Albedo

Jacques Chirac and Tony Blair don't exactly see eye-to-eye on how to make Europe more competitive, but they share the same comfortable privilege of being able to discuss it theoretically. And discussing it in theory is just what they and their fellow leaders from the other 23 member states of the European Union (EU) did in Brussels in March, as they nodded their agreement to a series of measures designed to boost the EU's economy over the next 5 years.  

"Europe must renew the basis of its competitiveness," EU leaders agreed at their Brussels summit meeting on 22–23 March, placing the emphasis on innovation and research. Their new bid to improve Europe's economic prospects through support to sectors such as high technology pharmaceuticals included a long list of proindustry factors, ranging from assistance to innovative smaller firms and high-tech start-ups, to promoting joint research between business and universities, effective intellectual property protection, elimination of unnecessary red tape, and improved access to risk capital. 

EU leaders also agreed to keep aiming for an overall 3% investment level in research and development, with tax incentives for private investment, better leveraging by public investment, and modernized management of research institutions and universities. The new European research programme now under preparation will be geared to stimulating private investment and helping to fill the technology gap. A European Research Council and a European Technology Institute are to be created to support cutting-edge research, and a new mechanism established for financing innovative smaller firms with high growth potential. 

The new plans include public–private technology partnerships and platforms to consolidate Europe's industrial fabric and to set long-term research agendas at national and European level. The EU's own investment bank is to be given a mandate for extending financial support for R&D, and for innovative technology-transfer networks. 

But attractive though all these concepts are, they tend to fall into the "jam tomorrow" zone of action. If they happen, they will be nice, but they haven't happened yet. 			

By contrast, the European pharmaceutical industry is already giving proof of a substantial pudding ready for eating. Across a broad range of activity, it is developing new products that help patients, push out the frontiers of knowledge, promote a strong research base, assure jobs, and maintain the buoyancy of Europe's exports into world markets. 

That is why drug companies are now being asked to give their views on how to regulate "biosimilars"  — copy products of biopharmaceuticals. At the same time as EU leaders were haggling over the theory of competitiveness in Brussels, the European Medicines Agency in London (UK) was releasing a draft note for guidance on the key factors in assessing this new area of pharmaceutical technology — in essence, generic medicines containing recombinant DNA-derived proteins. And companies have until the end of June to tell the agency what they think of the new rules. 

The emergence of biosimilars — a concept that has come into common usage only over the last year or so — is itself a demonstration of the competitiveness of the pharmaceutical industry. Innovation by some has naturally led to emulation by others: and because the make-up of biotechnology-derived products is so much more complex than classic chemical-derived products, there are some delicate questions to be answered about how far generic copies can rely on data from the original product to support a marketing authorization application.  

As the draft guideline points out, a company may choose to develop a new biological medicine claimed to be similar in terms of quality, safety and efficacy to an original, reference medicine product which has been granted an EU marketing authorization; but similar biological medicines are manufactured and controlled according to their own development, taking into account such factors as manufacturing processes, product characteristics, stability and comparability data. So in most cases, only limited comparison can be made against official data such as pharmacopoeial monographs or against other published scientific data.  

The biosimilar product is defined by its own specific manufacturing process for both active substance and medicinal product, and this process should be optimized taking into account state-of–the-art information on manufacturing processes (such as expression system/cell substrate, culture, purification and viral safety) and consequences for product characteristics. And because each product is defined by the molecular composition of the active substance resulting from its process, there is a risk of process-related impurities being introduced. So, reasons the agency, the biosimilar product is defined both by the characteristics of the molecule (including product related substances/impurities), and by its process. Each applicant will be required to demonstrate the consistency and robustness of his own process. 

Comparisons at the level of active substance and finished product are not going to be sufficient for a full evaluation of biosimilarity, the Medicines Agency says, so an extensive comparability exercise will be required to demonstrate that the biosimilar and reference products have similar profiles in terms of quality, safety and efficacy. And only when supported by sufficiently sensitive analytical systems can the demonstration of comparability at the quality level connect the biosimilar product to the nonclinical and clinical data previously generated with the reference product, it warns. 

A full quality dossier is required, supplemented by a demonstration of comparability — an additional element to the normal requirements of the quality dossier. The standard quality overall summary in the application should also deal with comparability issues in separate sections to facilitate review, cross referencing the appropriate separate sections of the dossier that contain the relevant data. 

