Dying breath Sunday Star Times | Sunday, 11 March 2007 It was New Zealand's biggest medicines scandal and cost hundreds of lives - and if a multinational pharmaceutical company had had its way, its drug could have killed hundreds more. Donna Chisholm reports. Author and scientist Neil Pearce packs 15 years of anger into 215 pages of his new book. If this is revenge, it has been served on ice. Adverse Reactions: The Fenoterol Story is a scientific whodunit. The victims: up to 600 New Zealand asthmatics who died in an epidemic lasting a dozen years, from 1976. The suspect: the drug fenoterol, marketed here as Berotec. Pearce was part of a team of four Wellington researchers who linked fenoterol to the deaths, but had to overcome powerful opposition - from the drug company and their own peers - before the drug was restricted. It is a story of the lengths to which a company went to protect its multimillion-dollar product. A story of naivete among well-intentioned doctors who refused to believe what the evidence was telling them. And of a timid Health Department, which had to be almost bullied into action. It is a story which Neil Pearce waited 15 years to write. "I was too angry at the time - I didn't want to write something that would just be seen as revenge or self-justification." Now, he says, is the time to learn the lessons of the fenoterol debacle. Multinational German-based drug company Boehringer Ingelheim entered the New Zealand market in 1973. They were the pre-Pharmac days, remembers Auckland epidemiologist Rod Jackson, when the country was quick to license new drugs and a few medical opinion leaders had a profound effect on the prescribing habits of many. "We often had drugs before the Americans. It was pretty loose back then." Fenoterol, launched here in 1976 against market leader Ventolin, was one of a group of drugs used to open the airways during an asthma attack. One of the older medicines in that group, it was less well-targeted than Ventolin, increasing the heart rate at the same time as it opened the airways - increasing the heart's demand for oxygen just when an asthmatic was having an acute attack and was least able to breathe. "So the marketers thought, how are we going to market it? And someone said, let's make it double strength and sell it like that," says Jackson, who did some of the earliest epidemiological work on Auckland asthma deaths. "Little did they know that's what killed people." The year fenoterol went on sale, asthma deaths began to rise. By 1977 there was an epidemic. At its peak in 1979, New Zealand had four times the death rate of any other country - and the highest per capita sales of fenoterol in the world. The drug's 30% market share -second in sales to only Ventolin - made New Zealand a unique fenoterol stronghold. Its licensing application was declined in the United States - no one is sure why - and its market share in every other English speaking country was less than 10%. Boehringer's marketing drive was helped by the fact the company was the major funder of asthma research in New Zealand. It fostered relationships with the leading asthma experts and funded a lavish annual asthma symposium in Rotorua where up to 50 specialists spent the weekend at the Sheraton.
It wasn't unique - in the 1980s, drug companies here spent about $25,000 a year on advertising and promotion to each GP. Concern about the asthma death epidemic prompted the Medical Research Council to form the Asthma Task Force in 1978. Chaired by Wellington professor of medicine Tom O'Donnell, its study of 271 asthma deaths between 1981 and 1983 was the most comprehensive ever done. But it failed to explain the epidemic - oddly, it did not examine in depth the link between the deaths and the drugs in use at the time. What made this even more astounding was that the epidemic had made headlines in 1981 when Auckland Medical School immunologist Doug Wilson suggested a combination of drugs might be causing the deaths. Wilson went on to become the medical director of Boehringer in New Zealand - and one of fenoterol's most public defenders. The task force, largely comprised of respiratory physicians, seemed unable to believe that the drugs that they had been prescribing for years - and to which many patients were responding well - could be to blame. "Clinicians believe their clinical experience is more important than anything else," says Jackson. Though the death rate quadrupled in five years, the total - just four or five per 100,000 people - was low and "very few doctors ever saw an asthma death. "I could give a group of clinicians a drug that increased the death rate four-fold and they would never know because each sees so few patients who die. That's the power of epidemiology -it highlights the incredible importance of doing studies which look across the whole population." Task Force members Malcolm Sears, Tom O'Donnell and Harry Rea were key clinical opinion leaders, says Jackson. "I think they saw the drug companies in a very positive light and didn't see the negative side. They saw them as providing new drugs and education and from their perspective it was a win-win. But there was nothing sinister about this. I believe they may have been naive, but certainly not dishonest." In a rich irony, the first doctor to suspect fenoterol was the culprit was the Boehringer Ingelheim research fellow at Wellington Medical School, Julian Crane. He'd returned from a Boehringer-sponsored trip to a conference in Florence in 1985 with a cold which turned into a wheeze. Grabbing one of the free samples of fenoterol in his office, he took a few puffs. Immediately he began to shake and his heart started to race. For the first time, he experienced the side effects his patients had been telling him about for years. Crane co-opted pharmacologist Carl Burgess and the pair designed a trial to study fenoterol and sent it to Boehringer for comment. The response was an emphatic no. It was only after Crane was no longer the Boehringer fellow that their research into fenoterol - alongside Pearce and respiratory physician Richard Beasley - could begin. Their results stunned them. When the group compared patients with serious asthma which had caused a hospital admission in the previous year, those prescribed fenoterol had more than double the death rate of the others. And in patients with very severe asthma who were also on oral steroids, those on fenoterol had 13 times the risk of death. "I had never seen anything like this before," says Pearce. "If they could, most epidemiologists would kill to get data like this."
