5.0 ELTROXIN FORMULATION SWITCH (33)
Hypothyroidism is a common medical disorder that is easily managed by replacement treatment with synthetic thyroxine. About 70 000 New Zealanders have hypothyroidism and are treated with thyroxine replacement medication. Since 1973 the only thyroid hormone replacement drug approved and funded by the government for use in New Zealand was the Eltroxin brand, made by GlaxoSmithKline. In 2007 the company moved the manufacture of Eltroxin from Canada to Germany. This resulted in a change in the tablets’ inert ingredients: the new formulation differed in markings, size, and colour and—according to some reports—also in taste and rate of dissolution on the tongue. The active ingredient (thyroxine) remained unchanged and continued to be made in Austria. The new formulation was approved by Medsafe (33).
In 2007 and 2008 New Zealand pharmacies changed to the new formulation of Eltroxin. The old formulation had been used for more than 30 years without problems; but after the new tablets were introduced the rate of adverse event reporting rose nearly 2000-fold—from 14 reports in 30 years to more than 1400 in 18 months (33).
Adverse reaction reports relating to the new formulation were first received in October 2007 by New Zealand’s Centre for Adverse Reactions Monitoring, CARM. By July 2008, 294 incidents of adverse reactions had been reported—most (251) reports were received after the Eltroxin formulation change hit the press. The number of adverse reaction reports peaked in September 2008 (at 492). The number fell in October that year to 177 and even further in November to 21, after an announcement that an alternative thyroxine brand was being approved.
About half of all the symptoms reported—such as weight gain, lethargy, muscle pain, joint pain, and depression—can be features of hypothyroidism, but other commonly reported symptoms are not: conjunctivitis, eye pain, headache, itching, skin rash, abnormal or blurred vision, nausea, and indigestion. The New Zealand Medicines and Medical Devices Safety Authority (Medsafe) consulted with local endocrinologists and sought information from the 30 countries in which the new formulation of Eltroxin is used. Some countries reported a small increase in the number of adverse reports, but none had such a dramatic increase as in New Zealand. Medsafe also had independent tests conducted, which found that the new formulation contained the ingredients listed by the ompany, had the same levels of thyroxine as the old formulation, and was bioequivalent to the old tablet.
Medsafe issued a press releases to clarify misinformation being spread through the media and internet sites about the new Eltroxin formulation. This misinformation included rumours that the new formulation was being manufactured in India and contained genetically modified ingredients and monosodium glutamate.
In response to public pressure two additional brands of thyroxine were approved for use in New Zealand in October 2008, enabling patients to switch brands without additional expense. Although these alternatives were provided as soon as they could be, the public perception was that Medsafe’s response to the adverse reactions reporting was too slow, as reflected by demands for immediate action from politicians in a press release headed “How long will Eltroxin sufferers have to wait?” By April 2009 the level of adverse reaction reporting had dropped back to nearly that before the formulation change and has remained low since. There have been very few media stories about the formulation change since November 2008. Despite the negative publicity about Eltroxin, data from Pharmac indicates that as of June 2009, many patients had gone back to the drug and about 80% of patients using thyroxine were taking the new formulation of Eltroxin.
The following two studies investigate this change from psychological and sociological viewpoints. Although this was not a brand switch, the studies provide an interesting perspective on the role that media, public reactions and governmental agencies play. These studies provide valuable insight from a different lens and also draw parallels to brand switches, highlighting areas that can be targeted for future improvement. 5.1.1 Gardner & Dew, 2011 (34)
This study uses the Eltroxin formulation switch to investigate the use of the Actor-Network Theory (ANT) in sociological studies. Although ANT is not relevant to this paper, the observations this study presents on the Eltroxin switch can be utilised to understand different forces in play during a brand switch, and how that can affect ADR reporting and patient outcomes.
The paper follows the events, noting when important changes occur and how they affect future events and the end outcome.
1. A sufferer of hypothyroidism, Lyn, made a link between her new symptoms and her new medicine after listening to people with the same problems discussing this on talk back radio. The radio provided the initial means for an otherwise discrete collection of individuals to form a group bound by the belief in the ill-effects caused by the new formulation.
2. The Southland Times published a story on this potential link, further disseminating the nascent groups rendering of the medicine to a wider audience. The article included discussions about Medsafe, Pharmac and GSK’s role. The newspaper drew a series of associations between bodily symptoms of Lyn, Eltroxin, and GSKs manufacturing processes in Germany.
3. Due to Lyn’s phone number being published in the article, she claimed to have received “hundreds” of complaints from people having the same symptoms. This prompted The Southland Times to publish another article which elaborated on the alternative medication (Goldshield brand) taken by Lyn that doesn’t cause any side effects. This article reaffirmed to the readership the series of associations made in the first article.
4. The article prompted patient’s to report their adverse reactions to CARM. It provided instructions to Eltroxin users, attempting to channel one series of actions into another series of actions. It encouraged the translation of anecdotal complaints of a group of dispersed individuals into coordinated and homogenous action by contacting CARM.
