Depressing Stories about Pharmaceutical Control

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?" ( www.haiweb.org), 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."

The DTCA trend

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."

Erroneous objectives?

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.