The drug licensing system should not be considered as part of a national drug policy, because the UK doesn't have one. We have instead a jungle of UK and European laws, introduced to address specific problems, none primarily to do with health. The 1968 Medicines Act was established to provide some basic regulation of the pharmaceutical industry, where previously there was none.

The Medicines Act is also the product of an age when patients had few rights. In the UK, at that time, the law prohibited consumers even from knowing the names of drugs prescribed for them, and harmful experimentation on unwitting humans wasn't proscribed (under the Declaration of Helsinki) until 1966. So it is not surprising that the 1968 Act makes no provision for consumer/patient involvement or participation. If the world has moved on since then, the drug licensing system has not.

The Act was a very much a first step in regulation, and the system that has grown up around it is mainly the outcome of successive, modest enough attempts at damage limitation and to secure 'fair trade'. Naturally, all this happened in the face of intensive lobbying by the main affected interests, especially pharmaceutical companies. Their success in this is underlined by the official sponsorship of the industry, not by the Department of Trade, but by the Department of Health.

Let it be said that the pharmaceutical industry detests regulation and puts about a lot of money to resist it. Drug company money reaches into every part of the system, and the industry has an almost legendary reputation for letting others get its own way. Nowadays, it even pays for the Medicines Control Agency and the Committee on Safety of Medicines. Through license fees, companies pay for all core activities in the UK regulatory system. This clearly has an important effect on the MCA/CSM budgets and on regulatory policies and practices too.

Increasingly, however, the scene is now shifting to Europe, and drug licensing procedures will be defined by the EU. Does this make the current system more acceptable for patients and consumers? On the contrary: the law was created by and is still administered through DG3, the European Commission's Directorate for Competition. There has never been an EC Directorate for Health.

Professor Rawlins' predecessor, when in office, said he thought that agencies like the MCA and CSM should "be immune from political and public pressure and above all free from the pressures of action groups". This word "immune" seems significant for its connotation of extreme resistance and lack of response. I offer two glimpses of evidence - both relating to the stranglehold of office - to suggest nothing much has changed.

The first involves Professor Sir William Asscher, the previous Chairman of the CSM, shortly after his retirement, by which time his Knighthood was secure. At a meeting organised in 1993, in support of a private member's Medicines Information Bill, Asscher declared:

The second illustration concerns the present Chairman, Professor Michael Rawlins. Writing to me in his personal capacity, ten years ago, he volunteered that he thought the medicines control system excessively and unnecessarily secretive. Very recently I asked him if he still thought so, and if I might attribute the following opinion to him. He agreed on both counts, which says more about the calibre of the man, than for the system he helps to run:

Recently, the MCA has claimed it has become more open - now even disclosing the counts of Yellow Cards, adverse drug reaction reports sent in for individual drugs. This was indeed a significant step forward - for reasons Asscher had explained at the aforementioned meeting in the House of Commons in 1993. He supported the Medicines Information Bill, he said, but definitely wouldn't want to see disclosure of adverse drug reaction reports. Why not? It was because this information "is exceedingly difficult to interpret and it requires, like a good wine, a certain degree of maturation and thinking about in order to ensure the right message gets across …":

When, last year, the MCA/CSM did finally release ADR data of course no mayhem ensued. However, if there has been a slightly increased trickle of useful information in recent years, it is not primarily the result of any internal reform. It is explained mainly by the introduction of the 1994 Code of Practice on Access to Government Information and, more recently, by this government's welcome proposal for Freedom of Information law. The Yellow Card data were released only because Social Audit complained under the Code; it took nine months of serious badgering, with the MCA ducking and weaving throughout, and the CSM nowhere to be seen.

The present medicines control system remains miserably secretive. Over the years, there have been numerous, sometimes serious drug problems, but no public enquiry into drug safety has ever been held. This matters not just because it hides data and diminishes science, but also because it perpetuates two great vices in medicine - the belief that meaning well means doing good, and the consistent inability to admit mistakes and learn from them. Both should be counted as serious obstacles to patients' safety and public health.

Nor does parliamentary scrutiny of the system make accountability much more of a reality. MPs are overwhelmed with other issues, lack resources and are typically intimidated by drug issues. They are also very much subject to party policies and treasury-inspired disciplines, and therefore pretty much out of touch.

