An international drug safeguard plan

J. &on.

Dis. 1964, Vol. 17, pp. 565-581. Pergamon Press Ltd. Printed in Great Britain

Editorial AN INTERNATIONAL

DRUG SAFEGUARD

PLAN

(Received 13 February 1964)

of the use of thalidomide during pregnancy, and subsequent anxieties about possible serious side-effects of other recently introduced drugs, have aroused concern in many countries, both among physicians and among the general public. Some risk necessarily attends every introduction of a new drug to clinical use. Even experimentation in several distinct species of animals provides no guarantee that a drug will not harm man. Indeed the surprise is not that the thalidomide tragedy occurred, but rather that, despite the introduction of so many new drugs, no incident of this magnitude is known to have occurred previously. The lesson to be learned is not one of how such incidents can be totally prevented: it is that the tragedy need not have been so great, need not have repeated its pattern so fully in several countries. To the physician, primary emphasis must always lie on healing the sick, not on studying drugs. He properly views with caution any new therapeutic measure that he suspects may do harm as well as good. Yet he must admit that too little is known about the total effects of even well-established remedies; to prefer indefinitely the side-effects of the drugs we know to all risk of other side-effects from new drugs is to halt all advance in drug therapy. The magnitude of that risk, however, must be minimized, by continual vigilance and by rapid collection of records of suspicious cases. THE tragic consequences

NEW

DRUGS

The accelerated discovery and development of new drugs has added greatly to the seriousness of problems concerned with their introduction to therapeutic practice. The large number of drugs under study at one time could reduce the degree of disinterested attention given to reports on any one drug. The menace of side-effects may be most emphasized during the testing of a new drug, but experience has shown that they can threaten patients even after a drug has been approved for general use; this risk is naturally greatest when the search for side-effects during the earlier testing has been incomplete, or when only one section of the population is liable to them. A full rationale for elimination or controlled use of drugs with noxious, side-effects must depend largely upon the insight into the complex of drug action gained by pharmacologists, physiologists, and biochemists. Success here cannot always keep pace with the introduction of drugs to therapeutic practice, especially when apparent benefits from a new drug create pressure for its wide use. Therefore, great importance attaches to empirical detection of these effects by the pharmacologists, physicians, and statisticians involved in laboratory and clinical testing, and also to development of a rapid warning system for suspicions about a drug after its release for general use. No 565

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one will deny the need for greater medical understanding; perhaps the parallel need for reliable, speedy, and efficient collection and analysis of information is not yet appreciated. Although the drama of thalidomide has focused world attention on drug safety, this drug may not typify the most important or most difficult situation. The cost of each month of delay in detecting the dangers of such a drug-in terms of human misery-is high, but side-effects so great could not long escape notice. Consider instead a drug that produces harmful effects much more rarely, perhaps in special environmental conditions or in persons with a particular gene;ic make-up or predisposition rooted in medical history; many more cases of these effects might occur, although spread over a long period of time, before their origin was suspected. Again, a drug of only moderate value for most cases might be much more effective (against the same disease) in certain circumstances; this would be important not only to the small minority of patients but also as a lead for research directed to more generally improved therapy, yet in the absence of systematic search the facts could long escape detection. A logically similar position may arise in respect of two drugs, or two therapeutic regimes based on the same drug, when the difference in average effectiveness is small and neither has major harmful side-effects. One of the alternatives can easily become tied as the preferred, either without planned trial or after trial inadequate to the disentangling of a complex pattern. Only massive evidence will then induce a change. Yet how much might it mean to the full picture of therapeutic benefit if the drug that is on average poorer is discovered to be especially good for persons of blood group B, persons with excessive thyroid activity, or persons engaged in heavy physical Iabour. In all these situations, elucidation of drug effects could add much to the totality of life and health. Good clinical studies, however, are always limited by availability of qualilied investigators and by the numbers of cases they encounter. To say that all possibilities should be investigated is unrealistic. Guidance on questions that merit use of limited clinical facilities may contribute as greatly to improved therapeutic practice as safeguards against the more dramatic disasters. This guidance should come from systematic collection, collation, tabulation, and analysis of all relevant information, from planned scanning of reliably maintained records, and from growing experience; these would provide clues to comparisons that may yield gains from controlled tests and other specially directed research. THE

INTRA-NATIONAL

SCENE

The prime responsibility for discovery and early study of new drugs no longer lies with academic scientists; it has become a business enterprise, at least in respect of drugs that are variations on a standard theme rather than of totally new character. Doubtless the major drug manufacturing companies wish to maintain high ethical standards in their research and in the exploitation of their products. Inevitably, however, the pressure to be first with a new product, which has the dual aim of giving therapeutic benefit as soon as possible and of capturing markets, creates a tension that did not exist in a more leisurely age. This could contribute to a relaxation of standards unless a compensating system of safeguards is applied. Within any one country, the nature of these safeguards is a question for tha country alone. Probably the trend in most countries will be to legislative action:

