject's voluntary confirmation of willingness to pleted or corrected. The conditions regulating the participate in a particular trial, and the documenta­ use and consultation of such documents must be tion thereof. This consent should only be sought respected. after all appropriate information has been given about the trial including an explanation of its status Pharmaceutical Product as research, its objectives, potential benefits, risks and inconveniences, alternative treatment that may Any substance or combination of substances which be available, and of the subject's rights and has a therapeutic, prophylactic or diagnostic responsibilities in accordance with the current purpose, or is intended to modify physiological revision of the Declaration of Helsinki. functions, and presented in a dosage form suitable for administration to humans.

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Principal Investigator Serious Event The investigator serving as coordinator for certain An event that is associated with death, inpatient kinds of clinical trials, e.g., multicentre trials. hospitalization, prolongation of hospitalization, persistent or significant disability or incapacity, or is Protocol otherwise life-threatening in connection with a A document which states the background, rationale clinical trial. and objectives of the trial and describes its design, methodology and organization, including statistical Sponsor considerations, and the conditions under which it is An individual, a company, an institution or an to be performed and managed. The protocol organization which takes responsibility for the should be dated and signed by the investigator/ initiation, management and/or financing of a clinical institution involved and the sponsor. It can, in trial. When an investigator independently initiates addition, function as a contract. and takes full responsibility for a trial, the investiga­ tor then also assumes the role of the sponsor. Quality Assurance relating to Clinical Trials Systems, processes and quality control procedures Standard Operating Procedures (SOP) which have been established to ensure that the trial Standard, detailed, written instructions for the is performed and the data are generated in com­ management of any defined situation occurring pliance with Good Clinical Practice. These include during the clinical trial. They provide a general procedures to be followed which apply to ethical framework enabling the efficient implementation and professional conduct, standard operating and performance of all the functions and activities procedures (SOP), reporting, and professional/ for a particular trial as described in this document. personnel qualifications. Trial Subject Raw Data The trial subject may be: Raw data refer to all records or certified copies of a) a healthy person volunteering in a trial, original observations, clinical findings or other b) a person with a condition unrelated to the use of activities in a clinical trial necessary for the recon­ the investigational product, struction and evaluation of the trial. Such material c) a person (usually a patient) whose condition is includes laboratory notes, memoranda, calculations relevant to the use of the investigational product; and documents, recorded data from automated instruments or exact, verified copies in the form of who participates in a clinical trial, either as a photocopies, microfiches, etc. The term can also recipient of the pharmaceutical product under include photographic negatives, microfilm or investigation or as a control. magnetic media.

1. Provisions and prerequisites for revisions of the Declaration of Helsinki and the Inter­ national Ethical Guidelines for Biomedical Research a clinical trial Involving Human Subjects issued by the Council for International Organizations of Medical Sciences 1.1 Justification for the trial (CIOMS). These principles must be fully known and It is important for anyone preparing atrial of a medicinal followed by all engaged in conducting clinical trials product in humans that the specific aims, problems throughout all phases (see sections 3 and 4). and risks/benefits of a particular clinical trial be thor­ oughly considered and that the chosen solutions be 1.3 Investigational product scientifically sound and ethically justified. Preclinical studies that provide sufficient evidence of potential safety and eventual clinical application of a 1.2 Ethical principles pharmaceutical product are a necessary prerequisite All research involving human subjects should be for a clinical trial. Similarly, the chemical and pharma­ conducted in accordance with four basic ethical prin­ ceutical studies prior to a clinical trial should establish ciples, namely justice, respect for persons, benefi­ adequate quality of the trial product. The pharmaceu­ cence and non-maleficence as defined by the current tical, preclinical and clinical data should be adapted to

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the appropriate phase of the trial. In addition, a 3. Protection of trial subjects compilation of information on safety and efficacy collected in previous and ongoing clinical trials else­ The personal integrity and welfare of the trial subjects where with the investigational product is vital for the as defined in the Declaration of Helsinki is the ultimate planning and conduct of subsequent trials. responsibility of the investigator who must also take into consideration the scientific validity of the trial for 1.4 Investigator and site(s) of investi­ which all involved are responsible. gation All investigators should have appropriate expertise, 3.1 Declaration of Helsinki qualifications and competence to undertake a pro¬ The current revision of the Declaration of Helsinki posed study. Prior to the trial, agreement on monitoring (Appendix 2) is the accepted basis for clinical trial and auditing procedures, and also on standard op­ ethics, which must be fully known and followed by all erating procedures (SOP), should be established. engaged in research on human beings. Independent The logistics and premises of the trial site should assurance that subjects are protected can only be comply with requirements for the safe and efficient conduct of the trial (see section 4). provided by an ethics committee and freely-obtained informed consent. 1.5 Regulatory requirements Countries in which clinical trials are performed should 3.2 Independent ethics review board/ have regulations by which these studies can be con­ committee ducted. All parties involved in a clinical trial should The aim of the work of the ethics committee is to comply fully with the existing national regulations or ensure the protection of the rights and welfare of requirements. In those countries where regulations human subjects involved in research, and provide do not exist or require supplementation, the compe­ public reassurance, inter alia by previewing trial pro­ tent government officials may designate, in part or in tocols. The work of the ethics committee should be whole, the present WHO Guidelines for Good Clinical guided by the Declaration of Helsinki and governed by Practice as the basis on which clinical trials will be national and other relevant international requirements. conducted. The use of these guidelines should not prevent their eventual adaptation into national regu­ The ethics committee should have documented poli­ latory law. Neither should they be used to supersede cies and procedures as a basis for its work, which an existing national requirement in those cases where should include the authority under which the committee the national requirement is more rigorous. is established, the number and qualifications of members elected, a definition of what it will review and its authority to intervene and maintain records of its 2. The protocol activities. The frequency of meetings and how it The clinical trial should be carried out in accordance interacts with the investigator and/or sponsor should with a protocol agreed and signed by the investigator be defined. and sponsor. Any change(s) appearing later should The sponsor and/or investigator must consult the be appended as amendments and be similarly agreed relevant ethics committee(s) regarding suitability of a on and signed by the investigator and sponsor. proposed clinical trial protocol (including annexes) and of the methods and material to be used in obtain¬ The protocol should state the aim of the trial and the ing and documenting informed consent of the subjects. procedures to be used; the reasons for proposing that it should be undertaken on human subjects; the The ethics committee must be informed of all subse­ nature and degree of any known risks; the groups quent protocol amendments and of any serious ad­ from which it is proposed that trial subjects be selected verse events occurring during the trial, likely to affect and the means for ensuring that they are adequately the safety of the subjects or the conduct of the trial. informed before they give their consent. The ethics committee should be asked for its opinion if a re-evaluation of the ethical aspects of the trial The protocol should be scientifically and ethically appears to be called for. appraised by one or more suitably constituted review bodies, independent of the investigator(s) and spon­ Subjects must not be entered into the trial until the sor. relevant ethics committee(s) has issued its favourable opinion on the procedures and documentation in A model list of items to be contained in a protocol is writing. given in Appendix I.

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When receiving the submission for a clinical trial the guardians or, if necessary, legal representatives must ethics committee should consider the following: be given ample opportunity to enquire about details of the trial. The information must make clear that the trial a) the acceptability of the investigator for the proposed is a research procedure, participation is voluntary and trial, on the basis of sufficient information made that refusal to participate or withdraw from the trial at available to the committee, in terms of his/her quali­ any stage is without prejudice to the subject's care and fications, experience, supporting staff, and available welfare. Subjects must be allowed sufficient time to facilities. decide whether or not they wish to participate.

b) the suitability of the protocol in relation to the b) The subject must be made aware and consent that objectives of the study and the justification of predict­ personal information may be scrutinized during audit/ able risks and inconveniences weighed against the inspection by competent authorities and properly anticipated benefits for the subjects and/or others, as authorized persons/sponsor, and that participation well as the efficiency of its design, i.e. the potential for and personal information in the trial will be treated as reaching sound conclusions with the smallest pos­ confidential and will not be publicly available. sible exposure of subjects. c) The subject must have access to information about c) the means by which patients will be admitted and by insurances and other procedures for compensation which necessary/appropriate information will be given, and treatment should he/she be injured/disabled by and by which consent is to be obtained. participating in the trial. The subject should know the circumstances under which the investigator or the d) the adequacy and completeness of the information sponsor might terminate the subject's participation in in lay language to be given to the subjects, their the study. relatives, guardians and, if necessary, legal repre­ sentatives presented in writing to the ethics commit­ d) If a subject consents to participate after a full and tee. All written information for the subject and/or legal comprehensive explanation of the study (including its representative must be submitted in its final form. aim, expected benefits for the subjects and/or others, reference treatment/placebo, risks and inconveniences e) provision for compensation/treatment in the case of — e.g., invasive procedures — and, where appropri­ death or other loss or injury of a subject, if attributable ate, an explanation of alternative, recognized stan­ to a clinical trial, and details of any insurance or dard medical therapy), this consent should be appro­ indemnity to cover the liability of the investigator and priately recorded. Consent must be documented ei­ sponsor. ther by the subject's dated signature or by the signature of an independent witness who records the subject's f) the extent and form of payment through which the assent (consent). In either case, the signature con­ sponsor will remunerate/compensate organizations, firms that the consent is based on information which investigators, and trial subjects involved. has been given, and that the subject has freely chosen to participate without prejudice to legal and ethical g) acceptability of major amendments in the protocol. rights while reserving the right to withdraw at his/her own initiative from the study at any time, without The ethics committee should give its opinion and having to give any reason. However, in case the advice in writing within a reasonable time, clearly reason for withdrawal relates to adverse event(s) the identifying the trial protocol, the documents studied and date of review. A list of those present at the investigator should be informed. committee meeting, including their professional sta­ tus, should be attached. e) Careful consideration should be given to members of a group with a hierarchical structure — such as medical, pharmacy and nursing students, subordinate 3.3 Informed consent hospital and laboratory personnel, employees of the The principles of informed consent in the current pharmaceutical industry, and members of the armed revision of the Declaration of Helsinki should be forces. In such cases the willingness to volunteer may implemented in each clinical trial. be unduly influenced by the expectation, whether justified or not, of benefits or that refusal might provoke a) Information should be given in both oral and written a retaliatory response from senior members of the form whenever possible. No subject should be obliged hierarchy. Other vulnerable people whose mode of to participate in the trial. Subjects, their relatives, consent also needs special consideration include