Formulation studies should be considered in the course of the development of a suitable dosage form, even if excipients are qualitatively and quantitatively the same as the reference product, to demonstrate suitability with regard to stability, compatibility with excipients, diluents and packaging materials, and biological and physico-chemical integrity of the active substance for its intended medicinal use. 

It is not expected that the quality attributes in the biosimilar and reference products will be identical: minor structural differences in the active substance such as variability in post-translational modifications may be acceptable (although they must be justified). The impurity profile in the product should also be fully justified, and will be assessed on a case-by-case basis. 			

Although the biosimilarity exercise will be easier when the pharmaceutical form, formulation, or strength of the biosimilar product are the same as the reference medicinal product, other approaches may be considered by the applicant. In any case, a clear scientific justification of the criteria followed to select the reference medicinal product should be provided, with specific attention to its critical parameters and quality attributes. The same reference medicinal product should be used for the quality, safety and efficacy parts of the application dossier. 

There are no short cuts available to copyists. The comparison of the biosimilar active substance to a publicly available standard as a reference (such as European Pharmacopoeia or World Health Organization) is not going to be sufficient to demonstrate biosimilarity of the active substance, because safety and efficacy profiles may not be sufficiently defined. In addition, the biosimilar manufacturer generally has no access to the originator active substance, so cannot directly compare his active substance to the one used in the originator's medicinal product. Still, the biosimilar manufacturer has to demonstrate, using state-of-the-art analytical methods, that the active substance used in the comparability exercise is representative of the active substance present in the reference medicinal product.  

There are situations where the analytical tools used for characterization may not be capable of directly comparing the biosimilar active substance versus the active substance present in the reference medicinal product. In these situations, the applicant will have to use other approaches to obtain representative reference active substance derived from the reference product, so as to perform the comparative analysis at the active substance level. This approach will have to be appropriately validated to demonstrate the suitability of the sample preparation process, and will have to include the comparison of the biosimilar active substance with active substance material derived from the reference and the biosimilar medicinal products. 

Here in a nutshell are all the elements of a competitive Europe: an industry that can and does innovate in high-technology areas, that is keenly geared to rivalry in pursuit of markets, that is able to cope with the most arduous levels of regulatory control as a part of product safety and guarantees of customer satisfaction, and very largely self-sustaining, generating most of its funding for innovation from its own sales in tough markets.  

				If EU leaders would just step down for an afternoon from their Olympian heights, and spend some time in the laboratory and on the shop-floor, they would soon see that what they like to discuss as future theory is already current practice in European pharmaceutical technology.

Articles

While Europe's political leaders were paying lip-service to creating a more competitive Europe at their spring summit in Brussels, European pharmaceutical technologists were tackling the serious business of turning political rhetoric into practical reality.

Brussels Report

The EU is trying to bring some clearer definition to the borders of its pharmaceutical legislation...

Defining The Borders

If the EU wants to be taken seriously by researchers, it has to start delivering on a climate that really aids research...

The European Search for Research

Defenders of the research-based industry are hoping for an early Christmas present from the European Court of Justice (ECJ). All the signs are that a small but significant victory is on the way against parallel importing. Right at the end of October, a senior judge responsible for a leading case at the court made clear his view that international drug firms do not necessarily have to make life easy for parallel importers. The formal ruling on the case at issue is expected within weeks. 

The main conclusion the judge drew is that "refusal by a dominant pharmaceutical undertaking to meet all orders of its customers so as to restrict parallel trade does not automatically constitute an abuse of a dominant position." In simpler terms, GlaxoSmithKline — the company at the heart of the case — is not obliged by European Union (EU) competition law to provide Greek wholesalers with unlimited quantities of its anti-epileptic Lamictal at Greek prices, so that Greek wholesalers can ship the consignments to the UK or Germany and sell them at the higher prices there. 

If this opinion from the Court's Advocate General is backed by the other judges on the case, it will offer some welcome relief to an industry that continues to suffer from opportunistic exploitation of the quirks of EU law. It won't bring parallel importing to an end, but it will allow manufacturers to say "no" to wholesalers who are clearly over-ordering domestically to furnish parallel trade. 

"Such behaviour should not be considered abusive where the differences in prices of medicines between the member states are the result of state intervention and in the light of the specific circumstances of the European pharmaceutical market," the Advocate General says in his opinion. This is one of the first explicit recognitions by the ECJ that there is something odd about the EU pharmaceutical market. 