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recent events are causing many governments to re-examine and revise existing legislation. The regulation of clinical trials, the relations between a drug company and the physicians and their patients who participate in a trial, the licensing of new drugs for general use, and the penalties for supplying false information to the licensing authority OI for concealing evidence of side-effects are likely all to pass under review. The new regulations of the U.S. Food and Drug Administration illustrate these points well, but no one procedure is likely to prove ideal for all countries. Special problems arise in connection with any drug that is to be introduced into one country after being first manufactured and tested in another. Whether the introduction involves import of the drug itself for distribution, or whether the intention is to begin manufacture in the recipienl country, the drug must satisfy any licensing requirements of the recipient country. Countries will differ in their willingness to take account of evidence on efficacy and safety accumulated outside their own territories. Nevertheless, any measures that encourage acceptance of well-authenticated evidence will benefit drug manufacturers by reducing the need for extensive tests in every country. Moreover, the public and the medical profession of one country will gain from any goodsystem of reporting noxious side-effects that operates in other countries; especially when these are rare, each instance recorded may be of great importance to the safe usage of this drug. Similarly, systematic compilation of records that will from time to time point to a need for special investigation, either of the safety of a drug in current use or of the possible superiority of a drug treatment differing from that currently used, should yield benefits that in the long term far outweigh the heavy costs of an effective plan. Whether or not compulsion is desirable, even within one country statutory requirements on the collection of information (with the reliability of detail that is necessary) are scarcely practicable at present. Much greater hope may lie in a plan for voluntary action, carefully balanced to secure benefits to all parties involved. This article is directed particularly at the development of adequate channels of information and the devising of rules for interpretation and action, with special stress on international exchange. It must be emphasized that some important information will properly be considered confidential by drug manufacturers and others; every mention of ‘transmission of information’ is to be taken as implying all reasonable protection of its confidential character. PHASES IN ESTABLISHING

A NEW DRUG

Between the chemist’s production of a compound that might have therapeutic and the release of that compound as a drug available for prescription, six phases usefully be distinguished : 1. Screening in biological tests. 2. Decision on whether clinical testing is desirable and justifiable. 3. Planning of clinical investigations. 4. Execution of these investigations. 5. Transmission of information to all concerned with the licensing, manufacture, use of a drug. 6. (In any country that operates a licensing system.) Evaluation of all evidence decision on whether a licence is to be granted.

use may

and and

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D. J. FINNEY BIOLOGICAL

SCREENING

OF

CHEMICAL

COMPOUNDS

Despite the ingenuity exercised by chemists in synthesizing compounds with structures thought likely to have beneficial therapeutic action, it appears that a first separation of the possibly useful from the useless can be effected only by biological screening. This involves testing each compound on small numbers of animals or bacterial cultures or in other suitable biological situations, and selecting the few compounds that seem to perform best. Statisticians have recently begun to study the efficiencies of screening processes [l-6]. They have learned much of how to plan a succession of stages of screening optimally, in order to separate a large number of compounds into the vast majority with no therapeutic activity against a particular disease and the small minority with some sign of activity. Exact definition of the problems is difficult, the theory is complicated, and the indications from the few animals that can be afforded for each of a large number of compounds can be unreliable, but substantial improvements are being achieved.

PROPOSALS

FOR

CLINICAL

TRIALS

Selection of a drug as successful in screening is not an immediate justification for a clinical trial. LITCHFIELD[7]has shown how little is known of the correlations between side-effects in man and in laboratory animals. Moreover, there is no sure way of determining the dose appropriate to man from results for one or more animal species. PAGET [8]has emphasized the responsibility of the physician who first uses a drug in humans, however many animal species may have received it without toxic reactions. Nevertheless, before a formal clinical trial is planned, it is reasonable to require evidence of freedom from toxicity and serious side-effects in two or more species of animal and, usually, in volunteer humans. As already noted, opportunities for making clinical comparisons between drugs are limited, by the numbers of suitable subjects available and by the availability of physicians with appropriate skills, interests and equipment. Certainly the opportunities in respect of any disease will almost always be too few for all the comparisons that seem of interest. Considerations of ethics and of medical progress agree in demanding that patients be not exposed to the worries (and occasionally the risks) nor physicians to the expenditure of time, involved in a controlled clinical trial unless responsible opinion judges the particular comparisons under test to have a reasonable chance of leading to improvements in medical practice. For example, the justification for testing a so-called new drug that is in reality only a well-established one modified in chemical structure in some apparently unimportant part of the molecule is open to question; lesser costs or probable freedom from noxious side-effects would be good reasons, but not the purely commercial advantage of marketing a di’rent product indistinguishable from the old in all but name. After considerable thought and discussion, sound principles will perhaps be enunciated and applied for guiding the steps between success in screening and agreement to undertake clinical trial. Rapidly expanded programs of chemical development of new drugs make this now one of the most important ethical and practical aspects of drug research. As is now recognized, a trial should be carefully planned and begun as soon as the need for it is clear, before prejudices develop and inhibit an

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unbiased approach. Yet the need for adequate preparative work must not be underestimated. The prerequisites of a trial fall into two classes. One class relates to the desirability of conducting a trial on this drug for this disease, in relation to the current predictions of success and the competing claims of other research. Without a formal controlled trial, objective assessment of the merits of a drug is scarcely ever possible, but without reasonable promise no trial should be conducted. The other class includes information on which to base the choice of dose levels, and frequency and method of administration. Even if alternative levels and methods are themselves to be the subject of further clinical study, some limitation to a small number of alternatives is inescapable. Circumstances will dictate what type of search is permissible in order to assess the highest dose that may safely be used without fear of toxicity. No precise rule is likely to be found, but the problem of choosing the dose for the first human subject has been encountered by many investigators; some form of operational research might enable rough rules at present in use to be improved. During the last thirty years of expansion in drug therapy, medical scientists with intimate knowledge of particular diseases have made preliminary clinical explorations of promising new drugs on small numbers of patients. Necessarily their approaches to these first studies of dosage, efficacy, and harmful effects have had strongly empirical features; the ability of the leading men in this field to combine broad experience with special knowledge of the pharmacology of new drugs must have meant much to the improvement of therapeutic practice, but in the first place it provides the evidence on which the justification for a more formal trial is to be judged. Can we not ask some of these investigators to attempt objective accounts of their processes of thought and of evaluation? If these accounts were brought together, both their differences and their agreements would be illuminating; from them, we might begin to understand better when and how a screened compound should become a drug under trial. The problems are not easy; they may call for combination of medical, pharmacological and biometric judgment in a new way; there can be no reason for not trying to solve them. PLANNING