From a consumer perspective, the present system operates pretty much as a cartel - a trinity of medical professionals, government and commerce. Between them, they confidently and confidentially take far-reaching decisions "in the public interest". Over the past 30 years, the leadership in the cartel has unmistakably passed from the medical profession to the industry, all the more reason to be concerned.

In The Antidepressant Web, I give what I hope is an extreme example of the kind of thing that happens in practice. Around 1990, the CSM's leading expert on the so-called SSRI antidepressants (eg Prozac) had personal financial interests with four leading manufacturers of SSRIs and indirect interests in another one. He seems to be what is called in America a "Marquee Professor", someone who really gets around and whom companies can rely on to say nice things about their products. This man's work undoubtedly had a profound influence on licensing decisions made by the CSM and, in my view, has led to fundamental misunderstandings about the long-term effectiveness of these drugs.

Very briefly, I fear that what the regulators now think of as the long-term effectiveness of antidepressants is in fact a manifestation of drug dependence - just as it proved to be with tranquillisers, such as Valium and Ativan, only a few years ago.

So how close are the regulators to the pharmaceutical industry? I particularly like the description of the present state of play by Dr Phillip Brown, the publisher of SCRIP World Pharmaceutical News, a mine of good intelligence for the industry (and a pity few others can afford it). Brown has concluded that drug regulation in the UK is "dull and uninspiring" and "self-serving", and has "little relevance to the safety of the patient in the real life situation". Apart from the curse of secrecy, he sees the main problem as the closeness between regulators and regulated, and he illustrates this by analogy with relationships in the top security of Parkhurst prison:

Brown doesn't precisely say whether he sees the regulators as gaolers or prisoners, but it may well have occurred to him that it could be the regulators who are imprisoned - by niggling law, lack of resources, and mountains of data, etc - while the industry enjoys (and often bestows) great comforts. Dr Duilio Poggiolini is a case in point.

Regulation entails checking that marketed drugs are of sufficient [a] quality, [b] efficacy and [c] safety. This basically means selective scrutiny of vast quantities of data generated by manufacturers, the results of tests and trials on relatively small and highly selected groups of patients, in some (qualitative and quantitative) respects quite unrepresentative of the patients prescribed those drugs in the real world. The scrutiny is mainly handled by MCA staff or, under the European system, by an assessor nominated by the company making the licence application.

[a] Since inspection reports and recall notices are kept secret by law, I cannot confirm my impression that, as a rule, lack of drug quality (ie purity etc.) has not proved a serious problem. Though there have been exceptions, involving the manufacture/distribution of certain vaccines, I would guess the companies and the MCA between them do a good job and keep things on a fairly even keel.

[b] The system is geared to establishing whether medicines are "efficacious", when it should be trying to find out what medicines do and do not contribute to health. The word "efficacious" does not mean "effective"; it means that the drug does what it claims to do, and can be used and promoted for specified "indications". However, the claims made in the licensed indications may be so bland, yet so sweeping in their terms as to make "efficacy" mean almost everything and yet nothing. Prozac, for example, is licensed "for the symptoms of depression", which is to stop just short of saying that it is tough on stains but kind to your hands.

What patients and prescribers want to know is that a drug is effective in procuring health - but this is not something guaranteed, or even much addressed by the present system. Increasingly, for example, you will find licences granted when surrogate markers of effectiveness are used, which may prove to have little relevance to health. Some cholesterol-lowering and anti-arrhythmic drugs would be examples of this. Indeed, a product license in itself is a surrogate marker of health and, whatever is implied, gives no indication of therapeutic value for money at all.

[c] The fatal flaw in the part of the control system concerned with safety, is the preoccupation with "the safety of medicines" rather than the safety of the patients who take them. Equally, the CSM is fond of pointing to its track record "by examining the fate of all new licensed drugs", rather than the fate of patients. The evidence suggests that many do not fare well.

But who decides whether the benefits are worth such risks? Initially, it is the MCA and CSM but, in their preliminary assessments, "safety" is regarded as an essentially molecular property. The reality is (or should be) that patients' safety is fundamentally to do with how well medicines are used, and with the acceptability of drug risk. The latter should be a matter for patients themselves, in consultation with doctors - but, in the absence of reliable data, these are clearly difficult decisions to make. Nor is the process helped much by the activities of pharmaceutical companies whose promotions naturally tend to celebrate the triumph of benefit over risk. The regulators have little control over drug promotion and prescribing activities, increasingly less as the industry makes deeper and deeper inroads into the system.