It puts its finger precisely on the perverse effect of two co-existing, but contradictory legal requirements: the EU single market rule that goods can move around freely within it; and the tough national price controls imposed on drugs in most member states. 

The single market is a good thing, generally — promoting competition, allowing economies of scale, widening customer choice — but it is based on the assumption that prices are set in light of market conditions. National price controls for drugs may be a good thing, too — certainly for hard-pressed social security institutions trying to make ends meet in the face of spiralling health care costs and demands. The European association of pharmaceutical parallel traders claims that in 2002, parallel trade between EU member states — amounting to an estimated 140 million packs — generated direct savings to patients and social health insurance systems in excess of â¬630 million.  

But these two approaches just don't mix. Ultimately, the diversion of profit from manufacturers to wholesalers is not in the interests of the consumer or of society. And since there is no prospect at present of member states relinquishing price controls, the only rational way to arrest the phenomenon is by making exceptions to the EU's single market and competition rules. This is what the Advocate General has wisely urged. He says a dominant undertaking is not obliged to meet orders that are out of the ordinary and is entitled to take such steps as are reasonable to defend its commercial interests. He points out that it is the price differentials created by the intervention of the states in the pharmaceutical market that create the possibility for parallel trade. This, coupled with the high degree of regulation of the pharmaceutical market by the EU and the member states, means that the normal conditions of competition do not prevail in the pharmaceutical market.  

He adds that requiring a dominant pharmaceutical undertaking to supply all export orders would in many cases impose a disproportionate burden, given the moral and legal obligations a company has to maintain supplies in all member states. He goes further — with words that will sound like music in the ears of the research-based industry. Given the specific economic characteristics of the sector, the Advocate General says, a requirement to supply would not necessarily promote either free movement or competition, and could even harm the incentive for pharmaceutical companies to innovate. And he spells out what the drug manufacturers have long been claiming, but had received little sympathy for from the ECJ until now. Such parallel trade, says the Advocate General, does not always produce any benefit for the consumer, or the member state as the primary purchaser. In some circumstances the only benefit is received by those in the distribution chain, he underlines.  

The opinion is perhaps the most explicit admission to date that something is rotten, not only (as Hamlet pointed out 400 years ago) in the state of Denmark, but right across the EU. The Advocate General emphasizes that his conclusions are highly specific to the pharmaceutical industry in its current situation and to the problem at issue in this specific case.  

The opinion comes in the wake of a formal ruling by the ECJ in January 2004 that allowed German pharmaceutical firm Bayer to maintain a quota scheme preventing French and Spanish wholesalers from selling the heart drug Adalat to UK pharmacists. The court ruled that Bayer had not been proved to be breaching EU competition law in the way it behaved when parallel importers were eating into its direct sales in the early 1990s. 

These developments don't amount to carte blanche for the industry to put an end to all parallel importing. "Conduct by a dominant pharmaceutical undertaking that more clearly and directly partitions the common market or had negative consequences for competition arising other than as a consequence of its restriction of parallel trade could still be considered abusive," according to the court. For instance, the ECJ has already clarified in earlier rulings that the protection of a trademark is not without limits, so it may not be used to artificially partition the internal market in a bid to frustrate parallel imports. A parallel importer may repackage a proprietary medicinal product and reaffix the trademark or even replace it with the trademark used in the market of destination, provided that repackaging does not adversely affect the original condition of the product or the reputation of the trade mark and its owner. But the GSK opinion does represent a further breakthrough in understanding.  

In addition, it comes as a blow to continuing European Commission efforts to allow wholesalers to export drugs to countries where prices are higher. They initiated infringement proceedings against several member states in 2003 because it felt they were not doing enough to encourage parallel importing.  

The Commission also issued a communication earlier this year aimed at easing parallel importing of medicines. Internal Market Commissioner Frits Bolkestein said at the time: "The ultimate aim is to ensure patients and health care providers can benefit from parallel imports, without taking any risks with patient safety." 

Aiming to help businesses and national administrations take full advantage of the internal market in medicinal products, the Communication covered the rights and obligations of the parties concerned, and the guarantees to which they are entitled according to EU law, the Commission said. Its tenor can be judged by the fact that it won instant acclaim from the European association representing parallel importers. 

Basing itself on judgements of the ECJ over the last 20 years, the Commission confirmed its conviction that there should be no major administrative barriers to parallel trade in pharmaceuticals. It insisted, for instance, that member state authorities should grant marketing authorizations for parallel-imported medicinal products through a simplified procedure. Against this background, confirmation in a formal ECJ ruling of the Advocate General's opinion on the GSK case in Greece will make life a little easier for research-based firms. 