OF TRIALS

During the last twenty years, the understanding of the structure of clinical trials has been greatly advanced. Requirements that once had to be hotly debated for each new trial are now widely accepted as constituents of a sound research program. Randomization of subjects, blind and double-blind procedures, use of controls and placebos, replication, coordination of studies in different centres, and other measures intended to eliminate bias and to increase precision, have amply proved their value, although undoubtedly they increase the administrative costs and difficulties of a trial. HILL [9] has recently summarized the ethical considerations that affect the planning of trials. Above all else, medical ethics demand that the planning be thorough and that detailed instructions be formulated and strictly followed, in order that whatever discomfort or risk the subjects experience shall lead to maximum improvements in medical practice. No detailed account of the methodology of clinical trials can be given here, but one or two points may appropriately be mentioned. Exact definition of categories of

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D. J. FINNEY

subjects for inclusion in the trial, and exact specification of treatments to be given and records to be made are necessary; in order to prevent bias, they must precede admission of any subjects. One potential source of confusion in international comparisons must be remembered. The first evidence pertaining to side-effects of a new drug is often obtained from healthy patients, members of staff involved in the research project or other volunteers in normal health; their experiences may be different from these of sick patients who receive the drug for therapeutic purposes, especially if side-effects happen to be of a character to which sections of the population (e.g. children, adolescents, or pregnant women) are peculiarly sensitive. Even volunteers from among the sick for whom the drug is intended may show atypical effects (both subjective and objective). Hence assessment of the relevance of findings in another country will always need to take account of how subjects were selected. EXECUTION

OF

CLINICAL

TRIALS

However well planned a clinical trial may be, it is useless unless the instructions are conscientiously and efficiently followed. Moreover, the importance of even one or two instances of noxious side-effects for the general evaluation of a drug indicates the need to write instructions that require every suspicious case to be reported. If evidence on the performance of a drug in one country is to carry any weight in respect of its introduction into another country, as much attention should be given to the degree of confidence that side-effects did not escape recording as to the indications of therapeutic benefit. Of special importance is the recording of rarely occurring idiosyncratic reactions since only extensive collection of evidence can bring to light unexpected associations. In so far as national legislation requires assurances of efficacy and safety before a new drug is licensed, it must surely be in the interests of manufacturers to obtain this information economically. Any tightening of regulations on the licensing of new drugs, such as that recently made in the United States of America, will in part be aimed at improving the quality of clinical trials, which may imply increasing their cost to the manufacturers. An international system of certifying the planning and execution of clinical trials, with strong emphasis on objective recording of all side-effects and idiosyncratic reactions, could aid manufacturers if its repute were such that its statements were acceptable as evidence to national health authorities. Any good clinical trial will provide for planned recording of untoward reactions that follow administration of a drug, whether or not these are thought at the time to have been caused by the drug. Nevertheless, a side-effect that occurs frequently enough to be important in assessment of drug safety may yet be too rare for more than one or two cases to be encountered during the trial and so its association with the drug may escape notice. A drug whose therapeutic merits are great is especially open to the risk that clinical trials pronounce in its favor before a low rate of idiosyncratic reactions (say 1 per cent or 0.1 per cent) is noticed, yet such a rate might consitute a serious defect of the drug. TRANSMISSION

OF

INFORMATION

Within any one country, the form in which information on efficacy and safety is transmitted to the licensing authority is solely a matter for national regulation. The

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present regulations in many countries have recently been discussed and summarized by WHO [lo, 111. In most countries, these consist primarily of rules on chemical composition and purity, labeling, packaging, and allied matters, and take little account of evidence on therapeutic benefits and safety or how this evidence was obtained. The situation may change rapidly as a result of the intensive discussions on drug safety initiated by so many governments. If a drug produced in one country is to become acceptable in another, two national systems of regulation are involved; the authorities .of the recipient country may in future require evidence of efficacy and safety, either by new trials in this country or from trials already conducted. If the drug is to be manufactured in the recipient country, information on chemical specifications must first be transmitted from one manufacturer to another, and doubtless information on efficacy and safety will pass at the same time. The public will gain in protection, and physicians will gain in assurance in the use of new drugs, if decisions can be based on experience in more than one country, especially in respect of side-effects. Thalidomide has exposed this issue as urgent. Manufacturers will economize and expedite (not eliminate) new testing if good certified evidence on the efficacy and safety of a drug in one country can be quoted in support of its introduction into another. All interests will be served by creation of machinery that, under proper safeguards, facilitates transmission of relevant information in a reasonably standardized form. Such machinery must : 1. Operate speedily as well as efficiently. 2. Have advantages so self-evident as to ensure the willing collaboration of reputable drug manufacturers as well as of medical and health authorities. 3. Pay regard to the needs of manufacturers for legitimate protection of confidential information on materials and processes. 4. Be precise in all its operations, while retaining a flexibility that permits adaptation to changing needs. LICENSING Conditions pertaining to the licensing of a new drug for sale to the public or for use by prescription are likely to become increasingly strict in many countries. Indeed, controls may be extended (as in the U.S.A.) to cover the phase of clinical trials. Reports indicate that the recent changes in the U.S.A. have led to inundation of the Food and Drug Administration with masses of evidence pertaining to new drugs, and this pattern may be repeated elsewhere. Despite differences between the laws of different countries, the principles of sound evidence on drug efficacy should remain constant. There is need for clarification and exposition of these principles, with especial reference to licensing requirements. Anything that can be done to encourage systematic and simple presentation of the results of clinical trials, so that their evidence can be concisely summarized in standardized form for various national authorities, will be valuable. MONITORING However great the precautions before a new drug is released, knowledge will never be complete, and errors and misjudgments must occur. For example, a slight average

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D. J. FINNEY

advantage for a drug may mask a bigger benefit for some classes of case and perhaps even inferiority to the previous alternative for others; or idiosyncratic responses of a dangerous character may occur too frequently for general usage of the drug to be advisable although too rarely to have been detected in the clinical trials; or the dose or method of administration recommended may not be ideal for all cases. Without an objective system of extensive and long-term monitoring, possibilities such as these may easily escape detection. By monitoring is meant any systematic collection and analysis of information from the normal therapeutic use of drugs, with the object of acquiring evidence on adverse effects or other phenomena associated with this use. Monitoring might involve a panel of physicians (or of hospitals), chosen for their interest and reliability and sufficiently numerous for the inevitable withdrawals and replacements not to cause too great a disturbance. These would undertake to report in detail all uses of specified drugs, together with information on the patients receiving each (sex, age, occupation and environment, health and medical history); they would also report every instance from a long, carefully prepared, list of untoward reactions and events among their patients, without regard to whether or not they believed a particular instance to be consequential upon the drug regime. Such reports would be continuously compiled and analyzed by one central computer, with a view to picking up any hints of unexpected drug behaviour. Monitoring is not an alternative to, but an important complement of formal clinical testing. Only exceptionally will monitoring information in itself be so striking as to lead to an immediate change of official policy or of therapeutic practice. The purpose is rather to ensure that the most effective use is made of observations on a large number of persons who receive a new drug, so that a warning of any untoward consequences can be given as early as possible and research effort directed at the circumstances. Three qualities of monitoring need to be distinguished. All would depend upon reporting of every instance of certain specified reactions and events, by a panel that would change as little as possible with time. They would differ in the availability of supporting information. They are: I.

Additional information available on attributes (sex, age, physical character istics, occupation, etc.) and medical history of each case. Increased possibilities of subclassification improve chances of detecting important associations. II. Record of drugs recently administered to each case, and of diagnostic circumstances, also reported. The possibility of rapidly detecting association between change in absolute frequency and the use of drugs should be much increased. III. No other information. Only the absolutefrequency of any one reaction is known, but any sudden changes in this will arouse suspicions about recent trends in therapeutic practice. Although the aim will be to secure the standard of I, I believe it would be a mistake to despise III. A sound monitoring program might begin relatively easily with II or III as its basis; as experience grew and ability to handle extensive records was acquired, evolution towards I should be encouraged. The system of ascertainment of cases must also be specified, and this affects the types of relative frequency and incidence rates that can be studied. The alternatives are : Notification arises from the occurrence of any one of a specified list of E (event): untoward reactions.

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Records of prescriptions are scanned for instances of specified drugs, and the histories of these cases are traced. P (patient) : All patients in specified categories (or a sample of these) are recorded and their drug histories are taken. Any attempt to begin monitoring with records obtained from a great number of physicians, indiscriminately chosen and of widely ranging abilities and enthusiasms for the task, is doomed to failure. Even for those who are keenly interested, maintenance of good recording practice will be difficult; those who are pressed to help against their inclination may begin satisfactorily, but almost inevitably the reports they send will become less and less reliable. The wisest course seems to be in the first instance to recruit, for a particular monitor field, reporters who volunteer to help on account of genuine interest in the project. One would then hope, by demonstration of the benefits of monitoring and by education in the requirements for recording, to increase steadily the number of participants. Monitor records will need to be stored on magnetic tape, and continuously tabulated and scanned by a computer. The computer program will carry instructions to signal any high incidence of a particular untoward reaction or any marked discrepancies between apparently similar drugs or similar groups of patients. I discuss elsewhere the logic and interpretation of monitoring [12]. Such a signal will not in itself be proof of a drug effect. The intention is to obtain warnings and leads-warnings that in some circumstances a certain drug may be less safe than is believed, and leads that suggest how a drug may be used more effectively. Each needs to be followed by planned research studies: pharmacological investigation may be wanted, or proposals for further clinical trials may emerge and be judged of more immediate importance than work with newer drugs. When attention has been directed to a particular question, determination of whether this drug is dangerous in these circumstances should not be difficult; the problem lies in selecting the questions that merit attention. In addition to protecting patients and physicians, a good monitor system will benefit drug manufacturers. At present, discovery of side-effects with low incidence rates is a haphazard process, largely depending upon the extent to which reports from one or two physicians stimulate others to look more closely at their cases, or to report reactions that they previously thought scarcely worth comment. Often early reports are in communications to the medical press. A particular side-effect may receive publicity, inadvertent or deliberate, without regard to whether the association with a drug has been clearly demonstrated or may be a spurious indication from few or biased records. If monitor reporting of an untoward reaction became standard practice, replacing the uncertainties of writing or not writing to a medical journal, informing or not informing the drug manufacturer, publicity would follow only from sound evidence. The records held by the monitor organization, both individually and in summary tabulations, would not be published, but would be confidential information on which recommendations for action would be based. A monitor signal, and the action taken or recommended because of it, would be notified to the manufacturer concerned at the same time as to health authorities or to research teams charged with responsibility for further investigations. When a drug has been clearly shown to be unsafe, maximum medical and general publicity is desirable; if monitoring operates objectively and efficiently, rumours and vague suspicions can properly be kept to a restricted circle during a phase of urgent special investigation. Consideration may be D (drug):

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D. J. FINNEY

given to the possibility that a manufacturer, faced with legal action on account of sideeffects alleged to have been caused by one of his drugs, might obtain from the monitor organization an up-to-date summary of information pertaining to the drug; this, of course, would be for use only in his legal defence, and not for advertising or any other purpose. Effective monitoring will be expensive, but less so in reality than the consequences of misuse of drugs. For much of the time, conclusions will be negative, but occasional dividends in the form of rightly aroused suspicions should amply repay the investment.