The Asthma Task Force, however "did not believe our data" and argued for a six-month delay while the facts were checked - a delay the researchers believed was unethical. News of the study spread quickly in medical circles and by the time the group arrived to present its findings to the Health Department in December 1988, "Boehringer had been there first", questioning the group's methods. But it was when the paper was submitted to The Lancet for publication in February 1989 that the company response really began to heat up. Boehringer commissioned a series of hostile reviews damning the study and defending fenoterol, with which it bombarded The Lancet and the Health Department. The Lancet then reneged on its decision to publish, relenting only when the researchers countered with supportive reviews from distinguished epidemiologists such as Sir Richard Doll. On publication day, Boehringer despatched a bulky publicity package to all doctors, pharmacists and health media the hour the Lancet embargo was lifted - catching out the researchers, who had expected the embargo to be lifted a day later. The Health Department's one-page letter advising doctors to review and modify asthmatics' treatment, was "feeble" by comparison, says Pearce. It was a further eight months before the Health Department - spurred by then Health Minister Helen Clark -finally removed fenoterol from the drug tariff. Drug company attempts to suppress evidence of adverse reactions are far from unique, says Pearce, now a professor and director of the Centre for Public Health Research at Massey University, and nothing has changed since the 80s. "Any epidemiologist or health researcher who discovers a drug is dangerous really has a difficult time. For everyone doing the research there are two, three or four people hired by the industry to dispute it. "Clearly it's a very major problem and it was a very major problem for this research. It very nearly didn't happen - at the cost of lives." For the pharmaceutical industry, says Jackson, a drug is innocent until proven guilty. "I think a drug should probably be guilty until proven innocent and I think we should err on that side when people's lives are at stake. But that's not a commercially viable approach. And this is where commercial pressure and the pressure to save lives clashes. "Drug companies continue to cover up bad news about their drugs and all of us are still incredibly naive about it. I don't think we realise how big a selling job the international pharmaceutical industry is doing on clinicians. I think we are all heavily influenced by them." Pearce and Jackson want tighter controls on drug company involvement in research - Jackson says all trials on humans should be on a register so the results have to be reported and adverse findings cannot be hidden. Results had to be available for independent analysis and governments had to take more responsibility to fund large-scale trials. Pearce says there needs to be stricter controls on funding of research by drug companies, and greater government support for independent researchers. After fenoterol was restricted in 1989, New Zealand's asthma death rate fell by 75% and is now one of the lowest in the world. Boehringer's Sydney-based medical director Dr Rob Creek, asked on Wednesday if the company would approach such studies differently in future, replied: "Would we stand by what we did previously? Well, as far as I'm aware, the answer is yes.
"If you don't happen to like it, you're at liberty to make a scientific criticism and review the data because data can be presented in various ways or conclusions drawn which may not be justifiable." Though it was restricted and no longer qualified for patient subsidies, fenoterol was not banned. It "wasn't proven to the accepted standard for a lot of people" that fenoterol caused the epidemic, he said. Asked if he accepted that fenoterol was implicated in the epidemic, he said: "I don't think I do, no." • Adverse Reactions: The Fenoterol Story by Neil Pearce, Auckland University Press, $40. PROBLEMS WITH OUR PILLS 2005: Pfizer suspends sales of its arthritis drug Bextra because of fears of fatal skin reactions. A study is launched into popular weight-loss drug Reductil after overseas reports of cardiovascular complications. 2004: Merck's anti-arthritis drug Vioxx is pulled from the market amid concerns it causes heart attacks and strokes. Anti-depressant Serzone is withdrawn after evidence it was linked to 20 deaths caused by a toxic build up in the liver. 2003: A major inquiry is launched in Britain into widely prescribed antidepressants, including Seroxat and Prozac, following a spate of suicides and reports of severe withdrawal reactions. 2002: Felo ER, a drug used by 50,000 New Zealanders for treating hypertension is recalled amid questions about its effectiveness. 2001: Controls on the use of the quit-smoking pill Zyban are tightened in line with British changes that followed the deaths of 37 people taking the drug. 1999: The third-generation contraceptive pills Marvelon, Mercilon, Minulet and Femodene are linked with seven fatal blood clots, a case of severe brain damage and at least another 40 cases of blood clots since 1987. 1989: Fenoterol removed from the drug tariff in New Zealand after being linked with the asthma deaths epidemic. http://www.stuff.co.nz/3988680a6619.html
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Artículo de Revisión Sinergia entre edulcorantes no calóricos y el ácido fumárico Mauricio Restrepo Gallego Ingeniero de Alimentos – Corporación Universitaria Lasallista, Especialista en Pedagogía y Psicología, profesor delprograma de Ingeniería de Alimentos, Facultad de Ingenierías de la Corporación Universitaria LasallistaCorrespondencia: Mauricio Restrepo Gallego, email: