[e-drug] The need for openness in drug regulation

["E-drug" <e-drug@healthnet.org>]

E-DRUG: The need for openness in drug regulation
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[The BBC Panorama documentary on the anti-depressant case and how the UK Regulatory Authority (MHRA, see http://www.mhra.gov.uk/) did (not) deal with this, has lead to several calls for more openness in drug regulation.
Is drug regulation in a crisis?
If a well-resourced European country cannot control its drug companies, how about a developing country?
Here an editorial and 3 pieces from the UK Guardian. Copied as fair use. 
Warning - long message. WB]

The need for openness 

Leader
Tuesday October 5, 2004
The Guardian 

Four years ago, in a famous editorial the New England Journal of Medicine posed a blunt question: "Is academic medicine for sale?" As our two-part series this week - along with BBC Panorama on Sunday night - demonstrates, the question was too narrow. It should not be confined to academic medicine but medicine across the board, with a simple answer: no, it is not for sale because the current owners could not be happier. At every level - medical education, GP prescribing, hospital treatment, drug licensing and regulation of the industry - the influence of giant pharmaceutical companies is not just unhealthy and detrimental, but borders on the corrupting. It is putting at risk the integrity of the medical profession, public trust in the national health service, and public confidence in the regulatory agencies. 
Our series this week has documented the way in which junior doctors are being selected and groomed by the industry to become mouthpieces for their latest products; senior consultants become trapped in conflicts of interests between their medical ethics and the industry's consultancy fees; and the regulatory body has failed to separate the public interest from the industry's interests, to the detriment of patients and healthcare standards. The root cause of the trouble is the dominance of marketing departments in the multinational companies. There is nothing new about lavish expense-free trips offered by industry - documented by an earlier Panorama programme many years ago - but it has reached new levels of insidious sophistication, as Sarah Boseley's story of this year's annual European conference of cardiologists sets out. At least half the 18,000 medics present were drug industry guests. Research has shown that once back at home, their prescribing is influenced by the marketing "symposiums". 

Thankfully, the Commons select committee on health is conducting a wide-ranging inquiry into the drugs industry's influence. Three important changes are needed. First, the need to ensure the independence of the regulatory body. Unlike now, both the body and its advisory boards should only comprise medical members with no connections to the industry. Second, it must be much more open. Patients have a right to know why a new medicine has been licensed as well as what side effects can be expected - a process American patients have enjoyed for years. Third, medics should not only be required to register their consultancies, but also list the amounts involved. Such openness is the best disinfectant to stopping "bought" medical pleading. 

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Drugs licensing flaws exposed 

Special report: Pfizer advised on how to get antidepressant approved by member of body deciding on application 

Sarah Boseley
Monday October 4, 2004
The Guardian 

A leading figure in the world of psychiatry gave a pharmaceutical company advice on how to get its new drug approved while he was sitting on the committee which was deciding the licence application. 
An internal memorandum from Pfizer, the world's largest drug company, says Stuart Montgomery would be happy to become a paid adviser and declare an interest to the Committee on the Safety of Medicines (CSM) once the drug, an antidepressant to rival Prozac, had been through the licensing process. 

The drug, sertraline, which acquired the brand name Lustral, became a billion-dollar success, but is now one of several banned from use in children in the UK because of evidence they can cause them to become suicidal. Their use in adults is under investigation. 

Dr Montgomery says his ad vice to Pfizer in 1989 was permissible because he was not receiving money from the company at the time. But Kent Woods, chief executive of the drug regulatory body which grants licences on the advice of the CSM, said such conduct was "absolutely unacceptable". 

"Not only does each member [of the CSM] on appointment sign a letter ensuring confidentiality but at every meeting, the chair as a matter of routine reminds everybody that proceedings are confidential," he said. If the company had questions, they should have talked to officials of the Medicines and Healthcare products Regulatory Agency (MHRA), not the independent CSM experts. 

Critics say the case exposes weaknesses in the drug licensing system, run by a regulatory body which, other papers obtained by the Guardian reveal, has an unquestioning relationship with drug companies. 