NATIONAL

AND

INTERNATIONAL

MONITORING

In the first instance, monitoring is likely to be undertaken on a national basis; several countries are already experimenting with simple reporting programs. Details must be carefully elaborated, with attention to special features of the medical scene in each country. In the United Kingdom, for example, the National Health Service provides possibilities of ascertainment by way of prescription forms. But early development of international collation of national monitor records is essential. Whatever standards may be set as the minimal evidence that should produce a signal calling for action, the delay will be reduced if records from several countries are combined: in respect of a particular drug, each of five countries might have too few reports of apparent side-effects for any special inquiry to be demanded, yet the totality of records might suffice to show a clear association with some use of the drug. There are obvious complications in establishing international monitoring, but this must come. Unless an early start is made, national organizations will diverge as they grow. Details of recording will differ in non-essential features, different arbitrary conventions will be adopted, and national attachments to different practices and terminologies will become strong; all these will be serious barriers to eventual integration in an international plan. TOLERATED

RATES

OF

INCIDENCE

The rate of incidence of adverse side-effects that can be tolerated without necessitating withdrawal or restriction of a drug evidently depends on the disease against which the drug is to be used and on the prognosis for individual cases with this drug or with alternatives. A rate thought reasonable for a drug that halts the progress of leukemia is likely to be quite improper in an analgesic; attempts to set a standard for the minimal relative frequency of an event that is to be judged important are useless unless made with reference to a particular drug and a particular disease. Nevertheless, clear objective thinking on this matter is needed, since very different opinions may be expressed on one set of circumstances. For example, triparanol, introduced as an inhibitor of cholesterol biosynthesis, was widely used in the U.S.A. and then withdrawn from use in April 1962 because of suspected harmful side-effects. In evidence submitted to a U.S. Senate Sub-Committee [13], the Deputy Commissioner of the Food and Drug Administration implied that 4 cases of cataracts in 300,000 patients who had received the drug “raised substantial doubt as to the safety of the drug”; he was taking into account results from tests on animals, and did not claim to refer to complete ascertainment of all cataracts in these patients. Yet, a month later, in

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discussions concerned with the question of removing the drug from the market, the manufacturers were content to claim that “the side-effects of all types reported to us to date total substantially less than 1 per cent of the patients treated”. Even when allowance is made for the inclusion of many different event-types, the contrast between rates of about 0.00001 and perhaps 0.005 is striking!

PROPOSAL

In relation to all the above statements, I make the following proposal: That a small international Working Party be invited to draw up a detailedplan to aid the international flow of essential information on tests of new drugs, with particular reference to the efficacy found in well-planned clinical trials and to all indications of important side effects. That the Working Party shall consider both short-term and long-term objectives. The urgent short-term need is to devise safeguards that will minimize the extent of the disaster if any new drug with highly specific and noxious side-effects is brought into use, by operation of a system of rapid warnings. In the long term, the need is to raise the standards, ethical and scientific, of all aspects of drug testing, to aid manufacturers by encouragement of international recognition of trials and records that conform to these standards, and to establish monitoring programs that will produce warnings of dangers and leads to improved drug use. That the Working Party shall give particular attention to recommending the scale of any continuing international activity, including, of course, assessment of staff and financial requirements. Remarks 1. This proposal is not intended to rival any plan operated by WHO. At present, WHO is acting only as a channel of communication between governments in respect of decisions by one government to restrict or prevent use of a drug. My proposal seeks to supplement this by initiating among a few countries a program more intensive than is at present practicable for all members of WHO. Certainly WHO must be represented on the Working Party, and the approval and support of WHO should be sought. The plan that I envisage is an aspect of world health that could logically be included within WHO, but whether or not the immediate aim should be to make it wholly a WHO activity is for the Working Party to discuss. Much good can be secured rapidly by an agreement that covers two or three countries, a pilot plan to which other countries may accede as experience grows; for this to be delayed by the difficulties inherent in a more extensive international agreement would be unfortunate. 2. The Working Party should be small enough for rapid and effective progress and must not be inflated excessively by insistence on formal representation of every relevant interest. The members should be individuals with ideas and talents to contribute, not delegates with positions to defend. Nevertheless, the membership obviously must in some way represent several of the countries (small as well as large) most concerned with new drugs, as well as the professions and disciplines involved-public health authorities, drug manufacturers, pharmacologists and others concerned with research into drug action, physicians and other clinicians, and statisticians. This Working Party

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D. J.

FYNNEY

should be established at the earliest possible date, with the intention of initiating business by correspondence and holding a meeting in 1964. 3. Although every country to which import or export of drugs is important should

