Healthy Skepticism Library item: 20539

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Publication type: Journal Article

Dukes MNG
Pharmaceuticals: Take Another Look
Pharmaceut. Med. 1985; 1:117-127

Abstract:

On Tuesday, 6 October 1829, Robert Stephenson drove a railway passenger train into history. The occasion was the trial of five steam locomotive engines on the newly completed Liverpool and Manchester Railway, and Stephenson carried the day by driving his train at the remarkable velocity of twenty-four miles an hour.1 His locomotive was, however, called the `Rocket’ and it is said that there were bystanders that day who, whatever their other feelings, deemed that name a trifle pretentious.

The same thing might be said, in 1985, of the title bestowed upon the venture which today formally comes into motion at this University: for, as the very first Policy Science. If some confess themselves sceptical at the designation of yet another form of health science, then they surely have good reason to be. The way in which society deals with the medicines which it takes sometimes has very little to do with plain common sense, let alone with the scientific approach. We are attached to our drugs yet at the same time we are grossly suspicious of them. Voraciously we call for the development of new drugs and then do our best to render that an impossible task. This is a field in which all the sciences of health intertwine with those of sociology, economics and law and where science itself may at any moment be overruled by emotion or bigotry.

Before going any further, let me suggest to you two reasons why the community should take this matter seriously. The first is purely financial and statistical. The prescribing and taking of drugs has in our time, rightly or wrongly, become the most important single element in the practice of medicine. Even in European countries, where there tire so many costly things which can he done for the patient, spending on drugs amounts to between 8 and 20% of every country’s total health expenditure.2 A substantial part of the doctor’s time is spent in choosing and prescribing medicinesand supervising their use. The further away one moves from the industrialised world, the greater the predominance of pharmaceuticals in health care becomes: in a country at a low level of development, there may be little else which one can do but distribute medicines. So much for the quantitative aspect of the situation, but the qualitative aspects of all this should concern us no less. Even after setting aside mere empty accusations, we encounter a lot of evidence that some things are very wrong in this field; the unregulated interplay of free professions and free business is not without its problems. Most of the world’s doctors receive far too little formal teaching about drug’s to be able to choose and prescribe them critically.3,4 The government agencies which are supposed to ensure that drugs are as safe and effective as possible still struggle with their standards and their workloads. And in the meantime the pharmaceutical industry is simultaneously hailed as a benefactor in some circles and condemned as an extortionate and heartless ogre in others. Such varied claims and criticisms are presented continually and with great emphasis to governments and international organisations; the problem is obviously to determine where truth ends and prejudice begins, to weigh up many alternative interests and then to design balanced overall approaches to the genuine problems and needs. If we can do that efficiently and on the basis of hard and quantified evidence, rather than under the influence of mere lobbying, then we can reasonably speak of drug policy science.

A starting point
It is difficult to say where the concept of drug policy science germinated. Perhaps rather subjectively; I am inclined to look back 5 years to the first of the World Health Organization’s European Studies of Drug Regulation in which I was privileged to take part.5 Together with my Norwegian colleague, Inga Lunde, I set their face value, the number of drugs marketed in the Federal Republic of Germany was sixty times greater than that in Norway and a hundred times greater than that on sale in Iceland: even after eliminating some statistical artefacts, there were still fifteen-fold differences in the number of drugs on sale between one country and the next. Even tile number of active substances in regular use showed a four-fold difference.

The first task then became to explain these differences and the second was to determine what their practical consequences for the public’s health might be. Even the explanations carried us well beyond mere twentieth century policies. The public attitude to medicines shifted distinctly as one moved South through Europe: in a situation in which a French patient might demand that his physician prescribe five drugs, a Danish patient would anxiously enquire whether his condition could not be treated with camomile tea alone. The roots of these things lay in geography, climate, culture and religion: policies and regulations merely reflected these more basic discrepancies. Such differences in attitude from country to country have in our time been eroded to some measure by the growing uniformity both of medicine and of commerce, but they seem likely to be with us for decades to come.