Defenders of the research-based industry are hoping for an early Christmas present from the European Court of Justice (ECJ). All the signs are that a small but significant victory is on the way against parallel importing. Right at the end of October, a senior judge responsible for a leading case at the court made clear his view that international drug firms do not necessarily have to make life easy for parallel importers. The formal ruling on the case at issue is expected within weeks.

For this relief, much thanks

Mystics would have us believe that "you can never step into the same river twice." The onward rush of the water imposes change even where no change is apparent. But had mystics contemplated the European approach to pharma politics, they may have altered their perceptions dramatically.  

For here, in Europe, it could reasonably be maintained that the onward rush of time has imposed no change at all during the last 25 years. Anyone could step back in at any point, at any moment, and find the same depressingly familiar debates, interminably failing to reach any real conclusions. 

This reflection is prompted in part by the premature departure of Erkki Liikanen, the genial Finn who has been largely responsible for EU pharma policy during the last 5 years in his role as Commissioner for Enterprise. In what was more or less his swansong, he chaired a forum on the European pharmaceutical sector in high summer in Brussels. The meeting was the final fling of the so-called G10 process of pharma policy planning — a 4 year high-level review of options that has in reality achieved practically nothing. 

Liikanen is going not because he has been fired — that hardly happens in the comfortable circles of senior EU policy making — but because he has been summoned back home to take over as chairman of his country's central bank. He only had 6 months to go anyway as Commissioner: all these senior jobs are up for grabs again, since a new Commission is due to take over from 1 November. 

But like water down the stream bed, the Commissioners come and go, and leave so little behind. The Liikanen-inspired G10 was intended to, in his own words, "establish consensus between key stakeholders on ways to improve the competitiveness of the pharmaceutical sector in Europe in a manner that was compatible with achieving our public health objectives." More simply put, it was a mechanism to bring pharma industry economics centre-stage in EU policy making, and to help make drug-pricing and reimbursement systems more realistic. 

This is where Liikanen's departure sets up resonances that echo down the long reaches of past decades. There have been some legendary predecessors in his post — a roll-call that includes the untiringly loquacious Martin Bangemann ("I always dreamed of being able to make speeches like Fidel Castro," he used to joke, and then go on to make speeches like Fidel Castro), or the somewhat waspish figure of Karl-Heinz Narjes (who never forgave the European pharma industry for jilting him after he offered support for its economic arguments, and the industry then declined to provide him with the supporting data). 

Each of them, in their own way, fought the same battle, to help keep the European pharmaceutical industry vigorous and vibrant, without precipitating violent reactions from the national governments that have always held the purse strings for health care. Each of them, in their own way, set up mechanisms to bridge the gulf between industrial and social security imperatives. And each of them, in their own way, failed to make any real headway. 

The industry still exists, of course. And it still makes money and provides jobs and new medicines. But it is hardly any longer a European pharma industry. Even the European Federation of Pharmaceutical Associations and Industries (EFPIA), the sector's principal lobby group, has long since abandoned its mission of defending a European pharmaceutical industry. In the face of the inevitable, it now seeks merely to promote pharmaceutical industry activity in Europe, irrespective of ultimate ownership. 

And even the level of activity, whatever the ownership, has consistently declined as a proportion of world pharmaceutical activity. The economic and regulatory constraints in Europe, and the perennial failure to establish a strongly entrepreneurial climate, have driven manufacturing and research away to more conducive locations. 

In 2002, EU-based pharma companies had an output of some 160 billion, 20 billion in R&D spend, and employment near 0.6 million, of which 90000 were engaged in R&D. But between 1990-2002, R&D investment in the US rose more than fivefold while in Europe it only grew by 2.5 times. In the 10 years from 1990, the major European research-based companies cut back the share of their worldwide R&D expenditure within EU territory from 73% to 59%. 

The US is now the leading inventor of new medicines, generating eight of the top ten worldwide products in 2002, compared with just two from Europe. And 70% of the sales of new medicines launched on the world market in 1998-2000 were made in the US compared with only 18% in Europe.  

The EU fiction about fixing the situation continues, however. The much-lamented decline in European pharmaceutical innovation is compensated for by the apparently limitless innovative capacity of bureaucrats to invent new forms of camouflage for their inability to intervene effectively in this protracted decline. 

