Chris Good

Thicket Grove, Maidenhead, Berkshire, UK

As Sir William Osler, the father of modern medicine, said: "The desire to take medicine is perhaps the greatest feature which distinguishes man from animals". Alone in the wilderness beyond the rigid confines of modern states, people may indulge their predilection to take medicines without any restriction save their ability to obtain the requisite ingredients. The conjoined paternalism of the modern state and the medical profession ensures that people are not allowed to indulge this desire without strict controls. These controls have themselves created problems with pricing and rationing. There is a tacit assumption in making certain medicines only available on prescription that the state and doctor know better than the patient what is best for that patient. This assumes that the state committees and doctors are adequately educated, a big presumption. It also assumes that all diseases have been discovered and named and their aetiology is known. Such pompous paternalism is obviously absurd. It is clear from recent history that there are still many diseases to be discovered and that existing diseases may have a new aetiology, e.g. peptic ulcer and H. pylori.

Modern states have introduced two mutually interactive concepts for the protection of the public, the provision of state health care and the licensing of medicines. Prescription only medicines are generally available as part of free or reimbursed state health care. Non-prescription medicines are available to the public at whatever price they are prepared to pay. A free health care system introduces unlimited demand for the provision of health care against the restrictions of a budget tailored to other demands on the gross domestic product (GDP). Thus the state is faced with the need to limit the costs of health care. Although only around 10% of the health care budget is spent on prescription medicines, the pharmaceutical industry is an easy and therefore prime target for cost cutting. A simple and effective way to cut the cost of prescription medicines is to restrict both the price of prescription medicines and those which can be prescribed on the state health care system. Another is to de-restrict medicines from being available on prescription only as soon as it is reasonably safe to do so, in order that the public may return to their earlier condition of paying for their own medicines. What are the grounds for restricting medicines to prescription only or general release? To understand this a brief review of the licensing of medicines may be helpful.

Since the dawn of civilization people were able to self-medicate with home remedies mixed with magic or religion or both, without any formal restriction. Gradually specialists in medical treatment evolved, variously known as shamans, priests, witchdoctors or quacks, and with them evolved the pharmacists who manufactured such medicines, principally from plants. It was the prescribing of remedies that allowed the so-called practitioner of medicine to charge a fee for his attendance and thus make a living. Unfortunately for the public, until very recently there were no regulations governing the provision of medicines to the public (1). From the beginning of the twentieth century the public had to rely on the rapidly expanding pharmaceutical industry, with its synthesis of active ingredients, to ensure that its medicines were effective and safe. Then came the thalidomide disaster between 1959 and 1962, with the birth of an estimated 10,000 deformed phocomelian babies in the affected countries. This resulted in the introduction of a voluntary licensing system in 1964 in the UK, one of the main affected countries, which was followed by a compulsory licensing system in 1971. Other Westernized countries followed suit.

Since the 1970s the sale and supply of all medicines have been controlled by law in most countries, the manufacturer being required to show that the medicine is of an acceptable quality, efficacy and safety. When satisfied on these criteria, the regulatory authority grants the manufacturer of the new medicine marketing authorization approval (MAA) for its sale. In the UK and several other Westernized countries, the sale and supply of medicines is regulated into three categories depending on the regulator's opinion of its safety. Those new active substances, whose safety has only been tested in a few thousand patients in clinical trials, are only available as prescription only medicines (POM). Those medicines that have been used on the market by a sufficiently large number of patients for the licensing authority to be further reassured as to their safety in the general population may be obtained over the counter from a pharmacist (P) without prescription. Those medicines which were in general use before licensing was introduced, or more recently licensed medicines that are regarded as generally safe for use by the public without restriction, may be obtained over the counter (OTC) with no more control than applies to other consumables. The various countries have different ways in which they categorize different medicines between these three categories. Controlled drugs are those liable to abuse or addiction and are always restricted to supply only on prescription. Their prescription is regulated by the Misuse of Drugs Regulations 1985 in the UK.