The question as to what these differences in belief, regulation or both meant in terms of public health demanded much more study. One cannot expect differences in the drug market or prescribing to affect dramatically such coarse parameters as overall mortality or morbidity, for so many other factors influence these things; but there are other ways of going about it. One of our favourite ventures was a retrospective analysis of restrictive drug decisions in Australia: 6 it proved possible to measure the extent to which the Australian authorities had, by restricting or refusing the sale of certain drug products, protected the Australian population from problems which developed elsewhere. It was also possible to assess the validity of the animal and human evidence on which these decisions had been based. Another study looked at over-regulation, found it and measured it; restrictive policies on anti-rheumatic drugs had in one country been carried to a point where some patients were indeed being deprived of drugs which they needed. 7

These few first studies, however, also showed that the tools needed to study and adapt drug policies were to hand; the whole thing was not as amorphous as had sometimes been thought. There seemed every reason to go on and study the effects of every form of regulated activity, industrial and non-industrial, relevant to medicines and their use, perhaps even including the relevant parts of the doctor’s training. One might also tackle some paradoxical situations, such as that which arises when the sale of a disreputable old drug provides the funds for creative research. Ultimately, one would hope to produce an overall cost/benefit analysis of drugs, and the policies pertaining to them. Many of those things are now being done. Here in Groningen, for example, Flora Haayer and her colleagues have examined the moderate extent to which the officially approved data sheet affects prescribing; 8 in Zwolle, Post has looked at the regional effects on prescribing of national measures to contain drug expenditure. From the United States, Ashford has contributed his remarkable work on the way regulation can affect product development, investments and profits.

These are only examples of what can be achieved, but they are typical. Although much has yet to be done, five years of the European Studies, and similar investigations by others, have already taught us a lot about the successes and failures of drug regulatory agencies and pharmaceutical companies which opened their files to the project team.

The simplest but most basic finding has been that drug regulation is very far from being a mere bureaucratic formality. In the countries of Northern Europe, up to a third of new drug applications are currently rejected, often on multiple grounds. Sometimes the drug itself is problematic, sometimes it is simply the studies performed with it which are inadequate. Obviously regulatory agencies do make mistakes, but it is striking that even agencies which work independently of one another often take identical decisions and for the same reasons. Even allowing for errors, delays and some unreasonableness, the usefulness of these agencies, which in most countries are the most powerful instruments of drug policy, is now beyond doubt.

Are the standards applied by these agencies reasonable? The answer, again very generally speaking, seems to be that experienced agencies, of which The Netherlands Committee for the Evaluation of Medicines is an excellent example, have set and maintained standards which perhaps 90% of Industrial companies would have attained in their absence but which the other 10% of industry would not. Self-policing by industry thus clearly does play an essential role, but on its own it is not sufficient. From the data one gets the impression – but it is so far no more than an impression — that self-policing lets us down in the very corner where the risks lie.

A third question is obviously whether drug regulation, which has largely been inspired by tragedies – such as those involving thalidomide, elixir of sulphanilamide, practolol or Stalinon – has succeeded in preventing further disasters of this type. Here we can be much less sure. Regulation as it exists to date has not proved very adept at anticipating new types of tragedy. It has been very good at shutting the stable door quickly after the horse has gone, but less successful at determining through which other doors horses may also escape. Drug regulation as we know it today would probably forestall anything like the elixir of sulphanilamide case – which involved the use of an untested and toxic solvent. Having learned from the benoxaprofen tragedy – which essentially involved the massive launch of a new anti-rheumytic drug which had not been properly tested in old people – regulation would probably prevent any closely similar train of events; but the fact remains that in some countries — with the creditable exception of Benelux – the benoxaprofen tragedy had to occur first before the lesson was learned.10 Sometimes the shortcomings of predictive science limit what we can do; it is, for example, doubtful whether we cam prevent another second-generation disaster like those with thalidomide or diethylstilboestrol; even though we forbid a hundred drugs which injure the unborn rat we may miss the very one which is going to injure the unborn child.

Finally, some of the operational problems in putting drug policies to work have become clear. Many regulatory agencies have to work under indefensible constraints. Most find themselves struggling without drug utilisation data or any other form of feedback which might indicate their measure of success. A lot suffer from a chronic shortage of staff and facilities despite the expressed willingness of the pharmaceutical industry to pay increased fees in order to avoid the resulting delays. Finally, it is evident that some regulatory bodies are too isolated; they can function much better when their activities form part of a total health policy; as two recent symposia of the World Health Organization on Drug Information and on Drugs in Pregnancy and Delivery showed very clearly, drug regulation information and drug education all have to develop together if the public interest is to be adequately protected.4,11 In other words, the community needs an integrated complex of well thought-out drug policies if it is to get the drugs it needs and to use them effectively and safely.