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patients with incurable diseases, persons in nursing • be experienced in clinical trial research methods or homes, unemployed or impoverished persons, pa­ receive scientific support from an experienced col­ tients in emergency rooms, some ethnic minority league; groups, homeless persons, nomads and refugees. • be aware of available relevant data and literature and all information provided by the sponsor; f) If the subject is incapable of giving personal consent • have access to human and other resources to (e.g., unconscious or suffering from severe mental assume full responsibility for the proper conduct of illness or disability), the inclusion of such patients in the trial. a trial may be acceptable if the ethics committee is, in • be aware of and comply with national regulatory and principle, in agreement and if the investigator is of the legal requirements. opinion that participation will promote the welfare and interest of the subject. The agreement of a legally valid representative that participation will promote the 4.3 Selection of trial subjects welfare and interest of the subject should also be The investigator is responsible for ensuring the equi­ recorded by a dated signature. If neither signed table selection and adequate number of suitable sub­ informed consent nor witnessed signed verbal con­ jects. It may be necessary to secure the cooperation sent are possible, this fact must be documented of other physicians in order to obtain a sufficient stating reasons by the investigator. number of subjects.

Only (open-label) emergency treatment with the in­ In order to assess the probability of an adequate vestigational product may be appropriate in those recruitment rate for subjects for the study it may be cases where consent cannot be obtained. useful to determine prospectively or to review retro­ spectively the availability of the subjects. A check g) In a non-therapeutic study, i.e., when there is no should be made by the investigator whether subjects direct clinical benefit to the subject, consent must so identified could be included according to protocol. always be given by the subject or that of a legally valid representative and their signature obtained. 4.4 Compliance with the protocol The investigator should agree and sign the protocol h) The trial subjects should be informed that they have with the sponsor and confirm in writing that he/she has access to appropriate (indicated) persons to obtain read, understands and will work according to the further information, if necessary. protocol and Good Clinical Practice.

i) Any information becoming available during the trial The investigator is responsible for ensuring that the which may be of relevance for the trial subjects must protocol is strictly followed. The investigator should be made known to them by the investigator. not make any changes in the study without the agreement of the sponsor, except when necessary to 4. Responsibilities of the investigator eliminate an apparent immediate hazard or danger to the trial subjects. Any change should be in the form of a protocol amendment, appended to the original 4.1 Medical care of trial subjects protocol and signed by the investigator and sponsor. The investigator is responsible for adequate and safe Major amendments, with justification, should be medical care of those subjects who participate for the submitted to and implemented after approval of the duration of the trial and the investigator must ensure ethics committee (see Section 3.2) and drug regula­ that appropriate medical care is maintained after the tory authority. trial for a period that is dependent upon the nature of the disease and the trial and the interventions made. 4.5 Information to subjects and informed 4.2 Qualifications consent The investigator is responsible for giving adequate The investigator should: information to subjects about the trial. The current • be an appropriately-qualified person legally allowed version of the Declaration of Helsinki (Appendix 2), to practice medicine/dentistry; and International Ethical Guidelines for Biomedical • have good knowledge and experience of the field of Research Involving Human Subjects issued by the medicine defined by the protocol; Council for International Organizations of Medical • have the qualifications and competence in accor­ Sciences (CIOMS) should be followed. The nature of dance with national regulations as evidenced by an the information that should be given is dependent on up-to-date curriculum vitae and other credentials;

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the complexity of the study, the nature of the investi­ 4.8 Notification to drug regulatory gational pharmaceutical product and its stage of de­ authority velopment. As governed by national regulations, the investigator, sponsor, or investigator jointly with the sponsor, should Information should be given in both oral and written give notification of the trial to, or obtain approval from, form in the language understandable to the subject. It the drug regulatory authority. The investigator should shouId be noted in the protocol how it is to be recorded ensure that any submission must be in writing, be that information has been given and when and by dated and contain sufficient information to identify the whom it will be given. protocol. Informed consent should be obtained according to the principles as described in Section 3.3. 4.9 Review by an ethics committee Prior to its commencement, the investigator must The investigator should supply subjects with, and ensure that the proposed trial has been reviewed and encourage them to carry with them, information about accepted by an independent ethics committee (see their participation in the trial and information about Section 3.2). contact personnel who can assist in an emergency situation. 4.10 Serious adverse events/reactions As governed by national regulations, the investigator 4.6 The investigational product is responsible for notifying (with documentation) the The investigator should be thoroughly familiar with the health authorities, the sponsor and, when applicable, properties, effects, and safety, including pre-trial data, the ethics committee immediately in the case of serious of the investigational pharmaceutical product(s) as adverse events/reactions, and must take appropriate described in the investigator's brochure or in the measures to safeguard subjects (see also Section 7). literature. The investigator should be aware of all relevant new data on the product that appears during 4.11 Financing the course of the trial as required. The relationship between the investigator and the sponsor (in matters such as financial support, fees, 4.7 Site of the trial, facilities and staff honorarium payments in kind, etc.) must be stated in Clinical trials must be carried out under conditions writing in the protocol or contract. which ensure adequate safety for the subjects. Se­ lection of the site is dependent on the stage of de­ 4.12 Monitoring, auditing and inspection velopment of the product and the potential risks in­ The investigator must accept and be available for volved. The trial site must have adequate facilities, periodic visits by the monitor/s and accept the impli­ including laboratories, equipment and sufficient cations thereof (see also Section 6). In addition, the medical, paramedical, and clerical staff to support the investigator must accept the auditing and/or inspec­ trial as required. tion procedures by the authorities and by persons appointed by the sponsor for quality assurance. Facilities should be available to meet all possible emergencies. 4.13 Record keeping and handling of The investigator should ensure that he/she has suf­ data (see Section 8). ficient time to conduct and complete the trial, and that other commitments or trials do not divert essential 4.14 Handling and accountability of subjects or facilities away from the trial in hand. pharmaceutical products for trial (see The investigator should provide adequate information Section 10). to all staff involved in the trial. 4.15 Termination of trial and final report The investigator should notify or obtain approval for In the case of premature termination of the trial, the the trial from relevant local hospital (medical, admin­ investigator must inform the drug regulatory authority istrative) management in compliance with existing and ethics committee where applicable. Reasons for regulations. termination must be stated.

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After completion of the trial, a final report must be investigator before the amendment is implemented; drawn up. The report should be dated and signed by any such agreement should be documented. the investigator to verify responsibility for the validity of the data. The sponsor may transfer responsibilities for any or all obligations to a scientific body (commercial, academic 5. Responsibilities of the sponsor or others), or to a contract research organization (CRO). Any such transfer should be stated in writing. 5.1 General role of the sponsor 5.2 Particular responsibilities The sponsor may be a pharmaceutical company, but may also be an investigator, a principal investigator or of the sponsor an independent institution or organization that ini­ a) To select the investigator, taking into account the tiates, funds, organizes and oversees the conduct of appropriateness and availability of the trial site and a trial. When the sponsor is a foreign company or facilities, and be assured of the investigator's qualifi­ organization it should have a local representative to cations and availability for the entire duration of the fulfil the appropriate local responsibilities as governed study; to assure the investigator's agreement to by national regulations. undertake the study as laid down in the protocol, and according to these guidelines of Good Clinical Prac­ The sponsor is responsible for the overall adequacy tice, including the acceptance of verification proce­ and reliability of the data and information that are dures, audit and inspection. presented to the investigator before the start of the clinical trial or that become available during the trial, b) To inform the investigator of the chemical/pharma­ as well as responsible for the pharmaceutical ceutical, toxicological, pharmacological and clinical product(s) involved. data (including previous and on-going trials), which The sponsor, investigator, or both, are responsible as should be adequate to justify the nature, scale and stipulated in the national regulations for the necessary duration of the trial, as a prerequisite to planning the contacts with the drug regulatory authority and inde­ trial and to bring to the attention of the investigator any pendent ethics committee, such as notification or relevant new information arising during the trial. All submission of the trial protocol, reporting adverse relevant information must be included in the events and submitting reports on the trial. Investigator's Brochure which must be supplemented and/or updated by the sponsor whenever new perti­ In clinical trials in which the investigator is a sponsor, nent information is available. he/she is responsible for the corresponding functions, including monitoring. c) To submit notifications/applications to the relevant authorities (where required) and to ensure the sub­ The sponsor should set up a system of quality assur­ mission of any necessary documents to the ethics ance (including independent auditing) for the conduct committee, and to ensure communication of any of the trial as defined in Section 13. Such a system modification, amendment or violation of the protocol, should operate independently of those conducting if the change may have impact on the subject's safety the trial. or the outcome of the trial, and to inform the investi­ The sponsor must establish written detailed standard gator and relevant authorities about discontinuation of operating procedures (SOP) to comply with Good the trial and the reasons for discontinuation. Clinical Practice. d) To provide and supply the fully characterized, The sponsor should agree and prepare a written properly coded and labelled investigational pharma­ contract/agreement with the investigator prior to the ceutical product(s) prepared in accordance with trial, setting out the distribution of responsibilities. principles of Good Manufacturing Practice (GMP), and suitably packaged in such a way as to protect the Both the sponsor and investigator must agree on and product from deterioration, and that any blinding pro­ sign the protocol as an agreement of the details of the cedure is ensured. clinical trial and the means of data recording (e.g. case report form (CRF)). Any major amendment to the Sufficient samples of each batch and a record of protocol should be submitted with its justification to analyses and characteristics must be kept for refer­ the ethics committee and drug regulatory authority, ence so that if necessary an independent laboratory is should be approved by the ethics committee, and able to re-check the investigational product(s), e.g. for should be agreed to by both the sponsor and the quality control or bioequivalence.