The G10 is only the most recent example, after years of round tables, seminars and conferences, and task forces that also proved inadequate to the challenge. And what a miserable example it is. Even Liikanen himself, the progenitor of the process, could not find much to say about it when he summed up its achievements during its epilogue this summer. He claimed there had been "some national initiatives in the spirit of G10," offering the fact that "national medicines agencies have all agreed to participate in a benchmarking exercise on their regulatory activities." 			

For those who do not inhabit this strange world of invented terminology, and may not be aware what benchmarking is, or why it should amount to a breakthrough, it may be helpful to set out just what Liikanen said about it. "We set out a first set of competitiveness performance indicators. The objective of these indicators is to establish an EU-wide tool for measuring the impact of EU and national G10-related measures. The process has started and we are currently updating the indicators." Stirring stuff, indeed. 

And on the key question of pricing — "one of the most controversial areas in our G10 communication" — all he could claim was that "our objective is to reflect first on the necessary conditions and second on possible pricing mechanisms that would allow faster, wider and better secured access to medicines for all European patients without sacrificing any national control over health care budgets." How far has the reflection advanced? Wait for it: "Work has also begun in this area. A working group of stakeholders had its first meeting on 24 May. We will need to see what comes out of this process, but it is clear that, with many member states examining their own pricing procedures, this is a good time to examine this issue." 			

And this is the sum total of the years of high-level thinking — despite the fact that, on Liikanen's own admission, "the wide variety of national schemes is having a significant impact at the European level." Similarly, its extended review of the question of relative effectiveness of medicines, G10, and Liikanen, can report little more than broad agreement that there are benefits in examining, along with national governments, existing national relative effectiveness systems. "Last year, we established a working group that is currently analysing these systems to see what approaches there are," the outgoing Commissioner boasted. But the objectives are limited. "The aim is not to develop a European system of relative effectiveness and, indeed, we firmly believe that this must not become part of the authorization process. However, it must be in everyone's interest to ensure that, whatever systems member states choose to use, there is greater transparency, speed and consistency." 

				And this despite the fact that systems for measuring the effectiveness of medicines "have become an increasing feature of national systems," and that "these various national systems are having an important impact on competitiveness at a European level."				It is a disappointing outcome in light of the unambiguous conviction — with which "everyone agrees" — that the European-based pharmaceutical sector "plays a vital role in the life of the EU ... not just an economic contribution, although this is substantial, but also in social terms with the provision of high quality employment, support for our science base and, of course, to our public health objectives."				It is disgraceful in light of the rallying cry of the Commissioner that "our key objective is to tackle the relative decline in competitiveness of the European-based pharmaceutical industry when compared with its American-based competitors." The undisputed evidence is already on the table, and has been growing for years, that "as a whole, Europe is lagging behind in its ability to generate, organize, and sustain innovation processes that are increasingly expensive and organizationally complex" (as a key commission study concluded 3 years ago). And it is bordering on the dishonest alongside the Commissioner's clear statement that "For an area  that used to lead the world in pharmaceutical innovation this is unacceptable," and his recognition that "without investing in innovation now we will undermine the long-term future of the industry."				

Liikanen is not personally to blame for the failure — other, perhaps, than for the failure in honestly acknowledging that efforts so far have been a failure. The G10 deficiencies are just another stage in a continuum of conspiracy to pretend that effective action is being taken. As the Commissioner himself conceded, "Many of you will know that, given the history of unproductive  discussions in this area, this was a very challenging objective." 			

The problem lies in the divided responsibilities within the EU — with member states retaining most of the power for the price of medicines, which inevitably subverts or even vitiates the discussion at EU level of industrial policy. So little serious improvement can be expected no matter how often Liikanen (or his predecessors, or his successors) repeat mantras about a new future, such as Liikanen's assertion that "our long-held objective is to create a 'Standort Europa' where Europe, once again, becomes the favoured location for pharmaceutical research and innovation. We want to do this in a way that meets the specific challenges facing this sector while also tackling the risks of deindustrialization and delocalization." 

The Deputy Prime Minister of Ireland (which has chaired EU business in the first half of 2004) maintained the same fiction at the same meeting. Mary Harney, who is also Irish Minister for Enterprise, Trade and Employment, ritually intoned her "firm belief" in "the need to regularly reiterate and highlight the importance of the pharmaceutical sector to the European economy." She too noted that "the productivity gap  vis-Ã -vis the US is widening in the high tech areas," because of "Europe's comparatively poor performance in R&D and innovation." And she was under no illusions as to the principal cause: "The constraints that stifle economic growth and innovation do not come from outside, but rather from inside the EU economies themselves." 