eventually be welcomed as a collaborator, success must not be allowed to depend upon complete agreement between countries with very different interests. 4. One approach that the Working Party might favour is that of devising an ideal pattern of control for drug testing, licensing and monitoring and then seeking to persuade governments to incorporate this into national legislation. The alternative is to design a plan that attracts the voluntary support of manufacturers, by reason of manifest advantages to them; this will necessitate a method of operation that makes evidence compiled and forwarded through the plan readily acceptable by national authorities, within the framework of existing regulations. This will not easily be achieved, but I strongly advocate a voluntary system. I believe chances of success to be higher if the plan is necessarily designed to be attractive to manufacturers as well as to the medical profession and the public; I think stability can be achieved only by seeking collaboration in common interests. Such a plan must give immediate benefits even if only a few major manufacturers in two or three countries participate initially, but must increase in value with the accession of more manufacturers in these and other countries. 5. The Working Party may be helped by having an outline of a plan as a basis for discussion and amendment. I therefore append a draft. This almost certainly needs extensive modification and more exact phrasing. I urge that, however drastic the revision, the aim be maintained as a proposal for international action. If efforts are diverted into consideration of the general ethical and scientific principles of drug research and clinical experimentation, important though these are, progress toward this needed action may be halted for a long time. We must not lose the sense of urgency. Much can be achieved quickly without disturbing the freedom of countries to determine their own research practices and to administer their own methods of drug licensing. 6. This paper has been written by a statistician with limited knowledge of medical organization and practice. My aim is to stimulate others better fitted than I to initiate appropriate action. We need to work for greater safety in drug therapy; we are likely to secure this by steady improvement from a reasonable collaborative start rather than from immediate formulation of an ideal plan. 7. I am grateful to many friends and colleagues for comments on the first version of this paper. My efforts were originally encouraged by Professor DAVIDD. RUTSTEIN of the Harvard Medical School, and my suggestions for monitoring the action of drugs in normal use derive largely from an excellent memorandum prepared by Dr. DAVID P. RALL of the U.S. National Institutes of Health. Nevertheless, the responsibility for the paper, and for all its inadequacies, is entirely mine. SUMMARY The rapid development of new drugs and the frequency with which drugs first produced in one country are later employed in others raise special problems of safety in drug therapy. Evidence on safety and therapeutic benefit must often be transmitted from one country to another, as the use of a new drug extends. Assurance is needed

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that this evidence will be efficiently collated and interpreted. Even more important, perhaps, is the compilation of records of any phenomena that may indicate noxious side-effects of a drug: these will be relatively rare, and may for long escape notice by one physician or even in one country. Systematic rapid reporting of any suspicious concomitants of the use of a new drug is therefore urgently needed. One or two odd effects may not impress a single physician; if he conscientiously reports them (with attendant details) solely because they follow drug treatment and not because he asserts causation, efficient analysis and interpretation of reports from many sources should enable delay in the issue of a warning to be minimized. Such a program needs to be developed into, or to be run in association with, a planned monitoring of new drugs in general use, designed to record a wide range of reactions that may be noxious sideeffects or even unexpected benefits from a drug. This paper contains a proposal that an international meeting be called soon for discussion of these problems. The aim should be to establish an International Drug Safeguard Plan, designed to facilitate collection and exchange of information on efficacy and on possible side-effects for any new drug that is to be used medically in more than one country. Collaboration by individual manufacturers should be voluntary, under a system of operation that preserves rights in confidential information and endeavors to make the Plan advantageous to all. A Working Party should seek to devise workable machinery without delay. Thereafter, attention should be turned to longer-term questions concerned with the principles of clinical testing, the prediction of side-effects, and the improvement of monitoring. A rough draft of a constitution for an International Drug Safeguard Plan is appended. D. J. FINNEY Department of Statistics and Research Group in Biometric Medicine, University of Aberdeen, Scotland

REFERENCES 1. DAVIES, 0. L.:

2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

The design of screening tests in the pharmaceutical industry, Bull. Inst. int. Statist.-36 (3), 226, 1958. DUNNE~~,C. W. : Statistical theory of drug screening, in Quantitative Methods in Pharmacology, DD. 212-231. North Holland Publ. Co.. Amsterdam. 1961. DUNNE~T, d. W.: Approaches to some problems in drug screening and selection, Gordon Res. Co& Statistics in Chemistry and Chemical Engineering, New Hampton, New Hampshire, 1961. DUNNETT,C. W. and LAMM,R. A.: Sequential procedures for drug screening, Amer. statist. Ass., Minneapolis meeting, 1962. FINNEY,D. J.: Screening processes: Problems and illustrations, in Contributions to Statistics, Statistical Publ. Co., Calcutta, 1964, In press. -G. E. P.: A statistical desian for drue screeninn. Biometrics. 19. 429. 1963. LIT&RELD, J. T. : Forecasting-drug effects in man from studies in laboratory animals, .Z. Amer. med. Ass. 177, 34, 1961. PAGET,G. E.: Toxicity tests: A guide for clinicians, J. New Drugs 2,78, 1962. ti, A. B.: Medical ethics and controlled trials, Brit. med. J. 1,1043, 1963. WORLD HEALTH ORGANIZATION: Distribution of and trade in pharmaceutical preparations, Znr. Dig. Hlth Legis. 13,381, 1962. WORLDHEALTHORGANIZATION:Control of new pharmaceutical preparations, WHO Chronic/e 16,456, 1962. FINNEY,D. J. : The monitoring of drugs. (In preparation.) Interagency Coordination in Drug Research and Regulation. Part 3: The Bureau of Medicine in the Food and Drug Administration. Washington, D.C.: U.S. Government Printing Office.

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APPENDIX DRAFT

CONSTITUTION

FOR AN INTERNATIONAL (I.D.S.P.)