Global aspects
So far I have spoken mainly of ways in which an individual country might seek to monitor and develop its own drug policies in a scientific manner, but it is clear that in doing such work one very soon transcends national borders, if only because one is dealing with a multinational drug industry. One cannot expect to deal with all matters adequately within the Netherlands alone, or even within the European Community, if one ignores what happens elsewhere. Adverse reactions, for example, have no respect for political frontiers, and for good sense and the best advice one may have to look outside the EEC, whatever laws and treaties say. One classic problem is the export of inefficacious or dangerous drugs to countries with which the agency has no close contact. Let me pause for a moment to take that specific example. There is something to be said, in this respect, for assuming the role of one’s brother’s keeper. I am not suggesting that an exporting country has any obligation in public international law to look after the interests of the foreign populations to which it exports drugs, but there are plenty of instances where an importing country desperately hopes that it will do so. One only has to visit a few drug regulatory authorities in developing countries to realise that some of them are pathetically incapable of doing what is expected of them, because of their lack of experience, personnel, laboratories and money. Authorities like these are constantly appealing to the World Health Organization for help in general and specific matters.
To argue, as some people do, that these countries have demanded their independence and therefore should take care of their own interests in drug matters may be valid in cold legal terms but in practice it is unrealistic and inhumane. To deny help to these countries – and that help can very readily be provided by the exporting country through the agency of the World Health Organization – is to leave them exposed to the very risks which drug regulation is supposed to counter. Doing good to one’s fellow men in drug regulation sometimes means following the dictates of one’s conscience rather than those of the statutes.

‘Quite another example of the need for a globally consistent approach if the drug world is to be put to rights relates to the so-called parallel importation by middlemen of drugs which carry the same name as those registered nationally and emanate from the same multinational concern but which have been made for a different market and may differ in some particular respect. Parallel importing of drugs has become commercially attractive primarily because the retail prices and the pricing structures of pharmaceuticals differ so very greatly from one country to another. If a particular product retails for thirty guilders in the Netherlands, an astute middleman flying around the world will soon find a market where it is retailing for ten; by importing it in parallel and selling it for twenty guilders he may build up a lucrative turnover. It is a business for which I can summon up no very great admiration. A great deal of the public money spent on drugs is diverted in this way from bona fide commerce and research into the pockets of speculative traders.
But there are worse aspects to it than that. The reason why a drug is unusually cheap in a particular country is sometimes that the government of that country is in effect subsidising the trade in one way or another in order to ensure that a relatively poor population can afford to buy medicines. If these medicines are to be whisked away by north European traders for purposes of profit, one will end up in the absurd situation that a poor country is in effect subsidising a wealthy one. A global approach to some aspects of drug pricing and trading could put an end to this type of malpractice. It is a typical example of a problem where there are such powerful vested interests on both sides that a thoroughly objective approach is needed if one is to find solutions Which are in the community’s best interest.

The consequences of fragmentation
The fact that drugs policies are not, up to the present, necessarily either scientific or integrated has many undesirable consequences. I have pointed out some of them; there are plenty of others. Try to draw a picture of drug policies in any particular country, or globally, today and you find yourself tracing something like a patchwork quilt. Some of the individual parts may have been developed reasonably successfully but a consistent, well thought-out overall purpose seems to be missing, and absurdities result. While one body wrestles to ensure that drugs are safe and effective, a second is; preoccupied with ensuring that they are merely cheap. As one arm of government struggles to maintain a modest drugs bulletin which will provide physicians with at least a modicum of impartial prescribing information, so another fails lamentably to promote the growth of clinical pharmacology, the only science which might create and sustain a generation of physicians having a sufficient understanding of drugs to use them as they should. And while one group of pharmacists preaches the virtues of a scientific profession, other of their brethren hasten to grow rich oil the parallel imports which undermine research. In any society which accords its members a degree of freedom one will live to tolerate inconsistencies. But are there not certain limits to the foolishness in which a community can afford to indulge? What not uncommonly happens is that, after an increasingly unbalanced situation has in the course of some years become entirely untenable, some sort of drastic social purgative has to be applied in the hope of correcting it. Very typical, I am afraid, is the recent course of events in the United Kingdom where dramatic economies in drug spending and prescribing freedom were suddenly and unexpectedly proposed in October 1984. With rather more foresight, could that situation not have been avoided? As it was, the sledgehammer correctives which were devised, suddenly and unexpectedly, appear, despite a welcome in sonic consumer circles,12 to have alienated the health professions, the industry and part of the public all at the same time.12 14,