But the recognition of the problem — and the identification of the solution — remained at a theoretical level. "Investment decisions of firms operating in a global market place are influenced by the economic climate that exists in the EU and in the member states," she said. So "Europe is not at the mercy of competition from lower-cost locations; it is very much the master of its own destiny." Her recipe, for which she claimed the backing of EU ministers responsible for industry, was clear and direct. "What is required is lighter regulation of industry and business, particularly for those sectors operating in a global market place where competition is intense, and we must be more supportive of innovation. Better regulation is crucially important for competitiveness." There are, she insisted, "compelling economic reasons for undertaking regulatory reform." 

Which is all very well. But if all the EU is able to do is to talk endlessly about the problem, rather than act, then the problem remains. And the G10 exercise demonstrates again that talk is the maximum output, obfuscating rather than clarifying what needs to be done. 

The new European Commission that will take up the reins of EU business in November faces many challenges. Prominent among them will be the urgent need to boost EU competitive capacity. It will be a step forward if the new chiefs of EU policy making abandon the pretence that benchmarking, innumerable working groups and long paragraphs of meaningless bureaucratese constitute a solution to the dilemma facing the pharmaceutical sector. For the pharmaceutical industry still being swept along in Europe's turbulent stream, it could be a matter of sink or swim. 

In Europe ... the onward rush of time has imposed no change at all during the last 25 years. Anyone could step back in at any point, at any moment, and find the same depressingly familiar debates, interminably failing to reach any real conclusions.

Stepping Back into the River

For more than 30 years, Charles Medawar has been calling to account the corporate world - and in particular the international pharmaceutical industry. His UK-based campaigning organization, Social Audit, has been one of the most prominent and prolific critics of profit-based medicine worldwide. With his latest denunciation - specifically of the marketing of Lilly's Prozac and GSK's Seroxat, but more generally of the inadequacies of contemporary medicines' regulatory systems - he has come close to scoring a direct hit. This summer should see the results of official British, European and US investigations into this class of antidepressants, in the face of mounting evidence regarding their side-s. Because Medawar locates his criticisms of these particular medicines within his general argument about regulatory passivity, laxity and hesitancy, widespread repercussions can be expected if negative conclusions are reached by the ongoing investigations by major drug control agencies. 

 Selective seroton reuptake inhibitors ( SSRIs ) in the dock

The first Social Audit alerts regarding  these medicines date back more than 7 years, in the light of adverse effect reports: weight gain, loss of libido, sensory disturbances and mood swings, even suicidal feelings. Since then, Medawar and his colleagues in sister organizations such as Health Action International have been painstakingly trawling for evidence, quizzing regulatory authorities and compiling the results. 			

The main thrust of the criticism is presented in a new book, "Medicines out of Control?" (

), which charts the promotion, regulation, prescribing and use of mood-regulating drugs. "The problems antidepressant users now face are largely the making of the present systems of medicines control. The nature and magnitude of these problems signal the urgent need to inject pharma-ceutical medicine with a dose of democracy and to subdue commercial pressures in the interests of health," says Medawar. 

What Medawar is calling for is "an overhaul of the secretive and profoundly inadequate system of medicines control," and hopes the unfolding crisis of dependency on antidepressants will prove to be a watershed. In questioning the adequacy of the official action taken so far, he raises basic questions about the competency of drug regulators and the lack of transparency in tackling user dependency and complaints in many countries. 

"Drug benefit-risk assessments are increasingly made on the strength of evidence that is hugely incomplete and highly partial, using evaluation procedures that are often chaotic and misconceived," he alleges. "Drug safety and effectiveness is, in part, a myth sustained by entrenched secrecy, the dominance of vested interests, misplaced optimism and an overwhelming lack of public accountability." He documents what he claims is "scrutiny that is often badly flawed;" official neglect of "the risks of dependency on antidepressants when user evidence suggests the contrary; the refusal of drug regulators to take account of valuable evidence from users;"and "failure to take stock of the extent of iatrogenic illness." 