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Records of the quantities of investigational pharma­ The monitor should be appropriately trained and fully ceutical products supplied must be maintained with aware of all aspects of the drug under investigation batch/serial numbers. The sponsor must ensure that and the requirements of the protocol, its annexes and the investigator within his/her institution is able to amendments. The monitor should have adequate establish a system for adequate and safe handling, medical, pharmaceutical and/or scientific qualifica­ storage, use, return and destruction of the investiga­ tions. The qualifications most appropriate for a moni­ tional product(s). tor will depend on the type of trial and the type of product under investigation. e) To appoint and ensure the on-going training of suitable and appropriately trained monitors and their The monitor or some other responsible person who clinical research support personnel. has been notified by the sponsor and is known to the investigator, should always be available at any time to f) To appoint appropriate individuals and/or commit­ the investigator for consultation or reporting of adverse tees for the purpose of steering, supervising, data events. handling and verification, statistical processing and trial report writing. The monitor should follow a predetermined written set of standard operating procedures (SOP). The main g) To consider promptly, jointly with the investigator(s), responsibility of the monitor is to oversee progress of all serious adverse events and take appropriate mea­ the trial and to ensure that this is conducted and sures necessary to safeguard trial subjects, and to reported in accordance with the protocol. A written report to appropriate national authorities according to record should be kept of the monitor's visits, telephone their requirements. calls and letters to the investigator. h) To inform promptly the investigator(s) of any imme­ Any unwarranted deviation from the protocol or any diately relevant information that becomes available transgression of the principles embodied in Good during atrial and ensure that the ethics committee is Clinical Practice should be reported promptly by the notified by the investigator(s) if required. monitor both to the sponsor and the interested ethics committee. i) To ensure the preparation of a comprehensive final report of the trial suitable for regulatory purposes 6.2 Particular responsibilities of the whether or not the trial has been completed. Sub­ missions of safety updates and annual reports may be monitor required by the authorities. a) To work according to a predetermined standard operating procedure (SOP), visit the investigator be­ j) To provide adequate compensation/treatment for fore, during and after the trial to control adherence to subjects in the event of trial-related injury or death, the protocol and assure that all data are correctly and and to provide indemnity (legal and financial cover) for completely recorded and reported, and that informed the investigator, except for claims resulting from mal­ consent is being obtained and recorded for all subjects practice and/or negligence. prior to their participation in the trial. k) To agree with the investigator(s) on the allocation of b) To ensure, prior to the trial, that the trial site has responsibilities for data processing, breaking of the adequate premises including laboratories, equipment, code, statistical handling, reporting of the results, and staff, and that an adequate number of trial subjects is publication policy. likely to be available during the trial.

c) To ensure that all staff assisting the investigator in 6. Monitor the trial have been adequately informed about, and will comply with the details of, the trial. 6.1 General role of the monitor The monitor is the principal communication link be­ d) To enable/ensure prompt communication between tween the sponsor and the investigator. The monitor the investigator and sponsor at all times. is appointed by the sponsor and should be accepted by the investigator. The number of monitors may e) To ensure that all CRFs are correctly filled out, in depend on the complexity of the trial and types of accordance with original observations and to clarify centres involved. with the investigator any errors/omissions.

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f) To ensure that all errors/omissions are corrected/ Reports on adverse events submitted by the investi­ commented on and that the investigator signs and gator to the drug regulatory authority should contain dates the final edited CRFs. In addition, that these both subject and trial identification data (i.e. unique procedures are carried out continuously during the code number assigned to each subject in the trial). entire course of the trial. When reporting adverse events to the sponsor, the g) To check that the supplies, storage, dispensing and investigator should not include the names of individual return of investigational pharmaceutical product(s) subjects, personal identification numbers or addresses. are safe and adequate and properly documented and The unique code number assigned to the trial subject in accordance with local regulations and, where appli­ should be used in the report and the investigator cable, the trial protocol. should retain the code. The name of the investigator reporting the adverse events should be stated. h) To assist the investigator in any necessary notifica­ tion/application procedure. After the trial has ended, all recorded adverse events should be listed, evaluated and discussed in the final i) To assist the investigator in reporting the data and report. results of the trial to the sponsor. 7.3 The sponsor j) To submit a written monitor report to the sponsor During the conduct of the trial, the sponsor has to (stating the findings and if actions were taken) after report adverse events/reactions to the drug regulatory each visit and after all relevant telephone calls, letters authority according to national regulations. and other contacts with the investigator (audit paper trail concept). The sponsor is responsible for reporting adverse events/reactions with the trial product to the local 7. Safety monitoring health authority as required by national regulations and to the other investigators involved in clinical trials The occurrence of adverse events must be monitored of the same product. carefully and recorded in detail during the course of the trial. The sponsor should also report as soon as possible to the investigator as well as internationally and nationally to drug regulatory authorities any trial with the same 7.1 General requirements product that has been stopped anywhere in the world The trial protocol should clearly state method(s) by due to action taken by any regulatory authorities, or which adverse events will be monitored. It should also any other withdrawals from the market for safety describe how this information is to be handled and reasons. analysed by the investigator and sponsor, and their responsibilities to report to each other and to the regulatory authority(s). The sponsor should provide 8. Record-keeping and handling of adverse event reporting forms. data National regulations may require the sponsor and/or The aim of record-keeping and handling of data is to the investigator to report certain types of adverse record, transfer, and where necessary convert effi­ events/reactions (e.g. serious, previously unknown, ciently and without error, the information gathered on etc.) to the regulatory authority and ethics committee. the trial subject into data which can be used in the If required, all such reports should be accompanied by report. an assessment of causality and possible impact on the trial and on future use of the product. All steps involved in data management should be documented in order to allow for a step-by-step retro­ 7.2 The investigator spective assessment of data quality and study perfor­ mance (audit paper trail concept). Documentation is The investigator has to report adverse events to the facilitated by the use of check-lists and forms giving sponsor immediately and to the regulatory authority details of action taken, dates and the individuals and the ethics committee in accordance with national responsible. regulations. Normally, adverse events associated with the use of the product must be reported to the A basic aspect of the integrity of data is the safeguard­ regulatory authority within specified time limits. ing of "blinding" with regard to treatment assignment.

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It starts with the randomization of patients into treat­ h) The final report of the trial should be drawn up as ment groups. It is maintained through all steps of data defined in the protocol and be signed by the sponsor/ processing up to the moment when the decision to monitor/investigator(s) and the responsible statisti­ break the code is formally taken. cian.

In the event of electronic data handling, confidentiality i) For a period of time defined by national regulations, of the data base must be secured by safety proce­ the investigator should maintain a confidential record dures such as passwords and written assurances to allow the translation of the unambiguous code used from all staff involved. Provision must be made for the to conceal the identity of the individual subjects of the satisfactory maintenance and back-up procedures of trial (subject identification code). the data base. 8.2 Responsibilities of the sponsor 8.1 Responsibilities of the investigator a) The investigator undertakes to ensure that the and monitor observations and findings are recorded correctly and a) When using electronic data-handling the sponsor completely in the CRFs and signed by the appropriate must use validated, error-free data processing pro­ person after delegation according to the protocol. grammes with adequate user documentation. b) If trial data are entered directly into a computer, b) Appropriate measures should be taken by the there must always be an adequate safeguard to monitor to avoid overlooking missing data or including ensure validation including a signed and dated print­ inconsistencies. If a computer assigns missing values out and back-up records. Computerized systems automatically, this should be made clear. should be validated and a detailed description for their c) When electronic data-handling systems or remote use be produced and kept up-to-date. electronic data entry are employed, SOPs for such systems must be available. Such systems should be c) All corrections on a CRF and elsewhere in the hard designed to allow correction after loading, and the copy raw data must be made in a way which does not corrections made must appear in an audit file. obscure the original entry. The correct data must be inserted with the reason for the correction, dated and d) The sponsor must ensure the greatest possible initialled by the investigator or the authorized person. accuracy when processing data. If data are trans­ For electronic data processing, only authorized per­ formed during processing, the transformation must be sons should be able to enter or modify data in the documented and the method validated. It should computer and there should be a record of changes always be possible to compare the data print-out with and deletions. the original observations and findings.

d) If data are altered during processing, the alteration e) The sponsor must be able to identify all data must be documented. entered pertaining to each subject by means of an unambiguous code. e) Laboratory values with normal reference ranges, f) The sponsor must maintain a list of persons autho­ preferably together with the specificity and sensitivity rized to make corrections, and protect access to the of the methods used, should always be recorded on data by appropriate security systems. the CRF or be attached to it. Values outside a clinically accepted reference range or values that differ im­ portantly from previous values must be evaluated and 8.3 Archiving of data commented upon by the investigator. The investigator must arrange for the retention of the subject identification codes for a sufficient period of f) Data other than those requested by the protocol time for reasons of safety and efficacy as instructed by acquired in the course of monitoring adverse events the national regulations. Patient files and other source or recurrent or new illness may appear on the CRF data must be kept for a period of time required by the clearly marked as additional/optional findings, and local rules for hospitals, institutions or private practice. their significance should be described by the investi­ The sponsor or owner of the product must make gator. appropriate arrangements for retention of all other documentation pertaining to the trial in a form which can be retrieved for future reference. Archived data g) Units of measurement must always be stated, and may be held on microfiche or electronic record, pro­ transformation of units must always be indicated and vided that hard copy is available. documented.