5. The Waikato Times also published an article after someone in the Waikato region experienced problems, exposing the controversy to 40,000 more people. Media coverage continued and increased, exposing the problems to more people.
6. A massive flow of reports was received by CARM, of which 40% were consumer reports. CARM became a voluntary passage point, where the actions of dispersed individuals were coordinated into a series of formal reports. They essentially acted as an inscription device, translating scattered action among members of the population into a format that could be subject to various statistical analyses. It produced an official appraisal of risk.
7. Medsafe issued statements saying the formulation had been retested and GSK ordered to issue information concerning the medicine directly to consumers. The statements also suggested that poor patient compliance should be considered as a possible cause of adverse effects. In doing this, Medsafe became delineated and engaged in action that induced other actors to delineate themselves.
8. Allan Campbell, a Temuka-based pharmacist, claimed that Medsafe, along with other government agencies has failed to react with sufficient haste. Support groups formed which criticised the government and requested subsidies of the Goldshield brand of levothyroxine. Opposition MPs also claimed ineffectiveness of the Government and Medsafe.
These actions strengthen the viewpoint that the new Eltroxin formulation was the cause of the adverse reactions. As more individuals, groups, and agencies become enrolled in this viewpoint, it becomes more factual and has a greater ability to induce entities to delineate themselves and act, as well as becoming more durable and difficult to dismiss.
9. As more politicians became entwined, only one out of the two viewpoints that had been originally expressed, had been disseminated with any success. Very few people and groups had taken the position that Medsafe was correct, regardless of the absolute truth. CARM and Medsafe were restricted to a monitoring role. The success of the anti-Eltroxin group is best indicated by the media coverage.
10. Medsafe and CARM provided information to MARC. The recommendations from the Committee meeting represented a further translation of action: the summary of adverse reaction reports composed by CARM, and the worldview constructed by Medsafe have prompted the Committee to act and to initiate activities that will put other actors into motion.
The media was vital: it disseminated the rendering of Eltroxin as the cause of adverse reactions, the risk, to a very large readership. Importantly, it enabled an otherwise diverse heterogeneous collection of dispersed individuals to group together behind various spokespeople. It also coordinated this group by illustrating a conduit for action: the media provided details of CARM and encouraged sufferers to report their symptoms. It therefore facilitated a widespread, concerted response to risk.
By reporting directly to CARM, sufferers could bypass the usual channel for reporting to GPs, who may be both placating and dismissive. Consequently, CARM received a large quantity of reports which were standardised through CARMs various ordering and sorting practices. Politicians acted as another conduit for action: the complaints of the worried, anxious individual became the basis for political sound bites and rhetoric.
5.1.2 Faasse, Cundy & Petrie 2009 (33)
The authors of this study discuss four major factors which they believe had roles in causing the massive amounts of reports received by CARM.
External factors – at the time of the formulation switch, Pharmac was under intense scrutiny due to decisions made around rationing the availability of Herceptin to only early stage breast cancer. Patients saw the formulation change as a cost cutting strategy by Pharmac,
despite the newer formulation being more expensive.
The negative perception and distrust of Pharmac from this are likely to have contributed to the problems. C
hampions – Alan Campbell, a pharmacist from Temuka, publicised patients’ concerns by giving media interviews. This brought the issue to the attention of the public, but also created fear and dissatisfaction that may have made the situation worse. There was also appeal in his position as a small town health professional taking on the “medical establishment”.
Media coverage –
Media coverage of the issue was widespread, but varied between regions. The intensity of the coverage was related to the rates of ADR reporting, showing the strong effect the media can have on ADR reporting rates and potentially the development of nocebo-based symptoms. In the Auckland region, where the news media did not particularly focus on the story, is home to around 31% of the New Zealand population but accounted for only 16% of all adverse reactions reported. In contrast 41% of all adverse reaction reports came from the Bay of Plenty, Canterbury, and Southland regions, which together have only 22% of New Zealand’s population. The Eltroxin story was covered extensively in local newspapers in these regions.
Patient factors –
Hypothyroid patients, even those taking thyroxine replacement therapy, had been found to have higher levels of emotional stress and more physical symptoms than people without hypothyroidism. Because of this, they are more likely to attribute physical symptoms to a medical intervention or illness. It is likely that patients taking Eltroxin misattributed unrelated physical symptoms to the new formulation. Additionally, they may have misattributed indications that they required a re-evaluation of their dose as instead being harmful adverse effects.
Although the authors did not consider this a separate factor, social media attention is discussed. Internet support groups and chat forums provided channels for false rumours to be spread about the drugs manufacture, ingredients, and the agenda of the “medical establishment”. The misinformation may have influenced patients’ beliefs and expectations about the likelihood of experiencing physical symptoms in response to the formulation change and also to the spread of physical symptoms in these patients.