There is a familiar ring to Medawar's charge that the results of much scientific research on medicines is tainted because most is financed by a pharmaceutical industry seeking products that will generate sales. But the gravity of concerns regarding selective serotonin reuptake inhibitors lends a new resonance to his rhetoric. Recent research suggests the number of users affected by drug withdrawal reactions from GSK's paroxetine (Seroxat/Paxil) is dramatically greater than earlier estimated. 

 Reliable medicines control in the dock too

"The turning point can be quite precisely dated - it came with a heavy flurry of revelations between October 2002 and the summer of 2003. If there was a pivotal moment, it was probably 25 June - when GSK quietly published a small print amendment to the prescribing instructions for Seroxat. The company had upwardly revised its 2002 estimate of the risk of withdrawal reactions - from 0.2% to 25%. The official risk of Seroxat/Paxil withdrawal problems had increased overnight from 1 in 500 to 1 in 4," underlines Medawar. And he goes on to demand: "What does it reveal about the quality and direction of medical science and the reliability of the medicines control system that - in spite of all the fuss and the precedents - it took more than a decade to identify a prominent and potentially hazardous adverse drug reaction that affects one user in every four?" 			

And against this background, some of the other equally familiar Social Audit allegations take on a new significance: secrecy about drugs' benefits and risks, inadequate and insufficiently independent postmarketing surveillance, and undue focus on commercial considerations at the expense of health considerations. The arguments are carefully marshalled to support some alarming suggestions.  

Excessive commercialization is a consequence of the evolution of the drug industry itself: the big companies - Pharmas as Medawar terms them -  "became so huge that they could hope to survive only by rapidly creating mass markets for 'blockbuster' and 'lifestyle' drugs. The advent of Prozac and related antidepressants heralded an era in which drug innovation gave way to intensive drug marketing: this was the only way the Pharmas could secure the return on investment they needed to be able to operate on their scale. Part of this new and imperative emphasis on marketing involves relentless demonstrations of the triumph of benefit compared with risk, and the promotion of drugs for much more than they are worth. In this case, it also meant that the Pharmas tackled problems by challenging perceptions of risk and by ignoring or denying evidence of harm. In so doing, they systematically exploited the dependencies of governments and the medical establishment. There was little resistance, partly because the Pharmas were also dependent on them. Commercial sponsorship both sustained and undermined the  reputation and independence of political, professional and academic institutions, drug regulatory systems, even patient organizations and the World Health Organization." 

One of the major targets of the criticism is what is seen as a growing trend towards promoting products as a part of daily life. There is an "urgent need to confront the disease awareness campaigns and under-the-counter, direct-to-consumer advertising (DTCA) now taking place in Europe despite the European Union (EU) consensus not to allow it," according to Anita Hardon, co-author of the book and scientific director of the Amsterdam School for Social Science Research. "This kind of promotion leads to an unsustainable demand for medicines and overuse of drugs such as antidepressants. The EU and European governments are not sufficiently acknowledging how this huge demand for and optimistic belief in drugs' benefits undermine the sustainability of public health systems," she says. 			

The book details some of the stages in this process. DTCA helped the Pharmas in the US to extend and segment markets, "allowing them to repeatedly relaunch their antidepressants for an expanding range of states of mind," it says. In Europe, the battle for DTCA started as far back as 1997, just after the US started to allow DTCA there. Proposals for DTCA were on the agenda at a senior level in the EU at the time of a major round table on the single market, chaired by Commissioner Martin Bangemann, in December that year. 

The industry request to the European Commission (EC) to take "a more flexible approach" to the prohibition on DTCA was taken seriously, says Medawar, because EU medicines policy and regulation was controlled not by a health department, but by the EC's department for business, the Directorate General for Enterprise. And he argues that the pressure on EU officials was clear from a major agenda item in 1998 transatlantic business  discussions sponsored by the US  government and the Commission: "The message was that the Pharmas stood for the liberation of consumers and fairness in trade: DG Enterprise responded promptly and said that talks about the possibility of lifting the ban on DTCA might be expected soon." 

The efforts to win EU authorization for DTCA "became most intense during 2000-2003." The major  pharmaceutical firms spearheaded a strategy in the UK to enlist user support for DTCA and, claims Medawar, organized a systematic campaign to build alliances with patient groups to persuade them to argue for a more liberal approach in the interests of their members. In due course, pressure from the industry and government in the UK led to the creation of the EU's Group of Ten (G10), a high-level strategy group mainly composed of government and industry representatives, with a brief to examine the balance between the economic and health challenges relating to pharmaceuticals. 