A recent attempt to limit the potential for toxicity in overdose is to restrict consumption with a limited pack size, e.g. paracetamol is now only available OTC in small blister packs of 36 tablets. Since the change in pack size, the number of attempted suicides by overdoses has fallen. However, this does not stop the carefully planned suicide who can build up and hoard an adequate suicidal supply. It does allow the manufacturer to increase the pack price and make further profits.

In the UK and many other countries, there is still no restriction on what medical practitioners may have manufactured or prescribed for a particular patient, whether the intended medicine is licensed or not, providing that it is legal and in the patient's best interests. In this context a recent case is of interest. A doctor was reported to the disciplinary body of the country's General Medical Council by the statutory health authority for prescribing single vaccine in place of the triple vaccine MMR, advocated by the health authority. This is clearly a political attempt to restrict a doctor's right to prescribe and may presage further steps in that direction. Another example is provided by the growing claims by patients that cannabis relieves their symptoms (mainly in multiple sclerosis). The possession and use of cannabis are illegal in the UK and therefore doctors are forbidden to prescribe it, despite patient claims for its benefit. The clear ethical solution is for the state to carry out proper clinical trials to test whether it is safe and effective. So far the state has avoided taking this obvious ethical action. There are probably several reasons, none of which are morally acceptable. One is the fear that making cannabis available on prescription would make it even harder to control its illegal use. This is clearly nonsense, since heroin and morphine are more dangerous drugs of addiction and socially disruptive, yet are available on prescription although otherwise illegal. They have a much longer and therefore apparently inherently respectable medicinal use. Indeed, until the introduction of legislation controlling the use of dangerous drugs, medicines such as laudanum (tincture of morphine) could be bought by the public from pharmacists without prescription. Coleridge Taylor wrote his famous poem "Xanadu" whilst dosing himself with laudanum for diarrhoea.

The regulation of medicines has developed ad hoc and is based on a plethora of mutually supportive concepts: politics, economics, paternalism, information and greed, which give rise to contradictory situations. Aspirin is available OTC for self-medication in proprietary preparations, yet would be unlikely to achieve marketing authorization according to today's standards whilst newer, safer and as effective analgesics are unlikely to achieve a licence. The authorities, in collusion with doctors and pharmacists who wish to maintain their monopoly on the dispensing of medicines, believe that they, the father figures, are best placed to decide what is good for the public, their children. The majority of people accept this regulation because they are vaguely aware of the disasters of the past and fear that there is too much specialized information about medicines for them to digest and come to rational conclusions about quality, efficacy and safety. Both the authorities and the people are agreed that the makers of medicines are not philanthropists who wish to benefit mankind, but greedy marketeers who wish to make as much money with as little effort as possible. There is nothing wrong with this desire. Most people are driven by it, whether gambling honestly in the stock market, the lottery, investments or in other ways, or dishonestly in crime, but the public also wish to be protected from the adverse effects of such greedy behaviour. So laws are introduced to protect the public. Since the majority of the public are reasonably law abiding, they support laws against criminal behaviour. The Napoleonic code introduced early in the nineteenth century sought to protect healthy people against the unnecessary nostrums of quacks by outlawing the administration of medicines to healthy people. This severely impeded the development of clinical pharmacology, which is based on studies in healthy volunteers, in France until reversed by the "Lois Huriet'' in 1989. Since the phenomenal growth of the pharmaceutical industry in the twentieth century, the public have sought protection from uncontrolled marketing of potentially toxic products.

This need for evidence of safety and efficacy is based on the scientific belief that evidence from studies of sample patients from the target population can be projected to the population as a whole. Whilst far from all people agree with this approach and prefer only anecdotal evidence to support their whimsical use of medicines, as Osler concluded in his 1913 lecture "... how crude and primitive may remain a knowledge of disease when conditioned by erroneous views of its nature'' (2). And self-evidently the same is true of its treatment with medicines. How should medicines be categorized, what information should be required to change that category and which categories should be reimbursed by the state?