That relationship is so close that the pharmaceutical trade body in June drew up a business plan for the regulator, concluding: "Our priorities are aligned." 

In the first of a two-part investigation into the influence of the drug companies over doctors and government, the Guardian examines the intimacy between the industry and the regulator. . Tomorrow it will focus on the sponsorship, consultancies and fees paid to doctors by drug companies. 

The MHRA is responsible for licensing medicines and regulating the industry. It relies on the advice of the independent experts on the CSM when it grants a new product licence. These experts, from all fields of medicine, are supposed to declare any pharmaceutical company interests, such as consultancies, fees and shareholdings, and must leave the room when drugs from com panies that have paid them are discussed. During his time on the CSM, Dr Montgomery disclosed payments for lectures and advice from Eli Lilly, the makers of Prozac, and from Organon, Beecham, Merck, Sanofi, Glaxo, Novo, Jouveinal, Duphar, Wyeth and Almirall. 

Dr Montgomery, who held a joint post with St Mary's hospital, Paddington, and Imperial College in London, was a psychiatric expert on the CSM. His opinion was crucial in 1989, when the Medicines Control Agency as it was then known was considering an application from Pfizer for a licence for sertraline. 

A confidential internal memorandum from Pfizer, dated April 24 1989, which was submitted in evidence to a recent court case in the US, has been obtained by the Guardian together with Mind, the national association for mental health, which has been campaigning for better drug regulation. Richard Brook, its chief executive, will today call for an external inquiry. "There is clear confusion about the role that Dr Montgomery was playing in this situation," he said. 

"It also makes it very difficult for outsiders to believe there was not a serious conflict of interest when one of the major experts on depression involved in the CSM is actually speaking to a drug company about how they best present their results for licencing." 

Dr Montgomery became a professor of psychiatry at Imperial College in 1993. The journal he edits, International Psychopharmacology, regularly publishes company-funded studies of antidepressants, as other journals do. He authors many of the papers, often jointly with other senior figures in the field. 

The memo reveals that Dr Montgomery met Pfizer officials at St Mary's. He told them the committee had accepted that the drug was effective but "the safety analyses require re-presentation" and he advised them how to go about it. 

He told Pfizer they must appeal against the CSM's initial decision. The memo reveals that Dr Montgomery is not going to declare an interest in Pfizer. 

"He would still like to remain a disinterested party at the CSM till the appeal was heard," says the memo. "Thereafter he would be happy to act as an adviser to Pfizer and declare an interest." 

The Pfizer drug got its approval first in the UK. Other European regulators were not happy that the data from clinical trials proved it worked. 

Dr Montgomery said he had no conflict of interest over Pfizer. "My comments to Pfizer in 1989 were the usual clarification of the objections of the CSM to their application. At that time I had no conflict of interest with Pfizer, I was not a paid consultant, I was not in receipt of research grants from Pfizer, and I did not own shares in Pfizer," he said in an email to the Guardian. 

"The extracts from the memorandum make it clear that I was a disinterested party and was not prepared to consider a relationship with Pfizer while an application was under review." 

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The drugs industry and its watchdog: a relationship too close for comfort? 

Rob Evans and Sarah Boseley
Monday October 4, 2004
The Guardian 

It would appear to be a happy and satisfying relationship. "Our priorities are aligned," says one document. There have been "notable successes" says another, citing "another example" of where the two sides "cooperated well". In business partners, this would seem to indicate a harmony of views. The documents obtained by the Guardian, however, relate to meetings between the drug industry and the watchdog body set up by government to police it. 
Critics say the drug regulator and the industry are too close. Their proceedings have long been shrouded in secrecy because of the drug companies' insistence on the commercial sensitivity of information relating to their products. 

Today, documents obtained by the Guardian under the open government code reveal the reality of relations between the Medicines and Healthcare products Regulatory Agency (MHRA) and the trade association of the industry it regulates. The documents show that: 

7 the regulator and the industry have been engaged in a joint lobbying campaign in Europe; 

7 the industry privately drew up its own detailed blueprint of how the MHRA should be run; 

7 the industry has been pushing for higher level representation at the MHRA against ministers' wishes. 