DRUG

SAFEGUARD

PLAN

1. A permanent International Drug Safeguard Committee shall be established. The Committee shall meet annually, but shall transact most of its business by mail. It shall operate an International Drug Safeguard Plan (or I.D.S.P.), and shall be empowered to modify that Plan in order to meet changing circumstances. 2. The Committee shall include representatives of the countries and of the scientific disciplines involved in its operations. (It should be kept as small as is consistent with adequate representation.) In order to maintain and make evident its independence, it shall not have representatives of manufacturing interests, and shall be in no way financially dependent upon the drug industry. (A SubCommittee for liaison with the drug industry, to which representatives of that industry could be added, would probably be desirable.) 3. The Committee shall concern itself with aspects of the safety and efficacy of any new drug that may involve more than one country, in relation to the interests of patients, the medical profession, manufacturers, and health authorities. 4. More specifically, the immediate and urgent task of the Committee shall be to reduce the total dangers from noxious side-effects of new drugs, by steps that will ensure rapid reporting of cases, international notification of such cases, and issue of warnings. Suitable measures are to be brought into operation at the earliest date possible. 5. The Committee shall also seek the longer term objective of raising the ethical and scientific standards of all aspects of drug testing, establishing a system of recognition for trials and records conforming to these standards, securing acceptance of these standards as having international validity, and encouraging systematic monitoring of drugs after their introduction to general use. 6. Members of the Committee, and of all Sub-Committees and associated bodies, shall at all times remember the necessity to preserve the confidential nature of some of the information that comes into their hands: the success of their efforts depends upon the continuance of trust in their conduct by drug manufacturers and by government agencies. Wherever the phrase ‘transmission of information’ is used, it is to be understood that this may be subject to the goodwill of manufacturers and can continue only so long as confidential matters are never improperly disclosed. 7. A small Executive Committee shall consist of: A clinician A pharmacologist A statistician A representative of WHO Three other members appointed by the main Committee. It shall have power to co-opt two additional persons. 8. The Committee shall endeavour to begin its activities with voluntary service from its members, but must soon make provision for a paid secretariat. The short term objective 9. Individual drug manufacturers in every country shall be eligible to affiliate to I.D.S.P., and a general invitation shall be issued. In giving his adherence to the Plan, a manufacturer shall automatically accept the obligations and responsibilities expressed in Clauses 10 - 21. In general, the advantages and obligations of the Plan will affect only manufacturers concerned with marketing their drugs in other countries or drugs from other countries in their own. (N.B. Solely for convenience of drafting, the word ‘manufacturer’ hereafter refers only to a drug manufacturer affiliated to I.D.S.P.) 10. If manufacturer X in country P proposes to permit one of his drugs either to be distributed or to be manufactured by manufacturer Y in country Q, X shall send to Y information on all toxicity tests, clinical trials, and related investigations for which he (X) was responsible in country P. This information shall include all evidence pertaining to efficacy and full records of any unexpected reactions among the subjects, whether or not these are thought to be side-effects of the drug. X shall also tell Y which manufacturers in other countries have already received this information, or any earlier version of it. Manufacturer Y shall be permitted to use this information in any application he may make for permission to market this drug in country Q, but in no other way without special permission. Y shall undertake to inform X on any trials for which he is responsible. 11. On receipt of a request from Y, the manufacturers in countries other than P and Q shall also send him information in similar form on any toxicity tests, clinical trials or investigations that they

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have conducted. Manufacturer Y shall be permitted to use this information in any application he may make for permission to market this drug in country Q, but in no other way without special permission. 12. The Executive Committee shall facilitate the reporting of clinical trials required under Clauses 10 and 11 by devising a standard form. This must provide for the basic quantitative information on doses and efficacy. It must also include a check list of unexpected reactions, comprising all types most likely to be encountered. It must require explicit sfutements about possible sources of misinterpretation or bias. In particular, points such as the following must be covered: (a) Source of subjects and method of selection for a trial. (b) Rules of allocation of subjects to treatments. (c) Detailed account of placebos or other control treatments. (d) Exact specification of doses and methods of administration. (e) Procedure in respect of subjects removed from trial, failing to complete course of treatment assigned, or changed in treatment for any reason. (f) Method of assessment of subjects at end of trial. (g) Adequate reference to statistical techniques employed. (N.B. Although some of the requirements may be met by use of a standardized blank form, there must be no suggestion that everything can be. reduced to this. Some standardization is necessary for rapid and efficient understanding and use of these reports, but the emphasis must always be on transmitting important facts rather than mechanically filling blank spaces. The form must therefore provide adequately for recording the features that are peculiar to one investigation. The Executive Committee will need to review frequently the possibility of improving the reporting.) 13. An exact copy of any information transmitted between manufacturers under the terms of Clauses 10 and 11 shall be sent simultaneously to the Executive Committee, as a confidential document for the use of the Executive. 14. The Committee and the Executive Committee shall take as an important duty the establishment of close relations with national public health or other drug licensing authorities. They shall aim to satisfy these authorities that evidence on drug safety and efficacy obtained through the operation of I.D.S.P. is trustworthy and of high quality, so encouraging expeditious processing of licensing applications. 15. A manufacturer who plans a clinical trial of a new product will of course conform strictly to the appropriate regulations of his own country. Whether or not he is legally obliged to do so, he shall ask every collaborating physician to reply to a questionnaire on side-effects. The questionnaire shall cover the occurrence and nature of such effects during the whole of the trial, and shall as a minimum include all cases from an extensive check list of reactions, whether or not there is reason to expect any of This information shall be available under the terms of Clauses 10 these us consequences of the drug. and 11. 16. A manufacturer who has had a drug under clinical trial shall normally arrange for a long-term follow-up of a sample of the patients who were involved. Members of the sample, at least 20 in all, shall be seen again by a physician at such regular intervals after the end of the trial period as seem appropriate; 3,6,12,18,24, and possibly 36 and 60 months are suggested. Information on these shall be available under the terms of Clauses 10 and 11. 17. If a drug that has been licensed or otherwise released for use comes to be particularly used in a definable sector of the population (as when a general tranquillizer becomes recommended especially for children, for pregnant women, or for persons with a specific nervous condition), the matutfacturer shall take steps to establish a sample of each such sector, at least 25 subjects in each, for regular observation and reporting as in Clause 15. 18. In addition, for a period after the introduction of any new drug, the manufacturer shall encourage physicians to report, in standard form, every instance of unexpected or unexplained symptoms occurring up to 2 Years after a patient received the drug. In order to avoid the overlooking of rare side-effects and idiosyncratic responses, the emphasis should be on the reporting of any unusual phenomena, whether or not the physician personally believes them to have been caused by the drug. Hospitals also should be asked to make these reports. The reports should be sent to the manufacturer with the least possible delay. 19. Each manufacturer shall forward an exact copy of every report received under Clause 18to the Secretary of the Executive Committee, by air mail, within 2 weeks of receiving it. 20. The Executive Committee shall devise standard systems for reporting reactions as required under Clauses 15-19. 21. The Executive Committee shall establish rules for taking action on these reports, in order to issue a warning when the accumulated evidence of side-effects associated with a particular drug appears to make this desirable. This warning shall be sent immediately to each manufacturer of the drug, to WHO, and to the appropriate government agency in each country of manufacture. It is to be clearly understood that a warning does not imply proof that the drug is unsafe, but only the desirability of