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The protocol, documentation, approvals and all other 9.3 Statistical analysis documents related to the trial, including certificates The type(s) of statistical analyses to be used must be that satisfactory audit and inspection procedures have specified in the protocol, and any other subsequent been carried out, must be retained by the sponsor. deviations from this plan should be described and Data on adverse events must always be included. justified in the final report of the trial. The planning of the analysis and its subsequent execution must be All data and documents should be made available if carried out or confirmed by an identified, appropriately requested by relevant authorities. qualified and experienced statistician. The possibility and circumstances of interim analyses must also be 9. Statistics and calculations specified in the protocol.

The use of qualified biostatistical expertise is neces­ The investigator and monitor must ensure that the sary before and throughout the entire trial procedure, data are of the highest quality possible at the point of commencing with the design of the protocol and CRFs collection and the statistician must ensure the integrity and ending with completion of the final report and/or of the data during processing. publication of results. The results of analyses should be presented in such Where and by whom the statistical work should be a manner as to facilitate interpretation of their clinical carried out is agreed upon between the sponsor and importance, e.g. by estimates of the magnitude of the the investigator and recorded in the protocol. treatment effect/difference and confidence intervals, rather than sole reliance on significance testing. 9.1 Experimental design The scientific integrity of a clinical trial and the credibil­ An account must be made of missing, unused or ity of the data produced depend first on the design of spurious data excluded during statistical analyses. All the trial. In the case of comparative trials, the protocol such exclusions must be documented so that they can should, therefore, describe: be reviewed if necessary. a) an a priori rationale for the targeted difference be­ 10. Handling and accountability of tween treatments which the trial is being designed to detect, and the power to detect that difference, taking pharmaceutical products into account clinical and scientific information and professional judgement on the clinical significance of The sponsor is responsible for ensuring that the statistical differences; pharmaceutical product(s) supplied for the trial (in­ vestigational product, or reference products including b) measures taken to avoid bias, particularly methods placebo) are of appropriate quality and subject to of randomization, when relevant, and selection of quality assurance procedures (see 5.2 d). patients. 10.1 Supply and storage 9.2 Randomization and blinding The arrangements made by the sponsor to supply the In case of randomization of subjects the procedure investigator with investigational pharmaceutical must be documented. Where a sealed code for each products for the trial should be described in the individual treatment has been supplied in a blinded, protocol. The manner in which investigational prod­ randomized study, it should be kept both at the site of ucts are recorded, delivered, dispensed and stored the investigation and with the sponsor. should be detailed. Records should contain informa­ tion about the shipment, delivery, receipt, disposition, In the case of a blinded trial the protocol must state the return and destruction of any remaining pharmaceu­ conditions under which the code is allowed to be tical products. The investigator must not supply the broken and by whom. A system is also required to investigational product to any person not targeted to enable access to the information on treatment received receive it. Preferably a local pharmacy or the pharmacy by individual subjects in the case of an emergency. department of the hospital should assume responsi­ The system must only permit access to the treatment bility for storage, delivery, return and keeping records schedule of one trial subject at a time. If the code is of the investigational pharmaceutical product(s). If it broken, it must be justified and documented in the does, the procedure in the pharmacy must be docu­ CRF. mented to make auditing possible.

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10.2 Packaging and labelling During the study visits the monitor should check: The sponsor is responsible for the correct packaging and labelling of the pharmaceutical products used. • that the pharmaceutical products for the trial are The investigational products should be labelled in used exclusively within the limits defined by the compliance with instructions from the national drug protocol; regulatory authority and the label should state that the product is for clinical research purposes only. • that supply records of investigational products are in order and that there are sufficient supplies; In blinded trials, the package should be labelled in a way that does not reveal the identity of the product. In • the expiry dates of batches; an emergency it must be possible to determine the identity of the actual treatment received by an indi­ • storage conditions of the pharmaceutical products vidual subject. for the trial;

In blinded trials all investigational product(s), includ­ • the handling of returned and/or unused pharmaceu­ ing reference products and placebos used, should be tical products. indistinguishable by appearance, taste, smell and other physical characteristics. If changes are made to 11. Role of the drug regulatory the control product formulation, the need for a com­ parative in vivo bioavailability and dissolution test or authority other in vitro studies should be considered. The role of governments is to provide the legal frame­ work for clinical trials. The aim should be twofold; to 10.3 Responsibilities of the investigator protect the safety and rights of the subjects participating The investigator is responsible for ensuring: in a trial and to allow only trials which may lead to conclusive data. This could be done by several • safe handling of the investigational products during means, including the specification of the competence and after the conduct of the trial, preferably in needed for investigators and the demand for approval cooperation with a pharmacy or hospital pharmacy; by relevant scientific/ethics committees. Regulatory authorities should have a mandate to revise or ter­ • that the investigational product is used only in minate trials. The system must allow for on-site in­ accordance with the protocol and only for subjects spection of the quality of the data obtained, with due included in the trial and by designated staff respon­ concern to subject confidentiality. sible to the investigator; 11.1 General responsibilities • that dosage and instructions for use are correct and The national drug regulatory authority should ensure that every subject involved understands them prop­ that the protocols of clinical trials, submitted in ad­ erly; vance for its review, are in accordance with existing national regulations and instructions. • that unused investigational products are returned to the pharmacy or sponsor or destroyed, and that Under national regulations and on the basis of its records of these activities are kept according to the review of clinical trial protocols and/or reports, the protocol. regulatory authority may propose revisions or request additional data on a clinical trial or may terminate a 10.4 Responsibilities of the sponsor and trial. monitor The regulatory authority should be able to check on The sponsor is responsible for: supervision of the conduct of the trial by requesting reports on the monitor's interaction with the investigator. • ensuring that the package of investigational product(s) is of a size suitable for the trial and adequate for the It should also be possible for the authorities to check trial subjects; the reliability and quality of reported results. • keeping sufficient samples from each batch used in The drug regulatory authority should file the subject the trial as a reference for future re-checking and identification code list submitted by the investigator/ control and as provided in national regulations. sponsor at the same time as the signed final report.

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National regulations should stipulate ways to report independent sponsor audit as well as for inspection by and handle misconduct discovered in connection with competent authorities. clinical trials. 13. Considerations for multicentre 11.2 Inspections Under national regulations the regulatory authority trials might inspect the conduct of a clinical trial by on-site Because a multicentre trial is conducted simulta­ visits. Such an inspection should consist of a com­ neously by several investigators at different sites parison of the procedures and practices of the clinical following the same protocol, some special administra­ investigator with the commitments set out in the tive arrangements are normally needed. Ideally, the protocols and reports submitted to the drug regulatory trial should begin and end simultaneously at all sites. authority by the investigator or the sponsor. A number of aspects are rendered more complex in Inspections may be carried out either routinely, ran­ multicentre trials such as: domly or for specific reasons. • the elaboration, discussion and written acceptance The inspection should determine whether the inves­ of the protocol and its annexes by all investigators; tigator has custody of the required records or, if not, who has assumed this responsibility. The data archives • ethics committee(s), and the number of committees should be tested for retrieval. to be consulted; • the organization of initial and intermediary meetings 12. Quality assurance for conduct of parties involved; of clinical trial • implementation of the trial; The sponsor is responsible for the implementation of • the randomization procedure; a system of quality assurance in order to ensure that all sites, data and documents are available for verifi­ • ensuring that the quality of the product is maintained cation. during distribution and storage in different loca­ tions; All observations and findings should be verifiable in • the training of investigators to follow the same order to ensure the credibility of data and to assure protocol; that the conclusions presented are derived correctly from the raw data. Verification processes must, • standardization of methods for evaluation and analy­ therefore, be specified and justified. Statistically con­ ses of laboratory and diagnostic data (e.g. set-up of trolled sampling may be an acceptable method of data an external quality control system for laboratory verification in a trial. assays); • control of adherence to the protocol including mea­ Quality control must be applied to each stage of data handling to ensure that all data are reliable and have sures to terminate participation of sites if necessary; been processed correctly. • role of monitor(s); The sponsor's audit should be conducted by persons/ • centralized data management and analysis; facilities independent of those carrying out the trial. • drafting of the final report; Any or all of the recommendations, requests or • publication. documents addressed in this Guideline or in national regulations may be subject to, and must be available A multicentre trial therefore may require a special for, an audit through the sponsor or a nominated administrative system, the scale of which will depend independent organization and/or competent authori­ on the number of trial sites involved, study end-points ties (inspection). and present knowledge of the investigational pharma­ ceutical product. One or several committees may be Sponsor and investigational sites, facilities and labo­ set up or the necessary functions may be performed ratories, and all data (including patient files) and by one or more designated person(s). The functions, documentation must be available for institutional and responsibilities and mandate of the committee(s) or