Taking a jump back to the more global view I would characterise the main consequence of fragmented policy as gross waste – waste of money, waste of knowledge, of effort and of lives. The world in which we live is not, by and large, getting the drugs which it needs, even where they exist. Let us assume that I, a multinational, succeed in developing a superior beta-blocker, a true godsend to the patient with high blood pressure which, unlike its predecessors, will not cause him to become fatigued and will not aggravate his asthma. Once I am satisfied that I have established its safety and efficacy in accordance with the current state of the art my patent protection may still, with luck, have twelve years to run. Introduction to anything like a world market will however entail convincing up to a hundred different national drug regulatory agencies and nearly as many different price regulatory bodies; in assessing my drug, a few of these agencies will be courageous or
efficient; a very few will be both; the rest will wait to see what others do. A lot of countries will not be able to afford my drug; but I dare not cut my price to them, for if I do some parasitic parallel importer from Europe will soon be on the spot to buy up the local stocks and destroy my turnover in the wealthier markets which would normally pay my overhead costs. What all this in practice means is that the bulk of the return on my research and development investment will have to be obtained hastily, before the generic manufacturers and middlemen take over, by hammering my sales message into physicians serving perhaps only the 5% most affluent of the world population until they prescribe my product. I shall have to convince them despite the fact that most of them have only a meagre grounding in drug therapy. So I shall have to shout, ring bells, simplify, exaggerate, take them to dinners and on cruises to gain their attention; all in all I shall have to spend on that process of persuasion a multiple of what I spent on research. And in the meantime, perhaps even for the next generation, my new drug, whatever its merits, weighed down by all these expenses, will be quite out of reach of the other 95% of the world’s people.
With any luck I shall have earned it good return on my investment; but I shall not have done a fraction of the good with my drug which I might have done.

A personal view of the drug industry

At this point, having ventured very far into the domain of the drug industry, I should perhaps say a little more about that industry itself, a chronic victim of prejudice, misrepresentation and over-simplification.

It is perfectly evident to anyone of reasonable intelligence that the pharmaceutical industry has rendered the world community enormous services, particularly during the past three decades, by initiating or co-ordinating such productive research into new drugs. Equally obvious, however, is that the drug industry is enormously heterogeneous. Look at a wide range of companies (and there are many thousands of them) across the world, and you soon find that as regards their scientific standards and their degree of social responsibility they range from the magnificent
to the disgusting. This is a point about which spokesmen for the pharmaceutical industry, and particularly those who have the unenviable task of speaking for industry as a whole, are very sensitive: it is one of those inconvenient truths which image builders do not like. But there are very good reasons for bearing it in mind: I can see no reason why it company which has shown a proper sense of social and scientific responsibility should not, in the framework of a monitored experiment, be accorded a greater freedom of action than the pharmaceutical industry as a whole currently enjoys. Much of the restrictive legislation which proves hindersome to such companies was introduced to protect the community from the lunatic fringe; it is hard to see why it should be imposed on all, merely to accord with the fiction that all companies are alike.

One obstacle, I do believe, to the acceptance of pharmaceutical companies as adult partners in the development of drug policies has been the ineptness with which the drug industry has sometimes presented itself. In situations where it has it perfectly good case to make, for example as regards parallel imports, the pharmaceutical industry has sometimes lamentably failed to make it,15 whereas on occasions where a little self-criticism would have been appropriate it has been aggressive. At certain moments, and particularly when it sadly underestimates the intelligence of its social
partners, the pharmaceutical industry makes itself look like its own worst friend.

The health professions
The sort of problem which one can document with respect to the pharmaceutical industry has its close analogies in other fields, notably as regards the health professions. The less said about the profession of pharmacy at the world level, the better, it has struggled monumentally with itself during the past two decades to take on a series of new roles; in a few countries, such as the Netherlands, a lot of progress has been made, hut even today, in most places on the globe, pharmacists are still being, trained primarily to perform a task in a world of magistral dispensing which, since the emergence of industrialised drug production, has almost vanished. The
World Health Organization finds itself devoting vast sums yearly to fellowships and courses intended to patch the experience and knowledge of pharmacists so that they can play some of the essential new roles in the health care services for which their university training should have fitted them in the first place. Matters like this surely belong very much to the province of public policies, both at the national and the global level.