Since 1989, when the then prime minister, Margaret Thatcher, took drug regulation out of the hands of the Department of Health, the MHRA has been 100% funded by the pharmaceutical companies. 

The MHRA's chief executive, Kent Woods, appointed in January, has no drug company background, but critics say the agency continues in the unquestioning belief that the regulator and the industry are working together in the mutual interests of public health. 

John Abraham, professor of sociology at Sussex University, who is well respected for his books on drug regulation, says that in 1989 there was a reconstruction of the regulators' mission alongside the new fees relationship. The MHRA came to believe the interests of public health are coherent with the promotion of the industry. 

"The criticism of the old Department of Health medicines department in the 70s was that it didn't have any teeth. Not only does it now not have any teeth, but it is not motivated to bite," he said. 

The MHRA told the Commons health select committee inquiry into the influence of the industry that it does not consider the fee relationship to be a problem. 

"I would suggest to a lay person there is a big problem with the concept of independence from industry of a body that is fully funded by industry," said Professor Abraham. The UK's regulatory agency competes with those of other countries to approve drugs for the whole of Europe. 

But Professor Woods says that neither industry funding nor close liaison is a problem. "It is important that the regulator understands the regulated industry. 

"I have to say that our areas of overlapping interests are not 100%. There are some things where we have common cause but our prime responsibility is to ensure we protect public health. These are aims which the industry shares. I don't think there is a necessary antipathy between what the ABPI [The Association of the British Pharmaceutical Industry] is trying to achieve and what we are trying to achieve. But there are other areas in which we can't agree." 

Richard Ley, spokesman for the ABPI, denied that the ABPI had the MHRA "in its pocket". "The objective of the MHRA is to ensure that medicines are assessed to be effective and as safe as possible. Those are also our aims. We have an absolute desire to have good quality medicines." 

The documents record the regular meetings and dinners between the MHRA and the ABPI over the past year. 

Among the "notable successes" of its close collaboration with the industry, the MHRA paper cited how it "cooperated well" with the trade association to lobby other European governments and the European commission on a review of legislation governing drug companies. It was, according to the briefing paper, "another example where the Association of the British Pharmaceutical Industry and the MHRA worked closely together". 

Minutes of a meeting between the ABPI and senior MHRA officials in April record that the "ABPI thought there was a remarkable concordance between MHRA and their priorities..." 

At their meeting with the MHRA top officials in June, the ABPI presented an eight-page blueprint detailing how it thinks the MHRA should be run to "build upon the excellent working relationship" between the industry and the regulator. According to this document, "our priorities are aligned [ABPI/MHRA]". 

Following this meeting, Nicky Lilliott, the ABPI's head of regulatory affairs, wrote to Professor Woods, to confirm that, as agreed, the ABPI would develop an action plan to discuss a wide range of issues for the future of the agency. "I would propose that over the summer the ABPI drafts an action plan and this is then circulated to yourself and colleagues for comments, with the intention to agree the action plan at our meeting in September." 

"The action plan would need assigned topic leaders, joint ABPI/MHRA, in order to achieve the agreed objectives/milestones. The main driver for the actions and timelines for these issues will be the implementation (of) the new pharmaceutical legislation by October 2005". Professor Woods said the action plan related to establishing a framework for bilateral meetings. The documents show the ABPI is unhappy at proposed changes to the structure of the MHRA. It used to have three people on the ministerial advisory board and two on the Medicines Commission, the drug licensing appeal body. 

Pressure


In a letter to Professor Sir Alistair Breckenridge in January, Dr John Patterson, the ABPI president, wrote: "We remain concerned at the lack of representation of the pharmaceutical industry at board level within the MHRA ... As the only regulatory agency that is fully industry-funded, we believe it is essential that we have a say on a variety of issues, not least financial matters relating to fees and service levels." 