184 WHO Drug Information Vol. 6, No. 4, 1992

person(s) should be described in the trial protocol, as 8. Description of and justification for route of adminis­ should the procedure for nomination. tration, dosage, dosage interval and treatment period for the pharmaceutical product being tested and the The responsibility for commencement and overall product being used as a control. performance of the trial could be the task of a commit­ tee/person. A second committee/person could be 9. Any other treatment that may be given or permitted appointed to provide advice on policy matters and concomitantly. supervision of data. A third committee/person should have access to the results obtained in the trial, includ­ 10. Clinical and laboratory tests, pharmacokinetic ing adverse events. It should be stated in the protocol analysis, etc., that are to be carried out. if and under what circumstances and how this commit­ tee/person can break the code. Interaction between 11. Description of how responses are recorded. De­ these committee(s)/person(s) is necessary. scription and evaluation of methods of measurement, times of measurements, follow-up procedures. A coordinating committee could also be set up or a co­ 12. Discontinuation criteria for trial subjects and in­ ordinator appointed with responsibility for the control structions on terminating the whole study or a part of of the practical performance and progress of the trial the study. and maintaining contacts with the regulatory authori­ ties and ethics committees. 13. Methods of recording and reporting adverse events/ reactions, provisions for dealing with complications. This system will provide adequate assurance that the study will be planned and conducted according to 14. Procedures for the maintenance of subject identi­ acceptable scientific standards. fication code lists, treatment records, randomization list and/or case report form (CRF). Records should APPENDIX I permit easy identification of individual patients/partici­ pants and the auditing and reconstruction of data. Model List of Items to be contained in a Clinical Trial Protocol 15. Information on establishment of the trial code, where it will be kept and when, how and by whom it The trial protocol should, where relevant, be required can be broken in the event of an emergency. to cover the following points: 16. Measures to be implemented to ensure the safe 1. Title and justification for the trial. handling and storage of pharmaceutical products, and to promote and control compliance with the pre­ 2. Statement of rationale, objectives and purpose of scribed and other instructions. trial. 17. Description of methodology on the evaluation of 3. Site of the trial, name and address of the sponsor. results, (e.g., statistical methods) and on the report on patients/participants withdrawn from the trial. 4. Name, address and qualifications of each investi­ gator. 18. Time schedule for completion of the trial.

5. Description of the type of trial (controlled, open), 19. Information to be presented to the trial subjects trial design (parallel groups, cross-over technique), including how trial subjects will be informed about the blinding technique (double-blind, single-blind), ran­ trial and how and when consent will be obtained. domization (method and procedure). 20. Staff instructions, i.e., statement of how the staff 6. Description of trial subjects. Criteria for inclusion involved are to be informed about the way the trial is and exclusion of potential trial subjects and process of to be conducted and about the procedures for drug recruitment, types, methods and time of allocation of usage and administration. subjects. 21. Ethical considerations and measures relating to 7. Number of trial subjects needed to achieve the trial the trial. objective based on statistical considerations.

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22. Medical care after the trial and modalities of post- Medical progress is based on research which trial treatment should be defined. ultimately must rest in part on experimentation involving human subjects. 23. Statements regarding financing, insurance, liabil­ ity, and delegation/distribution of responsibilities, i.e., In the field of biomedical research a fundamental when serving as a contract. distinction must be recognized between medical research in which the aim is essentially diagnostic 24. List of literature referred to in the protocol. or therapeutic for a patient, and medical research, the essential object of which is purely scientific and APPENDIX 2 without implying direct diagnostic or therapeutic value to the person subjected to the research. WORLD MEDICAL ASSOCIATION Special caution must be exercised in the conduct of research which may affect the environment, and the welfare of animals used for research must be Declaration of Helsinki respected. Recommendations guiding Because it is essential that the results of laboratory experiments be applied to human beings to further physicians in biomedical research scientific knowledge and to help suffering humanity, involving human subjects the World Medical Association has prepared the following recommendations as a guide to every Adopted by the 18th World Medical physician in biomedical research involving human Assembly, Helsinki, Finland, in June 1964.subjects . They should be kept under review in the Amended by the 29th World Medical future. It must be stressed that the standards as Assembly, Tokyo, Japan, drafted are only a guide to physicians all over the in October 1975 world. Physicians are not relieved from criminal, 35th World Medical Assembly, civil and ethical responsibilities under the laws of Venice, Italy, in October 1983 and their own countries. 41st World Medical Assembly, Hong Kong, in September 1989. I. Basic principles 1. Biomedical research involving human subjects Introduction must conform to generally accepted scientific It is the mission of the physician to safeguard the principles and should be based on adequately health of the people. His or her knowledge and performed laboratory and animal experimentation conscience are dedicated to the fulfillment of this and on a thorough knowledge of the scientific mission. literature. The Declaration of Geneva of the World Medical 2. The design and performance of each experimen­ Association binds the physician with the words "The tal procedure involving human subjects should be health of my patient will be my first consideration" clearly formulated in an experimental protocol and the International Code of Medical Ethics which should be transmitted for consideration, declares that "A physician shall act only in the comment and guidance to a specially appointed patient's interest when providing medical care committee independent of the investigator and the which might have the effect of weakening the sponsor provided that this independent committee physical and mental condition of the patient." is in conformity with the laws and regulations of the country in which the research experiment is The purpose of biomedical research involving performed. human subjects must be to improve diagnostic, therapeutic and prophylactic procedures and the 3. Biomedical research involving human subjects understanding of the aetiology and pathogenesis of should be conducted only by scientifically qualified disease. persons and under the supervision of a clinically competent medical person. The responsibility for In current medical practice most diagnostic, the human subject must always rest with a medi­ therapeutic or prophylactic procedures involve cally qualified person and never rest on the subject hazards. This applies especially to biomedical of the research, even though the subject has given research. his or her consent.

186 WHO Drug Information Vol. 6, No. 4, 1992 Consultative Document

4. Biomedical research involving human subjects 11. In case of legal incompetence, informed cannot legitimately be carried out unless the consent should be obtained from the legal guardian importance of the objective is in proportion to the in accordance with national legislation. Where inherent risk to the subject. physical or mental incapacity makes it impossible to obtain informed consent, or when the subject is a 5. Every biomedical research project involving minor, permission from the responsible relative human subjects should be preceded by careful replaces that of the subject in accordance with assessment of predictable risks in comparison with national legislation. foreseeable benefits to the subject or to others. Concern for the interests of the subject must always Whenever the minor child is in fact able to give a prevail over the interests of science and society. consent, the minor's consent must be obtained in addition to the consent of the minor's legal guard­ 6. The right of the research subject to safeguard his ian. or her integrity must always be respected. Every precaution should be taken to respect the privacy of 12. The research protocol should always contain a the subject and to minimize the impact of the study statement of the ethical considerations involved and on the subject's physical and mental integrity and should indicate that the principles enunciated in the on the personality of the subject. present Declaration are complied with.

7. Physicians should abstain from engaging in II. Medical research combined with research projects involving human subjects unless they are satisfied that the hazards involved are professional care (clinical research) believed to be predictable. Physicians should cease any investigation if the hazards are found to 1. In the treatment of the sick person, the physician outweigh the potential benefits. must be free to use a new diagnostic and therapeu­ tic measure, if in his or her judgement it offers hope 8. In publication of the results of his or her re­ of saving life, reestablishing health or alleviating search, the physician is obliged to preserve the suffering. accuracy of the results. Reports of experimentation not in accordance with the principles laid down in 2. The potential benefits, hazards and discomfort of this Declaration should not be accepted for publica­ a new method should be weighed against the tion. advantages of the best current diagnostic and therapeutic methods. 9. In any research on human beings, each potential subject must be adequately informed of the aims, 3. In any medical study, every patient — including methods, anticipated benefits and potential hazards those of a control group, if any — should be of the study and the discomfort it may entail. He or assured of the best proven diagnostic and thera­ she should be informed that he or she is at liberty to peutic method. abstain from participation in the study and that he 4. The refusal of the patient to participate in a study or she is free to withdraw his or her consent to must never interfere with the physician-patient participation at any time. The physician should then relationship. obtain the subject's freely-given informed consent, preferably in writing. 5. If the physician considers it essential not to obtain informed consent, the specific reasons for 10. When obtaining informed consent for the this proposal should be stated in the experimental research project, the physician should be particu­ protocol for transmission to the independent larly cautious if the subject is in a dependent committee (1, 2). relationship to him or her or may consent under duress. In that case the informed consent should be 6. The physician can combine medical research obtained by a physician who is not engaged in the with professional care, the objective being the investigation and who is completely independent of acquisition of new medical knowledge, only to the this official relationship. extent that medical research is justified by its potential diagnostic or therapeutic value for the patient.

187 Consultative Document WHO Drug Information Vol. 6, No. 4, 1992

III. Non-therapeutic biomedical 3. The investigator or the investigating team should discontinue the research if in his/her or their research involving human subjects judgement it may, if continued, be harmful to the (non-clinical biomedical research) individual. 1. In the purely scientific application of medical 4. In research on man, the interest of science and research carried out on a human being, it is the society should never take precedence over duty of the physician to remain the protector of the considerations related to the well-being of the life and health of that person on whom biomedical subject. research is being carried out.

2. The subjects should be volunteers — either healthy persons or patients for whom the experi­ mental design is not related to the patient's illness.

Acknowledgements The above text was developed during two meetings convened by the Division of Drug Management and Policies, World Health Organization, Geneva from 26 29 June to 3 July 1992. The participants were: Professor I. Darmansjah, University of Indonesia, Jakarta. Dr Y. Hirayama, New Drugs Division, Ministry of Health & Welfare, Tokyo, Japan. Professor E. Hvidberg (Chairman), University Hospital Rigshospitalet, Copenhagen, Denmark. Mr R. Laderman, Center for Drug Evaluation and Research, Food and Drug Administration, USA. Professor V.H. Lepakhin, Russian State Center for Drug Expertise, Moscow, Russian Federation. Professor J.O.M. Pobee, School of Medicine, Lusaka, Zambia. Mr M. Tsukano, New Drugs Division, Ministry of Health & Welfare, Tokyo, Japan. Dr S. Westman-Naeser, Medical Products Agency, Uppsala, Sweden. Professor A. Zanini, Instituto de Ciencias Biomedicas, Sao Paolo, Brazil. Professor Zhu Jun-ren, Shanghai Medical University, People's Republic of China. Ms M. Cone & Dr P. Maurice, International Federation of Pharmaceutical Manufacturers Associations (IFPMA), Geneva, Switzerland. Professor P. Dayer, International Union of Pharmacology (IUPHAR), Brussels, Belgium.

188 WHO Drug Information Vol. 6, No. 4, 1992

Recent Publications

Infectious disease: an ominous and These concerns, as perceived from within the USA, are starkly reflected within a report on "Emerging unpredictable threat Infections" published by the Institute of Medicine which emphasizes the immediacy of the risks and Over the past six years, this journal has been calls for a sense of urgency within governments (5). pointing to the threats posed by infectious disease It points to the current resurgence of tuberculosis in an ever more densely populated world. Compla­ and measles within the USA; the speed with which cency induced by the development of successive Lyme disease has become the most common generations of novel antibiotics and insecticides vector-borne disease within the country; and the has allowed governments to cut back on the staple vulnerability of the population to an influenza surveillance and reporting mechanisms that are the pandemic of the scale that killed 20 million people foundations of public health medicine. The emer­ worldwide in 1918-19. Further afield it looks to a gence of AIDS has jolted this complacency and plethora of threats to human populations from unleashed a frenzied effort to develop drugs and microbial diseases that have until now been vaccines to combat this particular disease. But, effectively controlled or localized. perhaps because it is not transmitted by casual contact or sneezing, its appearance has failed to It calls for the national and international disease sensitize policy-makers to the possibility of further surveillance activities of the Centers for Disease — and perhaps more devastating — pre-emptive Control to be upgraded as a matter of highest microbial attacks. Far less has it established priority. As yet, State and local health officials are awareness of an urgent need for worldwide required by law only to report tuberculosis and monitoring of patterns of infective disease and the other diseases for which quarantine measures are spread of antibiotic-resistant organisms. enforced. But surveillance alone can never be sufficient. The report, more speculatively, calls for The warning signals are clear enough. Notwith­ fresh thinking on means for responding efficiently to standing contrary trends in some developed urgent community needs for new vaccines and countries, and impressive developments in meth­ drugs; for central government to maintain stockpiles ods of contraception (1), the world population has of selected vaccines; and for manufacturers to continued to grow at a rate that exceeds predictions develop — subject to government purchase (2). Civilizations are venturing into environments guarantees — "surge capacity" for vaccine produc­ and risking contact with viruses and other micro­ organisms previously existent only in animal tion to assure adequate supplies at the earliest populations. The genetic variability of retroviruses phase of an epidemic. The very scale of the and other microorganisms increases their ability to problem inhibits realistic discussion of their adapt to new environments and new hosts. These redressment in a global context. But global ap­ microorganisms possess the potential to develop proaches there must be, if secure protective resistance to widely-used antimicrobial drugs. In strategies are to be developed against these many cases the genetic apparatus responsible for potentially catastrophic threats. these changes can be transferred from species to species by plasmids which have the ability to References encode for resistance to several antibiotics. Longer- 1. Reproductive health: a key to a brighter future. Special term climatic trends may encourage the spread and Programme of Research, Development and Research enhance the transmissibility of diseases endemic in Training in Human Reproduction. Biennial Report 1990 - tropical climates (3, 4). The mosquitos and other 1991. Ed. Khanna, J., van Look, P., Griffin, P. World vectors responsible for the transmission of many of Health Organization, Geneva 1992. these diseases have similarly developed resistance to widely available insecticides. Modern interna­ 2. World Resources Institute, International Institute for tional travel provides for rapid spread of both Environment and Development and United Nations pathogens and vectors. Environment Programme. World Resources 1988-89. Basic Books, New York (1988).

189 Recent Publications WHO Drug Information Vol. 6, No. 4, 1992

2. Mason, J. The greenhouse effect and global warming. Monitoring the Environment the Linacre Lectures 1990- 1991, ed. Cartledge, B. Oxford University Press, 1992.

3. Climate and disease: the deadly hitch-hikers. The Economist, 325: 93-95, 31 October 1992.

4. Emerging Infections: microbial threats to health in the United States. Committee Chairmen: Lederberg, J., Shope, R., Institute of Medicine, Washington, D.C., 1992.

190 WHO Drug Information, Vol. 6, No. 4, 1992

International Nonproprietary Names for Pharmaceutical Substances (INN)

Notice is hereby given that, in accordance with article 3 of the Procedure for the Selection of Recommended International Nonproprietary Names for Pharmaceutical Substances, the following names are under consid­ eration by the World Health Organization as Proposed International Nonproprietary Names. The inclusion of a name in the lists of Proposed International Nonproprietary Names does not imply any recommendation of the use of the substance in medicine or pharmacy.

Comments on, or formal objections to, the proposed names may be forwarded by any person to the INN Programme of the World Health Organization within four months of the date of their publication in WHO Drug Information, i.e., for List 68 Proposed INN not later than 30 June 1993.

Proposed International Nonproprietary Names: List 68 Lists of proposed (1-65) and recommended (1-31) international nonproprietary names can be found in Cumulative List No. 8, 1992. Proposed International Chemical Name or Description, Molecular and Graphic formulae Nonproprietary Name Chemical Abstracts Service (CAS) registry number (Latin, English) Action and Use*

alestramustinum estradiol 3-[bis(2-chloroethyl)carbamate], 17-ester with L-alanine alestramustine C26H36Cl2N2O4 139402-18-9 antineoplastic

alglucerasum glucosylceramidase (human placenta isoenzyme protein moiety reduced) alglucerase C2532H3854N672O711S16 143003-46-7 glucocerebrosidase (for non-glycosylated protein)

*Action and Use: The statements in italics indicating the action and use are based largely on information supplied by the manufacturer. The information is meant to provide an indication of the potential use of new substances at the time they are accorded Proposed International Nonproprietary Names. WHO is not in a position either to uphold these statements or to comment on the efficacy of the action claimed. Because of their provisional nature, these descriptors will be neither revised nor included in the Cumulative Lists of INNs. 191 Proposed International Chemical Name or Description, Molecular and Graphic formulae Nonproprietary Name Chemical Abstracts Service (CAS) registry number (Latin, English) Action and Use* alovudinum 3'-deoxy-3'-fluorothymidine alovudine C10H13FN2O4 25526-93-6 antiviral

altumomabum immunoglobulin G 1 (mouse monoclonal ZCE025 anti-human antigen CEA), altumomab disulfide with mouse monoclonal ZCE025 light chain, dimer radiodiagnostic monoclonal antibody

ardeparinum natricum Sodium salt of depolymerized heparin obtained by peroxide degradation (at ardeparin sodium elevated temperature) of heparin from pork intestinal mucosa; the end chain structure appears to be the same as the starting material with no unusual sugar residues present; the low molecular weight heparin produced differs from the starting material in molecular weight only; the average relative molecular mass range is 5,500 to 6,500 daltons, 98 per cent of which ranging between 2,000 and 15,000; the degree of sulfation is approximately 2,7 per disaccharidic unit. anticoagulant

atrinositolum D-myo-inositol 1,2,6-tris(dihydrogen phosphate) atrinositol C6H15O15P3 28841-62-5 neuropeptide antagonist

avicatoninum 1-butyric acid-2-L-alanine-3-L-serine-7-(L-2-aminobutyric acid)-26-L-aspartic acid- avicatonin 27-L-valine-29-L-alaninecalcitonin (salmon) C147H243N41O46 103451-84-9 calcium regulator

azasetronum (±)-6-chloro-3,4-dihydro-4-methyl-3-oxo-N-3-quinuclidinyl-2H-1,4-benzoxazine-8- azasetron carboxamide C17H20ClN3O3 123040-69-7 serotonin receptor antagonist

192 Proposed International Chemical Name or Description, Molecular and Graphic formulae Nonproprietary Name Chemical Abstracts Service (CAS) registry number (Latin, English) Action and Use* berefrinum m-[(2R,5R)-2-tert-butyl-3-methyl-5-oxazolidinyl]phenol mixture with m-[(2S,5R)-2- berefrine tert-butyl-3-methyl-5-oxazolidinyl]phenol C14H21NO2 105567-83-7 mydriatic

besigomsinum (+)-(6S,7S, biar-R)-5,6,7,8-tetrahydro-1,2,3,13-tetramethoxy-6,7- besigomsin dimethylbenzo[3,4]cycloocta[1,2-f][1,3]benzodioxol-6-ol C23H28O7 58546-54-6 hepatoprotectant

bizelesinum 1,3-bis[2-[[(S)-1 -(chloromethyl)-1,6-dihydro-5-hydroxy-8-methylbenzo[1,2-6:4,3- bizelesin b']dipyrrol-3(2H)-yl]carbonyl]indol-5-yl]urea C43H36CI2N8O8 129655-21-6 antineoplastic

cefcapenum (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-pentenamido]-3-(hydroxymethyl)-8-oxo- cefcapene 5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, carbamate (ester) C17H19N5O6S2 135889-00-8 antibiotic

cetefloxacinum (-)-7-[(2S,3R)-3-amino-2-methyl-1-azetidinyl]-1-(2,4-difluorophenyl)-6-fluoro-1,4- cetefloxacin dihydro-4-oxo-3-quinolinecarboxylic acid C20H16F3N3O3 141725-88-4 antibacterial