There are problems too as regards the medical profession, which has tended to defend a known if imperfect status quo rather than to risk innovation. Again there are sensitivities, matters which it is considered improper to speak of in public, but which have their repercussions for drug policy. I would mention only the tragically slow progress of the new discipline of clinical pharmacology in so many centres, a discipline which like no other can ensure that drugs are better evaluated, better understood and better used. Time and again the path of the clinical pharmacologist has been obstructed or rendered unnecessarily devious by those of his colleagues
who see in him a rival or even a threat to their prescribing independence. Clinical pharmacology, as the World Health Organization has time and time again stressed, needs support from the makers of health policy if it is to serve the community in the way it should and can.

Pricing and research
A few words, in conclusion, on drug prices and drug research. I mention them in one breath because existing drug prices are often defended in terms of the need to finance research and development. In reality, the link is not at ill simple. National drug pricing authorities around the world, like drug regulatory agencies, wrestle with an impossible task. Few of them have any insight at all into the principle of transfer pricing, fewer still into the real costs of research, the merits of a company’s research programme, or the overhead expenses and profits of a multinational corporation.

Most such commissions end up by applying arbitrary formulae15 to determine what constitutes a fair price. There is no simple answer to these dilemmas, but one can at least provide such bodies with more insight into the relative value to the community of the drugs the prices of which they are supposed to assess; that will help to ensure that truly innovative research earns the greatest rewards.

Whether drug regulation as it currently functions does inhibit research is a disputed matter. In some areas it probably does; the development of powerful analgesics for severe pain may well have been impeded by the way in which narcotics regulations have been interpreted. Whether such things have hindered research across the board I simply do not know; the point deserves study. We already know how to Identify and weed out the less useful sort of’ regulatory requirement which merely creates work and paper. Beyond that, however, I can only repeat what I said just now: the efficacy and safety standards currently applied by the better regulatory if these agencies did not exist; if these agencies have made life more difficult for the less competent and less creative minority then that is just as it should be.

Structural effects of drug policies

If, in the coming years, drug policy science emerges as a worthwhile tool, what will its effects be? I have already briefly defined its purposes: it must ensure that the potential which drugs have to serve the community properly is better exploited, both nationally and globally; it should provide us with better drugs and drugs which are better used. In achieving those basic purposes, some structural changes are going to be inevitable. The profession of medicine is bound to alter as the influence of clinical pharmacology makes itself felt. The profession of pharmacy will break down yet further into a range of allied hut distinctly new professions. The pharmaceutical industry is likely to find its process of consolidation and integration much accelerated, with a greater emphasis on research potential on the one hand and the efficient production of low-cost unbranded drugs for the developing world on the other. Above all, the flow of funds will find itself better directed; if the preposterous sums currently spent across the world on drug advertising and promotion could be reduced by only 10% the funds available for industrial new drug research would be doubled.

Conclusion
Here, then, are some of the broad lines along which one might work to create scientific drug policies. Some of this may seem very elementary. That is exactly what it is. It is all so obvious that one wonders why it was not done long ago, but the fact is that it has never consistently happened. Drug policies have emerged, if they have emerged at all as the result of conflicting pressures, prejudices and lobbies. They have not always served us badly, but with the technical means which the community has at its disposal they could serve us much better. Drug policies depend upon the symphonic functioning of many different sectors of society. They should function
by analysis, proof and persuasion rather than by coercion; pharmaceuticals are sufficiently important to us all to justify the effort. With a great part of the total health expenditure already in a manner which cannot readily be modified, it is no wonder that the costs and benefits of drugs have come under close scrutiny, but they deserve to be scrutinised with rather more understanding than has often been the case until now. Happily there are signs of change. One or them is the recognition, inherent in the fact that I have the privilege of standing here today, that drug policy has become an academic discipline. Not everything will be achieved overnight, and
some things may not he achieved at all, but the important thing is to begin and to believe. There is some merit in hitching one’s wagon to a star. That is exactly what Robert Stephenson did in 1829. As his locomotive puffed sedately along at all of twenty-four miles an hour it opened an era of transportation which indeed did culminate in rockets. Perhaps in taking drug policies as our province of study from this day onwards, we may one day see our efforts culminate in something which will fully deserve the name of science.

References
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Notes: * Inaugural Lecture at the University of Groningen on taking up the Chair in Drug Policy Science.

Author’s full title is as follows: Dr M. N. G. Dukes, MD, MA, LLB, Regional Officer for Pharmaceuticals and Drug Utilization, World Health Organization, 8 Scherfigsvej. DK-2100. Copenhagen 0, Denmark.