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instituting precautions such as closer observation of all cases. (In so far as misjudgments the errors should be in the direction of too frequent warnings rather than too few.)

are made,

The long term objectives 22. The Committee shall establish sub-committees to advise on raising the standards and improving the efficiency of drug testing. Specific activities of this kind are listed in Clauses 23-30, which are not to be regarded as exhaustive. 23. Under advice, the Committee shall examine problems of the transition from screening of compounds to clinical trials. (See “Proposals for Clinical Trials” in this paper.) 24. The Committee shall sponsor the collection and examination of evidence on the relation between side-effects in animal species and in man, and on the relation between toxic doses for different species. 25. The Committee shall arrange for preparation and publication of some simple experimental designs, with detailed instructions for their use, that can be readily adapted to some of the commoner situations encountered in drug research. (N.B. There must be no suggestion that experienced investigators should restrict themselves to these standard designs: ideally the design of a trial, though conforming to basic principles, should be decided in relation to the particular drugs under study and the stage of their investigation, to the circumstances of the investigator and the facilities he has, and to the type and source of the subjects. Nevertheless, ready availability of advice on simple designs might save the less experienced investigators from some of the many pitfalls and enable them to produce results conforming to the high standards of I.D.S.P. With the growth of experience, technical and organizational skill should lead to more sophisticated use of clinical trials.) 26. The Committee shall endeavor to obtain early knowledge of intentions to submit a new drug to independent clinical study in two or more countries at one time. It shall then, through the Executive Committee, encourage coordination of studies. (N.B. This does not mean forcing into a single pattern but only a sharing of aims, and preferably some agreement on standards of diagnosis and assessment. In this manner, comparability of findings may be improved; without it, apparently contradictory results in the two countries consequent upon non-essential differences of technique may prove inexplicable.) 27. The Committee shall seek advice on the circumstances that make closer international (or intranational) collaboration in clinical trials advantageous. It shall report on the principles to be adopted for trials in which coordination in more detail than the minimum contemplated under Clause 26 is desirable. It shall do all in its power to aid particular cooperative trials, administratively and technically, in the knowledge that some of the most important clinical investigations require this approach. 28. The Committee shall consider the practicability of a system of certification for clinical trials, embodying statements by an impartial body about the design, execution, and interpretation that would be evidence readily acceptable by national health authorities. 29. The Committee shall encourage, and give all possible aid to, the development of monitoring programs for the action of recently introduced drugs in normal use. It shall aim particularly at the early establishment of pilot programs in a few countries where the existing health organization and maintenance of medical statistics provide specially suitable circumstances, with a view to the expansion of these programs and their eventual international linkage. At the earliest possible moment, the Committee shall call together an expert sub-committee for the study of this matter. (N. B. This is closely related to Clauses 18-21. The provisions of Clause 18 are to be regarded as an immediate step to secure reporting of side-effects, even though the reference population is ill-defined and the reliability of reporting uncertain. A good monitoring program should go far beyond this; it should be tied to comprehensive and reliable reporting from a clearly defined population. Once it is working, it may replace the Clause 18 procedure, and may become the most important component of I.D.S.P. Sections 11 and 12 outline the requirements; FINNEY[12] discusses them in more detail.) 30. The Committee shall seek advice on the manner in which high speed computing equipment can aid the routine storing, collating, and summarizing of information. It shall then seek to obtain sufficient time on a suitable electronic computer, recognizing that this facility will become essential as soon as any major responsibility for monitoring is accepted, and that study and preparation in advance are needed. (N.B. Mechanization of much of the routine of handling records must not be allowed to develop into a wholly mechanical outlook on the problems. In the interpretation of information received by the Committee and in the formulating of recommendations, medical and scientific judgment of high quality will always be required. The computer should be employed so as to avoid wastage of those with special talents on tasks of routine abstracting and tabulation, thus conserving them for the contributions they alone can make.)

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Notes (a) The meetings of the Working Party will require financial aid, and the subsequent operation of I.D.S.P. continuing financial support to a much greater extent. Sponsorship by WHO seems the obviously desirable solution, but if this proves impracticable possibly one of the great Foundations may be willing to help. (b) This draft is written with the assumption that reputable drug manufacturers would be willing collaborators and would be fully trustworthy in their collection, transmission, and use of information. I know of no reasons for supposing the contrary; I suspect that no similar plan will be workable unless this assumption is substantially correct; I believe that, despite the labour it will cause them, a welloperated plan willeventually benefit all manufacturers who wish to produce drugs of high quality.