After more pressure, MHRA officials discussed alternative arrangements. Roy Alder, a senior MHRA official, suggested in March that "there could be scope for industry to make a similar input to MHRA business and operational policy" through other ways. He wrote: "Ministers are clear that the MHRA board should have no current industry people. There seems no option on this issue." He suggested someone recently retired from the industry could possibly be put on the board, "but ministers may want to avoid any perception of industry interests at board level." 

The Committee on the Safety of Medicines (CSM), made up of independent experts, advises the MHRA on which drugs to license after studying clinical trial data on safety and efficacy. Its members are supposed to declare any sponsorship or payments they receive for lectures or advice from industry. The last complete declaration of interests of CSM members, for 2001, shows 17 out of 36 members had personal financial links to the industry, while others have declared non-personal interests such as research grants. 

The documents show that industry has been agitated about ministers' "unrealistic" plans to tighten the rules on conflicts of interests. The ABPI complained ministers were "being too restrictive in the requirement for experts to not hold any personal interests in the pharmaceutical industry." 

Professor Abraham claims there is too much of the "revolving door" syndrome at the MHRA. Not only do CSM members take fees from industry, but many agency officials used to work for drug companies, such as the former head of worldwide drug safety at GlaxoSmithKline, who is now the MHRA's head of licensing. 


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Junket time in Munich for the medical profession - and it's all on the drug firms 

How 'opinion leaders' among doctors are won over by cash on offer from the giants of the pharmaceutical trade 

Sarah Boseley
Tuesday October 5, 2004
The Guardian 

Like twin rivers in spate, several thousand people flow down parallel pavements the length of Munich's vast conference halls. Here and there, a signboard held by a rep bobs above the flow. They are heading for the car park, where dozens of buses hired by drug companies are waiting to take them to dinner. These are not package tourists, but doctors. 
This is the main annual European conference for cardiologists - a huge affair of 18,000 delegates. Most travel there courtesy of the drug companies. They have their registration paid, their flight paid, their hotel paid and their meals paid. Out of courtesy, they attend the "satellite symposium" before dinner promoting their sponsor's drug. 

Many senior doctors or "opinion leaders" hired to speak on behalf of the drug companies at these events will sleep in the best hotels and collect between #1,000 and #2,000 for their talk, if they are not already on an annual retainer of #10-20,000 from each company they advise. 

Most doctors say the sponsorship of doctors by the drug companies is normal, inevitable in a capitalist society, and does no harm because, they insist, they are not influenced. Others say it is shocking. Raymond MacAllister, senior lecturer in pharmacology at University College London, believes the profession is under a mass delusion. "If the general public knew what was going on, they would be astonished," he said. 

Edwin Gale, a professor of diabetes at Bristol University's division of medicine, once took drug industry money but changed his mind after he was asked to investigate a class of drug by a colleague who wanted somebody "who is not in the pocket of the companies". He was shocked to discover that the drugs had been kept on the market in the US for three years after it became clear that people were dying of liver failure. 

In an article he was asked to write for Clinical Medicine, the journal of the Royal College of Physicians, last November, he analysed the science that shades into marketing, the professors who end up as promoters, and called on each doctor to make a moral decision about their own involvement. Most do not recognise what is happening, he said. "Doctors are so incredibly gullible because they suspect themselves of the very highest motives." 

The article brought him support even from some scientists in the employ of industry, he said. "They said they are sickened by the process they are involved in. One said I just wondered when doctors were going to wake up to what is going on." 

There are rules on gifts to doctors - nothing much more than a pen or a coffee mug is allowed. So in the Munich exhibition halls, vast as aircraft hangars, the big companies run quizzes at their space-age stands. Doctors sit on stools at a table, fingers on buzzers, or crowd round the posters filling in questionnaires about the company drugs. It is every one a winner and they walk off with a digital camera, a calculator or silver computer mouse. Many doctors wander the stands with bags crammed with booty. 

Sponsorship is part of the NHS fabric. Every doctor must keep up to date with about 50 hours of continuing medical education a year. Five days in Munich listening to the scientific presentations at the European Society of Cardiology meeting nets a doctor 18 hours of credits. But the NHS has a limited pot of money, so in fields like cardiology, psychiatry and rheumatology where drugs are big business, the companies step in. 