193 Proposed International Chemical Name or Description, Molecular and Graphic formulae Nonproprietary Name Chemical Abstracts Service (CAS) registry number (Latin, English) Action and Use* cilansetronum (-)-(R)-5,6,9,10-tetrahydro-10-[(2-methylimidazol-1-yl)methyl]-4H-pyrido[3,2,1- cilansetron jk]carbazol-11 (8H)-one C20H21N3O 120635-74-7 serotonin receptor antagonist

cladribinum 2-chloro-2'-deoxyadenosine cladribine C10H12ClN5O3 4291 -63-8 antileukaemic

clinprostum (+)-methyl (3aS,5R,6R,6aS)-1,3a,4,5,6,6a-hexahydro-5-hydroxy-6-[(E)-(3S)-3- clinprost hydroxy-1-octenyl]-2-pentalenevalerate C22H36O4 88931-51-5 platelet aggregation inhibitor

dezinamidum 3-[(α,α,α-trifluoro-m-tolyl)oxy]-1-azetidinecarboxamide dezinamide C11H11F3N2O2 91077-32-6 anticonvulsant

dimiracetamum (±)-dihydro-1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-dione dimiracetam C6H8N2O2 126100-97-8 nootropic

duloxetinum (+)-(S)-N-methyl-γ-(1-naphthyloxy)-2-thiophenepropylamine duloxetine C18H19NOS 116539-59-4 antidepressant

194 Proposed International Chemical Name or Description, Molecular and Graphic formulae Nonproprietary Name Chemical Abstracts Service (CAS) registry number (Latin, English) Action and Use*

ecadotrilum N-[(S)-α-(mercaptomethyl)hydrocinnamoyl]glycine, benzyl ester, acetate (ester) ecadotril C21H23NO4S 112573-73-6 endopeptidase inhibitor

enadolinum N-methyl-N-[(5R,7S,8S)-7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-4- enadoline benzofuranacetamide C24H32N2O3 124378-77-4 analgesic

enazadremum 4,6-dimethyl-2-[(6-phenylhexyl)amino]-5-pyrimidinol enazadrem C18H25N3O 107361-33-1 antipsoriatic

fialuridinum 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-iodouracil fialuridine C9H10FlN2O5 69123-98-4 antiviral

195 Proposed International Chemical Name or Description, Molecular and Graphic formulae Nonproprietary Name Chemical Abstracts Service (CAS) registry number (Latin, English) Action and Use* ganefromycinum An antibiotic produced by Streptomyces lydicus. ganefromycin Ganefromycin is a complex antibiotic with two major components: a and p.

component α (2E,4E,6E)-7-[(2R*,3R*,5H*)-5-[7-[(3E,5E)-3-[[O-2,6-dideoxy-3-O-methyl-α-lyxo- hexopyranosyl-(1→4)-O-2,6-dideoxy-3-O-metnyl-β-ribo-hexopyranosyl-(1→4)-2,6- dideoxy-3-O-methyl-α-lyxo-hexopyranosyl]oxy]-2-[(2S*,3S*,4S*,6R*)-tetrahydro- 2,3,4-trihydroxy-5,5-dimethyl-6-[(1E,3Z)-1,3-pentadienyl]-2H-pyran-2- yl]propionamido]-2-methoxy-1,3-dimethyl-3,5-heptadienyl]tetrahydro-3-hydroxy-2- furyl]-2,4,6-heptatrienoic acid, 23-phenylacetate 114451-31-9

component β (2E,4E,6E)-7-[(2R*,3R*,5R*)-5-[7-[(3E,5E)-3-[[O-2,6-dideoxy-3-O-methyl-α-lyxo- hexopyranosyl-(1→4)-O-2,6-dideoxy-3-O-methyl-β-ribo-hexopyranosyl-(1→4)-2,6- dideoxy-3-O-methyl-α-lyxo-hexopyranosyl]oxy]-2-[(2S*,3S*,4S*,6R*)-tetrahydro- 2,3,4-trihydroxy-5,5-dimethyl-6-[(1E,3Z)-1,3-pentadienyl]-2H-pyran-2- yl]propionamido]-2-methoxy-1,3-dimethyl-3,5-heptadienyl]tetrahydro-3-hydroxy-2- furyl]-2,4,6-heptatrienoic acid, 24-phenylacetate 114451-30-8

C65H95NO21 (empirical molecular formula) growth stimulant; antibacterial (vet.)

glemanserinum (±)-1-phenethyl-α-phenyl-4-piperidinemethanol glemanserin C20H25NO 107703-78-6 serotonin receptor antagonist

grepafloxacinum (±) -1 -cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-7-(3-methyl-1-piperazinyl)-4-oxo-3- grepafloxacin quinolinecarboxylic acid C19H22FN3O3 119914-60-2 antibacterial

196 Proposed International Chemical Name or Description, Molecular and Graphic formulae Nonproprietary Name Chemical Abstracts Service (CAS) registry number (Latin, English) Action and Use" gusperimus (±)-N-[[[4-[(3-aminopropyl)amino]butyl]carbamoyl]hydroxymethyl]-7- gusperimus guanidinoheptanamide C17H37H7O3 104317-84-2 immunosuppressant

icodextrinum dextrin, having more than 85% of its molecules with molecular masses between icodextrin 1640 and 45000 with a claimed-average molecular mass of approximatively 20000 [C6H12O6]n 9004-53-9 peritoneal dialysis fluid

icoduline 6-(2-thiazolylamino)-m-cresol icodulinum C10H10N2OS 138511-81-6 non steroidal anti-inflammatory

idoxifenum 1-[2-[p-[(E-β-ethyl-α-(p-iodophenyl)styryl]phenoxy]ethyl]pyrrolidine idoxifene C28H30INO 116057-75-1 antineoplastic

igmesinum (+)-α-[(E)-cinnamyl]-N-(cyclopropylmethyl)-α-ethyl-N-methylbenzylamine igmesine C23H29N 140850-73-3 σ opiate receptor antagonist Proposed International Chemical Name or Description, Molecular and Graphic formulae Nonproprietary Name Chemical Abstracts Service (CAS) registry number (Latin, English) Action and Use* iobitridolum N,N'-bis(2,3-dihydroxypropyl)-5-[2-(hydroxymethyl)hydracrylamido]-2,4,6-triiodo- iobitridol N,N'-dimethylisophthalamide C20H28I3N3O9 136949-58-1 contrast medium

itasetronum 2-oxo-N-1αH,5αH-tropan-3α-yl-1-benzimidazoline-1-carboxamide itasetron C16H20N4O2 123258-84-4 serotonin receptor antagonist

leminoprazolum (±)-2-[[o-(isobutylmethylamino)benzyl]sulfinyl]benzimidazole leminoprazole C19H23N3OS 104340-86-5 antiulcer

levosimendanum mesoxalonitrile (-)-[p[(R)-1,4,5,6-tetrahydro-4-methyl-6-oxo-3- levosimendan pyridazinyl]phenyl]hydrazone C14H12N6O 141505-33-1 cardiac stimulant

lomerizinum 1-[bis(p-fluorophenyl)methyl]-4-(2,3,4-trimethoxybenzyl)piperazine lomerizine C27H30F2N2O3 101477-55-8 cerebral vasodilator

198 Proposed International Chemical Name or Description, Molecular and Graphic formulae Nonproprietary Name Chemical Abstracts Service (CAS) registry number (Latin, English) Action and Use*

losoxantronum 7-hydroxy-2-[2-[(2-hydroxyethyl)amino]ethyl]-5-[[2-[(2- losoxantrone hydroxyethyl)amino]ethyl]amino]anthra[1,9-cd]pyrazol-6(2H)-one C22H27N5O4 88303-60-0 antineoplastic

monatepilum (±)-N-(6,11-dihydrodibenzo[b,e]thiepin-11-yl)-4-(p-fluorophenyl)-1- monatepil piperazinebutyramide C28H30FN3OS 132019-54-6 calcium channel blocker

nasaruplasum prourokinase (enzyme-activating) (human clone pA3/pD2/pF1 protein moiety) nasaruplase C2031H3121N585O601S31 99821-44-0 enzyme

niravolinum N-methyl-2-(m-nitrophenyl)-N-[(1S,2S)-2-(1-pyrrolidinyl)-1-indanyl]acetamide niravoline C22H25N3O3 130610-93-4 diuretic

odapipamum (+)-(S)-8-chloro-5-(2,3-dihydro-7-benzofuranyl)-2.3,4,5-tetrahydro-3-methyl-1H-3- odapipam benzazepin-7-ol C19H20CINO2 131796-63-9 dopamine D1 receptor antagonist

orbifloxacinum 1-cyclopropyl-7-(cis-3,5-dimethyl-1 -piperazinyl)-5,6,8-trifluoro-1,4-dihydro-4-oxo-3- orbifloxacin quinolinecarboxylic acid C19H20F3N3O3 113617-63-3 antibacterial Proposed International Chemical Name or Description, Molecular and Graphic formulae Nonproprietary Name Chemical Abstracts Service (CAS) registry number (Latin, English) Action and Use* osateronum (+)-6-chloro-17-hydroxy-2-oxapregna-4,6-diene-3,20-dione osaterone C20H25ClO4 105149-04-0 antiandrogen, progestogen

paclitaxelum (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-1,2a,3,4,4a,6,9,10,11,12,12a,12b- paclitaxel dodecahydro-4,6,9,11,12,12b-hexahydroxy-4a,8,13,13-tetramethyl-7,11 -methano- 5H-cyclodeca[3,4]benz[1,2-b]oxet-5-one 6,12b-diacetate, 12-benzoate, 9-ester with (2R,3S)-N-benzoyl-3-phenylisoserine C47H51NO14 33069-62-4 antineoplastic

pidobenzonum 5-oxo-L-proline, p-hydroxyphenyl ester pidobenzone C11H11NO4 138506-45-3 melanine synthesis inhibitor

ramorelixum 1-[N-acetyl-3-(2-naphthyl)-D-alanyl-p-chloro-D-phenylalanyl-D-tryptophyl-L-seryl-L- ramorelix tyrosyl-O-(6-deoxy-α-L-mannopyranosyl)-D-seryl-L-leucyl-L-arginyl-L- prolyl]semicarbazide C74H95ClN16O18 136639-71-9 luteinizing-hormone-releasing- hormone inhibitor