When new drugs first come to market, not a great deal is known about their safety profile; it usually takes years, even decades, for the full facts to emerge. There is a simple test of this: put a ruler alongside the "warnings" or "side effects" sections in the drug data sheets issued, first, when the drug was launched, and then at later stages of the drug's life. The small-print warnings thicken and extend - though they still often appear to be designed mainly to protect, not patients, but backs.

The MCA and CSM are basically responsible for checking safety before drugs are marketed, not after. They do make re-assessments of safety but, in general, this is a passive and unsystematic activity and "fraught with a range of legal and practical impediments". The basic posture of the regulators is to wait and see - very much assuming that no news is good news, and that what they see is what there is. The strong tendency is to act, not when there are clear signs of risk, but only when there is compelling evidence of harm.

The main instrument of control over drugs on the market is the Yellow Card system - a scheme in which individual prescribers can report to the MCA/CSM what they suspect to be adverse reactions, on the basis of their patients' experience with individual drugs.

This system was started over 30 years ago, but still the vast majority of doctors never report most of the ADRs they see. The CSM itself estimates that, even with serious reactions, it rarely gets more than one Yellow Card for every ten reportable events, but I believe even this estimate to be very high.

Nevertheless, the MCA/CSM (also the industry) greatly rely on the Yellow card system. They see it as the justification for quickly getting drugs to market - the reasoning being that the flow of Yellow Cards will alert the regulators to any problems there turn out to be. It is true that the Yellow Card system has flagged certain problems with particular drugs, but it has missed a great many too.

And the question now, with antidepressants, is whether the same thing is happening again. As described in The Antidepressant Web, the MCA and CSM in 1996 published an analysis based on Yellow Card returns which concluded that withdrawal symptoms from antidepressants were very rare - affecting something of the order of one patient in 10,000. My best estimate would be of a problem affecting at least one in ten. I am very nearly sure that the MCA/CSM is overlooking a problem with the antidepressants to compare with that for benzodiazepine tranquillisers. The Table below, based on the MCA/CSM's data, partly explains why:

	Introduced	Ballpark No.	Yellow Card	reports of:
		of NHS scripts	withdrawal reactions	dependence- all forms
Temazepam (BDZ)	1977	50m	5	3
Diazepam (BDZ)	1963	180m	20	16
Fluoxetine (SSRI)	1989	9m	59	10
Paroxetine (SSRI)	1991	6m	802	9

BDZ = benzodiazepine tranquilliser; SSRI = Selective Serotonin Reuptake Inhibitor antidepressant)

On the basis of this and other case studies,¹⁶ I would be inclined to argue that the quality of scientific assessments by the MCA/CSM is often uncertain, and at times a disgrace. Factors other than secrecy have helped to obscure this. Thus, from the recent furore over third- generation oral contraceptives, the public might have inferred that just the suspicion of an excess risk of the order of two or three per thousand might be enough to get the regulators to leap into action. They would be profoundly mistaken if they thought so.

6. Conclusions …?

Because this is a debate, I have tried to give a balancing, rather than balanced account. In the available time¹⁷ it would have been hard to speak also about some of the advantages and successes of the present system, mentioning also the commitment and hard work of many individuals involved, and the obstacles that beset them. Nevertheless, I consider this motion is pretty much a travesty and that the public deserves much better than it now gets. Bear in mind too, that I have mainly focused here on what regulation does, and sets out to do - leaving aside major areas in which it makes hardly any impact at all.

References

11. In the US, the cost of drug-related morbidity and mortality (140,000 deaths/year) has been estimated at $136bn/year (D.C. Classen et al, Adverse Drug Events in Hospitalized Patients, JAMA, January 22/29 1997, 227, 4, 301-306 and J.A. Johnson, J.L. Bootman, Drug-related morbidity and mortality: a cost of illness model, Arch Intern Med, 1995, 155, 1949-1956.. No official estimates are available in the UK.

	Contents page
	Section 5.1 - Editorial notes & What's New?