As mentioned above, medicines are generally divided into three categories by the licensing authority: POM, P and OTC. What are the grounds for altering a medicine from one category to another? Practically all medicines based on new active substances are first categorized as prescription only until sufficient information and experience have been gained regarding their safety. Whether or not the cost of their prescription is covered by the state depends on not only medical but also political considerations of their perceived personal and social benefits. Some examples may clarify this. The antifungal imidazoles clotrimazole and ketoconazole were strictly limited prescription only medicines when they were marketed in the early 1970s for topical fungal infections. They are now available OTC for the self-treatment of thrush and dandruff, ketoconazole being regularly promoted on the radio. Peptic ulceration was generally treated surgically when simple antacids failed to relieve symptoms. Increasingly sophisticated forms of highly selective vagotomy were practised by gastric surgeons to try and separate the acid-suppressing effects of such an operation from its considerable undesirable adverse effects. Surgeons made a good living from such operations, but the cost to the health service in terms of operating theatre and hospital bed costs, morbidity and mortality were considerable. The introduction of the H2 antagonists in the early 1970s dramatically changed treatment, although it was feared that lowering the gastric pH would encourage the formation of carcinogenic nitroso compounds and that treatment would mask the development of gastric cancer. There has been no evidence to support these fears. The H2 antagonists became extremely popular, so much so that gastric surgeons practically went out of business overnight, whilst the health service made considerable savings. That is, until doctors realized that H2 antagonists could be used to treat most forms of dyspepsia and the drug bill rocketed. With these increasing costs and the passage of time, the licensing authorities realized that initial fears about the adverse effects of H2 antagonists were unfounded. They reversed their previous reluctance to de-restrict H2 antagonists and made them P products, saving the health service a fortune.

A similar re-categorization or de-restriction of the proton pump inhibitors can be expected now that they have replaced H2 antagonists as the most expensive treatments for various forms of dyspepsia. With the general acceptance of Marshall's evidence for the pathogenic role of H. pylori in dyspeptic conditions, antibiotics have been added to proton pump inhibitors as combination therapy. So far the licensing authority have been reluctant to de-restrict antibiotics, no doubt for fear of further increasing the already rapid rate of development of antibiotic resistance.

A further interesting example of de-restriction of an expensive class of medicines is the moving of the non-steroidal anti-inflammatory drug (NSAID) ibuprofen, used for the relief of pain and inflammation, from POM, to P to OTC. In the 1980s, NSAIDs came under increasing scrutiny regarding their toxicity, in the wake of the "Opren scandal'' which was claimed to reverse the arthritic process but whose successful marketing in the early 1980s was followed by its withdrawal the next year in association with 86 deaths. Ibuprofen was marketed by Boots of Nottingham. In a review of the safety of NSAIDs conducted by Professor Langman and his group from the Nottingham School of Medicine, ibuprofen was classified as being in a class of its own and the safest NSAID. The review was based on reports of adverse reactions to the Committee on Safety of Medicines, of which Professor Langman was a member. Following this review, ibuprofen was deregulated to P then to OTC pain relief. Thus those patients able to afford it were once more able to treat themselves with an effective NSAID without prescription.

There is good evidence that pharmaceutical companies themselves may resist changing their medicines from POM to P or GSL as this may reduce their profits. Recently an advisory panel of the FDA said that it had not identified any serious safety concerns with three allergy remedies and voted that these three medicines were safe enough to be bought at pharmacies and supermarkets without a prescription. Health insurers showed that these medicines are safer than many of the other allergy medicines already sold over the counter. The manufacturers resisted the move, saying that the health insurers were trying to save money (3).

Deregulation of a medicine from POM to P and OTC should be ethically acceptable if the decision is based on good evidence that the medicine is most unlikely to pose a threat to the health of the individual or society when used as directed. The individual is already allowed to decide on the management of his or her own health with regard to two well-known toxic substances, tobacco and alcohol, and with dangerous appliances such as the car. Each when abused can have disastrous consequences for not only the abuser but also others not directly involved in their abuse. Thus society accepts the right of the individual to take risks and this right should be extended to the taking of medicines without prescription, providing adequate warnings are given in the patient information leaflet. The problem of deregulation only becomes an ethical issue when the medicine is no longer available on prescription for those who cannot afford to pay for it otherwise. Any medicine considered sufficiently safe and also effective for de-restriction to P or OTC should remain available on prescription for such patients. This is usually but not always the case. In some cases the government health service prescription charge may exceed the cost of the medicine, but those who can least afford it are usually exempt from such charges.