Everything is paid for. The Munich hotels had drug company desks in the foyers, with schedules of dinners and the industry's satellite symposia times on the noticeboards and buses that drew up outside after breakfast and dropped doctors back after dinner. 

In the company sights, says a cardiologist who attended the Munich conference but does not want to be named, is the hospital formulary. This is the list of drugs, drawn up by a committee, that the hospital consultants can prescribe for their patients, who then get the prescription continued by the GP. 

"There is overt pressure," he said. "the local hospital drug reps come to us and say - will you make an application to the formulary committee? You have to be able to argue back to them." Those doctors who refuse to help will be out of favour come conference time, he said. He did once make an application to the formulary committee because he was impressed by a certain heart drug. It was accepted. As far as the drug company was concerned, he "was the cat's pyjamas. The year after they took me to America for a conference. I was comfortable with what I had done, but you can see how easily that becomes a trap to fall into," he said. 

A study in the Journal of the American Medical Association in 2000 showed that the more free meals a doctor has from a drug company, the more often he is likely to ask for their drug to be put on the approved list. Also associated with such requests is meeting drug reps, accepting funding to travel to conferences and accepting research funds. 

Dr MacAllister says the formulary committee he sits on in his large teaching hospital is robust. "But in a district general hospital, they are more likely to say - he's the heart specialist - let him have it." 

There is still more concern about the independence of senior doctors, often involved in drug trials for the industry, who are recruited by the companies as consultants and can earn considerable amounts of money speaking to conferences about new drugs and giving companies advice on marketing their products. In the trade, such an authoritative academic is known as a "silvertop". 

Professor Gale had a consultancy around six or seven years ago: "I was earning about #25,000 a year (extra), of which #20,000 was formally a consultancy fee. 

"I know people who have been offered #30,000 to #50,000 a year to sit on advisory committees," said Dr MacAllister. A colleague was paid #800 by a company when a talk he was to give was cancelled. Robin Murray, professor at the Institute of Psychiatry, who said he could be offered $2,000 for a talk which he would put into his research fund, said the issue was not with the drug companies, but with the clinicians. "You don't necessarily expect your colleagues to speak in support of whatever drug they are being paid to support. It is very dismaying to find academic psychiatrists that one has hitherto respected supporting one drug on a Monday and another on Tuesday," he said. 

Increasingly, he said, academics are putting their names to drug trial research papers which are "ghost-written" by company employees. "Academics, particularly academic pharmacologists, have somehow begun to believe that it is acceptable to present company data as if they were a hired gun," he said. 

If the audience knew those academics had not taken part in the collection of the trial data, he said, "they would be much less impressed." But the doctors who advise companies and carry out research say the concern is misplaced. 

Philip Poole-Wilson, professor at the National Heart and Lung Institute of Imperial College, London, who was the lead author in a trial of Bayer's drug nifedipine and spoke at their satellite symposium in Munich, said it was up to individuals to obey their consciences. 

"I'm not going to be manipulated by any company, by any amount of people or anybody. I'm going to say what I want to say and that's that. I regard myself rather like a barrister - that I'm a cardiologist, I know the subject, I'm prepared to speak on it when invited and if I am invited I expect to be paid." 

John Betteridge, professor of endocrinology and metabolism at University College London, who also spoke in Munich and has declared interests in seven pharmaceutical companies as an expert adviser to the Committee on the Safety of Medicines, maintained that doctors were independent of drug company influence. "I think it would be very unusual if doctors used drugs if they thought they weren't the best for that particular patient," he said. 

Nonetheless, a paper produced by the Pharmaceutical Marketing journal suggests "opinion leaders" are carefully recruited and groomed. 

It urges "careful identification of the people you should be working with. The key is to evaluate their views and influence potential, to recruit them to specially designed relationship-building activities and then provide them with a programme of appropriate communications platforms." 

Joe Collier, professor of medicines policy at St George's school of medicine in London, said: "Here is an industry that abuses its power to manipulate what is being prescribed. The cynicism ... seems to know no bounds."

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