"The G10 process evolved as something closer to a legislative instrument, with a direct and specific input into the formulation of law," says Medawar. And, in his analysis, G10 was in effect a Trojan horse "to smooth the path for DG Enterprise, helping to steer its forthcoming proposals" for DTC drug promotion. The dominant figures in orchestrating the process were, according to Medawar, Paul Weissenberg, the director responsible for pharmaceuticals in DG Enterprise, and Brian Ager, the director general of the European Federation of Pharmaceutical Industries and Associations (EFPIA).  

When the EC presented its major legislative package in 2001 to update all of the EU's rules on pharmaceuticals, it proposed a pilot programme under which information could be provided directly to consumers on a handful of major disease categories. Immediately controversy broke out concerning why these proposals had been made (Albedo, "Whose Europe is it Anyway?," Pharm. Technol. Eur., 14[2] 10-16 [2002]), and when the European Parliament voted on the package it vehemently rejected the plans. Nonetheless, the final package adopted by EU ministers, effective 1 May, makes explicit provision for an extensive pilot programme in patient information. 

Meanwhile, DG Enterprise encouraged the founding of a new pan-European patients' organization, the European Patients Forum, which was immediately awarded a place on the EU's main working group of patient organizations. It was also proposed by the G10 as "a mechanism to consider patients' needs in relation to information and how they can best be met." And its president was a man identified by Medawar as a friend of the pharmaceutical industry, Rodney Elgie. Pharmas' approval of Elgie "was underlined by his close association with EFPIA," he says, observing that the Pharmas' preference for Elgie set the tone for further reflections on industry links with patients. 

The way in which the DTCA battle unfolded in Europe "revealed the workings of democracy at its worst and best," says Medawar. On the positive side, for Medawar, "much more attention was paid to patients' views." But on the negative side, Pharmas were becoming expert at the subversion and manipulation of patients' views, by buying their way into patient organizations and other similar devices. As a result, patients' views "were increasingly orchestrated by marketing departments, public relations agencies and Pharma-sponsored patient organizations." 

The official European machine has made other mistakes too, says Medawar. He records that the pharmaceuticals unit in DG Enterprise decided in 2000 to modify its policy on consultation - cutting some of its critics out of the loop. The new policy was explained by the head of the unit, Philippe Brunet, in a letter to Health Action International (Europe) - "the one pan-European consumer-health organization that had researched the health implications [of antidepressants] and called for a proper debate." Brunet's explanation for excluding the independent consumer bodies it had traditionally consulted was that "they are not able to do what we have historically looked to them to do, namely the representation of the interests of consumers as patients." Medawar adds that "Brunet's letter went on to propose the name of Rodney Elgie, as if to signal the kind of patient representation he had in mind."  

The EU is also accused of obsessive secrecy in its dealings with the public. In February 2002, Social Audit did a quick sample analysis (about 7%) of the 22000 documents listed on the website of the European Agency for the Evaluation of Medicinal Products, which suggested that eight out of ten documents were considered so secret that neither title nor content could ever be disclosed. Only 4% were classified as public documents; in 4% the title was given but the text was not currently available; in 11% the text was definitively confidential. For 3%, the classification was "restricted," meaning neither the title nor text were currently available; and 78% were classified as "confidential" - indefinitely on the secret list. 

But above all, Medawar suggests that the underlying policy objectives for pharmaceuticals are ill-founded. The main impetus for the recent EU changes in its pharmaceutical rules was the concern that the Pharmas were migrating to the US because the US was doing "better" than Europe; but, says Medawar, the perception was based on the assumption that drug innovation was what really mattered, and that quality of innovation could be measured just by the economic returns. 

The conclusion is uncompromising: "For all the triumphs and gains,  pharmaceutical medicine is losing sight of health and dangerously lacking in public accountability." The case history of antidepressants demonstrates "alarming flaws in the evaluation, regulation and use of medicines, so basic and embedded as to suggest some deepening rift between the forces that drive medicine and health. The SSRI crisis was not essentially to do with rogue molecules. The shape of the crisis was much influenced by the relationships that developed between the professional, business and governmental organizations involved - and between individuals and organizations. How else would collaborations of essentially decent, honest, intelligent people end up in such a mess?" asks Medawar. Later this year we may all see some answers.  

What Medawar is calling for is "an overhaul of the secretive and profoundly inadequate system of medicines control," and hopes the unfolding crisis of dependency on antidepressants will prove to be a watershed.