At one time the British National Formulary classified medicines as A, B or C depending on the Joint Formulary Committee's assessment of the medicine's therapeutic usefulness. Doctors were discouraged from prescribing other than class A or B medicines and preferably only class A. Some members of this Committee were also members of the Committee on Safety of Medicines appointed to advise the government on the licensing of new medicines under the 1971 Medicines Act. Thus the prescribing of medicines already granted marketing authorization by the government could still be restricted by this classification. However, the classification had no statutory power and fell from use by 1976, although medicines which cannot be prescribed on the NHS are still marketed.

The system has now been reinforced in the form of the National Institute for Clinical Excellence (NICE), set up by government to advise on best medical practice. This Institute tells medical practitioners what therapeutic guidelines they should follow and which medicines they may prescribe on the National Health Service. It thus basically decides which medicines will be reimbursed by the government and which will not. It is difficult to understand how on the one hand the government can license a medicine as safe and effective and then decide on the other hand that it is not therapeutically justified and refuse to pay for it. There are many examples of medicines not being prescribable on the National Health Service (NHS). Sildenafil was licensed by Pfizer for treatment of male impotence. NICE decided that this use was not justified on the NHS. Strong protests caused NICE to change its mind and allow it for certain patients with a chronic underlying disease such as diabetes mellitus. NICE also decided that Wellcome's recently approved antiflu tablet did not qualify for reimbursement, then again changed its mind, apparently due to consideration of further evidence following strong political pressure from Wellcome. It is difficult to understand how clinical judgements can vary so rapidly on consideration of apparently the same clinical evidence. At present, NICE has successfully resisted attempts to get p-inter-feron listed as a prescribable medicine for multiple sclerosis.

Countries approach the rationing of state-funded medicines in different ways. In the UK companies are allowed to set the prices of new medicines at market launch themselves. The government allows each company to make a certain profit each year determined by its various allowable costs. If this limit is exceeded, the government is refunded and prices adjusted to meet next year's allowance. In France the price of every new medicine is determined by the government once it has been approved by the same government for marketing. This adds a further delay before marketing. Furthermore, not only is the price set by the government, but also the reimbursement level. This is similar to the old three-tier BNF system of classes A, B and C. When last checked, 80% of class A drugs were reimbursed after use, the patient paying at first; other categories qualified for 70% or 60% reimbursement, down to nothing for some products that might be very useful, such as urine testing sticks, but nevertheless did not qualify. This level is currently being reduced in line with the need to contain the budget and reduce French social security costs.

These and other cases raise the important issue of whether the state should limit its health care budget and if so, how it should divide its health care budget. Clearly it must limit the cost of health care to what it can afford. To do otherwise is to invite bankruptcy on a national scale. Therefore it must ration the amount of money available for all the different aspects of health care, including medicines. It must do so in order to control the insatiable demand for and expense of health care. But should the state be deciding which patients get appropriate treatment and which do not, unless they can afford it themselves? In an ideal social order, no such distinction should be made, but in the real world of practical socialism, there has to be rationing and expensive new remedies cannot be exempt from this. But should the decision be made centrally for all doctors and patients by one committee such as NICE, or should it be left to individual hospitals and practices to set their own prescribing policies? At present in the UK we have both systems, so that even those medicines approved for reimbursement on NHS prescription may not be approved by the local therapeutic prescribing committee as items to be stocked or dispensed. There is yet another level of control exercised by the government on doctors' prescribing habits. Each year general practice doctors' prescribing costs are analysed and compared in such a way that individual doctors can be advised that their costs are higher than average and must be reduced. This should have the net effect of reducing the average annual prescribing cost, since high prescribers are constantly being advised and disciplined.

It is clearly immoral to deny a needy patient the appropriate treatment on grounds of cost alone. But who decides what is meant by needy and which patients are most needy? A relevant example of this problem is provided by that company which was advised by the licensing authority to withdraw its anti-acne product on the grounds that the antibiotic contained therein was unsafe and increased resistance when used topically. The company's appeal to the Committee on Safety of Medicines was rejected on the grounds, amongst others, that acne is a trivial condition. This judgement was made by a panel of middle-aged to elderly men who had long forgotten the agonies immature teenage acne patients may suffer when having to confront the world with their disfigured faces. The appeal was taken to the Medicines Commission supported by the live testimony of dermatologists dealing with such patients daily, who pointed out that to such patients acne is no trivial condition and may cause suicide. The appeal was won and the medicine continued on the market. Likewise who is best placed to decide which impotent patients should benefit from sildenafil? Who is best placed to decide which patients require cosmetic plastic surgery to alter their physical appearance to be what they consider more attractive, whether remaining of the same sex or changing to the opposite? Who decides whether anorexic patients are social misfits or ill people?

Who should be treated on the NHS? It is a dangerous policy to limit treatment only to those considered deserving patients. Do they include those wanting plastic surgery breast implants, plastic nose jobs, or only heart transplants for non-smokers? If limited to those not taking part in hazardous pursuits, we should have to exclude not only all smokers, all alcoholics, all drug addicts and those injured during criminal activities, etc., but also all vehicle drivers and all those doing sporting activities.

Attempts in the past to withhold treatment from patients who abuse themselves have understandably produced an outraged public reaction. Wherein lies the moral difference between a person who smokes for pleasure and possibly damages their body and another person who races motor cars and possibly damages theirs? Both are highly hazardous but, to some, enjoyable pursuits. Are certain clinical conditions, for example homosexuality, any more abnormalities or rather illnesses like genetically determined mental diseases such as Huntington's chorea or George Illrd's porphyria? The situation becomes absurd. It is impossible to draw a line between acceptable and unacceptable activities or illnesses. Health care and provision of medicines cannot be judgemental and dependent on following a centrally decided acceptable lifestyle. Who makes the rules as to who is eligible for treatment? Those in authority may not always be in the best position to decide.

Surely such delicate and individual decisions cannot be taken empirically by a central committee, which clearly has a political remit to make sure that state funds are rationed appropriately. The state has the right to decide which medicines are sufficiently safe and effective in specific indications to support its medical culture, and grant marketing licences accordingly. It also has the absolute right to determine how much it is prepared to pay for such remedies in the state health care system. Thereafter any decision about which patients should be treated has to be taken by the patient and administering doctor at the time, with the patient's best interests at heart. Only at this level can a rational and ethical decision be taken as to who may or may not benefit. As the September 2001 BNF (4) rightly says: "The prescriber and patient should agree on the health outcomes that the patient desires and on the strategy for achieving them''. This is important, but recent issues appear to make no reference to prescribing costs. More importantly with regard to the ethics of reimbursable medicines, the March 1989 BNF (5) says: "It should be emphasised that cost effective prescribing must take into account other factors such as dose frequency and duration of treatment that affect the total cost'', and goes on: "The use of more expensive drugs is also justified if it will result in better treatment of the patient or a reduction of the length of an illness or the time spent in hospital''. Thus there should be several important factors personal to the individual patient that go into a clinician's choice of the best treatment for that patient, which cannot be decided empirically at a distance for all patients. It is probably highly pertinent to the changing state health care attitude to rationing of reimbursable medicines that this later clause is now omitted from the BNF.

A final ethical problem with reimbursable medicines arises when they are withdrawn from the market, for reasons unrelated to safety. The licence may be withdrawn more for political than medical reasons. What can then be done to maintain the continued prescribing of effective remedies when no longer available? It is not ethical to stop a patient's medication when he/ she is well controlled on it. By special arrangement with the government and manufacturer, special supplies may be made available for named patients for a limited period until suitable alternatives are found or they can be weaned off the medicine.

Not all patients like going to a doctor or believe in their ability to help. Such patients may prefer to avoid medication or provide self-medication. Every effort should be made to deregulate as many medicines as possible and as quickly as possible. The evidence supports the view that patients can in general safely be trusted to self-medicate with a wide range of what were originally and previously regarded as dangerous new medicines. They are no more likely to come to harm than on prescribed medicines. The government should nevertheless ensure that the prices of such self-medications remain reasonably affordable. This deregulation should ease the demand for prescription medicines and thus reduce the burden on the state health budget. This in turn would remove the need for political bodies such as NICE and inappropriate decision taking about what can or cannot be prescribed on the state. Either a medicine is considered effective and safe or it is not.

However, regrettably, emotional arguments usually appeal more strongly to most people than logical arguments. Nowhere is this more true than in the demand for immediate availability of potentially new discoveries in medicine to suffering patients at "reasonable prices''. There has been a recent demand for the provision of illegal drugs such as marihuana for patients suffering from multiple sclerosis, despite the lack of any convincing evidence that it is effective. There is much anecdotal evidence from individual patients who claim that it helps them, but no well-designed, placebo-controlled studies such as required by the Licensing Authority for pharmaceuticals before approving new active substances. This paradox is key to most emotional argument, which takes individual cases in isolation without regard to the wider population implications. The Licensing Authority was set up as a result of the emotional outburst in the wake of the thalidomide-provoked phocomelia epidemic. The public did not want unscrutinized medicines going on the market. They want well tried and tested medicines with proven efficacy and safety, especially when other effective remedies are already available for that disease. The conflict between emotion and logic becomes particularly acute with possible treatments for diseases for which there is no effective treatment. To be compellingly tenable, ethical decisions should always apply across the whole spectrum of activities. The ethic that to kill is wrong is a moral imperative. This is clearly not universally applicable without disastrous results. To kill is to extinguish life. Yet to kill plant life is generally held to be acceptable in order to sustain life, also to maintain order by weeding out unwanted plants or to provide building material in the form of wood, leaf thatch or bindings. To kill bacterial and viral life is also acceptable in an attempt to restore health or prevent disease. Indeed, in an époque devoted to saving endangered species, it is quite acceptable to eliminate the smallpox virus, malaria and tuberculosis. So the argument about the ethic of killing becomes progressively more narrowed to animal life, vertebrate life, human life, the enemy and finally those who no longer desire or deserve it. Somewhere along this slippery continuum people, for various reasons, desire to take an ethical stand, but it is difficult to maintain a steady stance on such a slippery slope.

So it is with the licensing of medicines and their categorization for reimbursement. Having subscribed to the state health care plan, patients expect it to pay for everything. People also want to be protected from exploitation by unscrupulous quacks or companies yet want to be free to choose what they do to themselves and how they spend their money. A classic example of this is the use of tobacco and alcohol. Most societies agree that it is undesirable to allow young children to purchase tobacco or alcohol so limit its sale to those above a specified age. Adults are allowed to poison themselves to death with both.

In conclusion, most people want to be allowed to treat themselves and decide their own fate, but they also want to be protected from the dangerous and expensive products of the unscrupulous. At some time in their lives they have probably treated themselves with their own remedies which have been passed on as part of family lore, from friends, through advertising, or their own trial and error. Such self-remedies may not even be classified as medicines, but are lotions and potions made up at home, purchased over the counter or concocted from plants. People usually have great faith in such remedies, faith being the essential ingredient in their continued efficacy, but there is little or no objective evidence for their efficacy or safety. There is clearly a need to regulate the medicines produced by pharmaceutical companies, but this in no way addresses the problem of self-medication with home remedies or inappropriate use of other people's medicines. What the state has the right to decide is which medicines are safe and effective enough to be marketed, whether on prescription or not. It also has the right to decide how much it is prepared to pay for such prescribed medicines. It does not however have any moral right to decide who can have them and who cannot, nor whether they are available on the NHS, if safe and effective. Decisions about which patients get what must be left to individual patient-doctor contracts, otherwise the state will be imposing arbitrary judgements inappropriately.

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