200 Proposed International Chemical Name or Description, Molecular and Graphic formulae Nonproprietary Name Chemical Abstracts Service (CAS) registry number (Latin, English) Action and Use*

raxofelastum (±)-2,3-dihydro-5-hydroxy-4,6,7-trimetriyl-2-benzofuranaceticacid, acetate raxofelast C15H18O5 128232-14-4 antiasthmatic, anti-inflammatory

safironilum N,N'-bis(3-methoxypropyl)-2,4-pyridinedicarboxamide safironil C15H23N3O4 134377-69-8 collagen inhibitor

sameridinum N-ethyl-1-hexyl-N-methyl-4-phenylisonipecotamide sameridine C21H34N2O 143257-97-0 analgesic, local anaesthetic

sanguinarii chloridum sanguinarine chloride or 13-methyl[1,3]benzodioxolo[5,6-c]-1,3-dioxolo[4,5-i]= sanguinarium chloride phenanthridinium chloride C20H14CINO4 5578-73-4 anti-inflammatory; antimicrobial: antifungal

sebriplatinum (+)-cis-(1,1-cyclobutanedicarboxylato)[(2R)-2-methyl-1,4-butanediamine- sebriplatin N,N']platinum C11H20N2O4Pt 110172-45-7 antineoplastic

sepimostatum 6-amidino-2-naphthylp-(2-imidazolin-2-ylamino)benzoate sepimostat C21H19N5O2 103926-64-3 protease inhibitor

201 Proposed International Chemical Name or Description, Molecular and Graphic formulae Nonproprietary Name Chemical Abstracts Service (CAS) registry number (Latin, English) Action and Use*

siratiazemum (+)-(2S,3S)-2,3-dihydro-3-hydroxy-5-[2-(isopropylmethylamino)ethyl]-2-(p- siratiazem methoxyphenyl)-1,5-benzothiazepin-4(5H)-one acetate (ester) C24H30N2O4S 138778-28-6 antianginal, antihypertensive

sonerminum 3-157-tumor necrosis factor (human) sonermin C767H1204N210O229S2 144916-42-7 antineoplastic

sulopenemum (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[[(3S)-tetrahydro-3-thienyl]thio]-4-thia-1 - sulopenem azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, (R)-S-oxide C12H15NO5S3 120788-07-0 antibacterial

tallimustinum N"-(2-amidinoethyl)-4-[p-[bis(2-chloroethyl)amino]benzamido]-1,1',1"-trimethyl- tallimustine N,4':N',4"-ter[pyrrole-2-carboxamide] C32H38CI2N10O4 115308-98-0 antineoplastic

tarazepidum (-)-N-[(S)-2,3-dihydro-1 -methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-5,6- tarazepide dihydro-4H-pyrrolo[3,2,1-ij]quinoline-2-carboxarnide C28H24N4O2 141374-81 -4 choleocystokinin inhibitor

202 Proposed International Chemical Name or Description, Molecular and Graphic formulae Nonproprietary Name Chemical Abstracts Service (CAS) registry number (Latin, English) Action and Use*

teloxantronum 7,10-dihydroxy-2-[2-[(2-hydroxyethyl)amino]ethyl]-5-[[2- teloxantrone (methylamino)ethyl]amino]anthra[1,9-cd]pyrazol-6(2H)-one C21H25N5O4 91441-48-4 antineoplastic

thymoctonanum N-[N-[N2-[1-[N-[N-(N-L-leucyl-L-α-glutamyl)-L-α-aspartyl]glycyl]-L-prolyl]-L-lysyl]-L- thymoctonan phenylalanyl]-L-leucine C43H67N9O13 107489-37-2 immunomodulator

tiquesidum (25R)-5β-spirostan-3β-yl4-O-β-D-glucopyranosyl-β-D-glucopyranoside tiqueside C39H64O13 99759-19-0 antihyperlipidaemic

tirapazaminum 3-amino-1,2,4-benzotriazine 1,4-dioxide tirapazamine C7H6N4O2 27314-97-2 antineoplastic

203 Proposed International Chemical Name or Description, Molecular and Graphic formulae Nonproprietary Name Chemical Abstracts Service (CAS) registry number (Latin, English) Action and Use* troglitazonum (±)-all-rac-5-[p-[(6-hydroxy-2,5,7,8-tetramethyl-2-chromanyl)methoxy]benzyl]-2,4- troglitazone thiazolidinedione C24H27NO5S 97322-87-7 hypoglycaemic

valsartanum N-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]-N-valeryl-L-valine valsartan C24H29N5O3 137862-53-4 antihypertensive

zamifenacinum (R)-3-(diphenylmethoxy)-1-[3,4-(methylenedioxy)phenetyl]piperidene zamifenacin C27H29NO3 127308-82-1 muscarin receptor antagonist

204 AMENDMENTS TO PREVIOUS LISTS

Chronicle of the World Health Organization Vol. 7, No. 10, 1953

Proposed International Nonproprietary Names (Prop. INN): List 1

p. 304 delete insert corticotrophinum corticotropinum corticotrophin corticotropin

Chronicle of the World Health Organization Vol. 12, No. 3, 1958

Proposed International Nonproprietary Names (Prop. INN): List 6

p. 103 delete insert corticotrophinum zinci corticotropinum zinci hydroxydum hydroxydum corticotrophin zinc hydroxide corticotropin zinc hydroxide

Supplement to WHO Chronicle Vol. 37, No. 5, 1983

Proposed International Nonproprietary Names (Prop. INN): List 50

p. 14 icospiramidum replace the chemical name by the following: icospiramide 8-[cis-4-cyano-4-(p-fluorophenyl)cyclohexyl]-1-(p-fluorophenyl)-4-oxo-1,3,8- triazaspiro[4.5]decane-3-acetamide

WHO Drug Information, Vol. 4, No. 2, 1990

Proposed International Nonproprietary Names (Prop. INN): List 63 p. 4 delete insert docetaxolum docetaxelum docetaxol docetaxel

WHO Drug Information, Vol. 4, No. 4, 1990

Proposed International Nonproprietary Names (Prop. INN): List 64 p. 13 leuciglumerum replace the molecular formula and the graphic formula by the following: leuciglumer (C6H13NO2-C6H11NO4)n

205 WHO Drug Information, Vol. 5, No. 4, 1991 Proposed International Nonproprietary Names (Prop. INN): List 66 p. 4 dexfosfoserinum replace the chemical name by the following: dexfosfoserine (+)-L-serine dihydrogen phosphate (ester) p. 6 ilatreotidum include the following CAS registry number: ilatreotide 119719-11-8

WHO Drug Information, Vol. 6, No. 2, 1992 Proposed International Nonproprietary Names (Prop. INN): List 67 p. 9 satumomabum include the following CAS registry number: satumomab 144058-40-2 p. 12 limaprostum replace the chemical name by the following: limaprost (E)-7-[(1R,2R,3R)-3-hydroxy-2-[(E)-(3S,5S)-3-hydroxy-5-methyl-1-nonenyl]-5- oxocyclopentyl]-2-heptenoic acid

Procedure and Guiding Principles The text of the Procedures for the Selection of Recommended International Nonproprietary Names for Pharmaceutical Substances and General Principles for Guidance in Devising International Nonproprietary Names for Pharmaceutical Substances will from now on be reproduced in uneven numbers of proposed INN lists only.

206 SELECTED WHO PUBLICATIONS OF RELATED INTEREST

Price*(Sw. fr.)

The use of essential drugs Fourth report of the WHO Expert Committee WHO Technical Report Series, No. 796 1990 (57 pages) 8.-

WHO model prescribing information: drugs used in anaesthesia 1989 (53 pages) 11.-

WHO model prescribing information: drugs used in parasitic diseases 1990 (128 pages) 21.-

WHO model prescribing information: drugs used in mycobacterial diseases 1991 (40 pages) 9.-

Guidelines for developing national drug policies 1988 (iv + 52 pages) 11.

The International Pharmacopoeia, third edition Volume 1: general methods of analysis. 1979 (223 pages) 24.- Volume 2: quality specifications. 1981 (342 pages) 36.- Volume 3: quality specifications. 1988 (407 pages) 64.-

Basic tests for pharmaceutical substances 1986 (vi + 204 pages) 34.-

Basic tests for pharmaceutical dosage forms 1991 (v + 129 pages) 24-

International Nonproprietary Names (INN) for Pharmaceutical Substances, Cumulative List No. 8 1992 (xlvi + 692 pages) 140.-

Further information on these and other World Health Organization publications can be obtained from Distribution and Sales, World Health Organization, 1211 Geneva 27, Switzerland

* prices in developing countries are 70% of those listed here.