Medicines monitoring questioned
The withdrawal of a drug linked to two deaths has raised questions about Australia’s system for monitoring widely used medications. Clara Pirani reports
companies to conduct a post-marketing study as a condition of registration.
The TGA also expects to be informed of the results of any post-marketing safety studies being conducted by a company, whether or not done in response to a request from a regulator.
Drug companies are legally required to report all serious suspected adverse reactions to the TGA/ADRAC, where ‘‘ serious’’ is defined as ‘‘ a reaction that results in death, is life-threatening, results in hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, is a congenital anomaly, or is an other medically important event or reaction’’.
Doctors are not legally required to report suspected adverse drug reactions to the TGA or ADRAC. However, up to a third of the approximately 10,000 reports of adverse reactions received by TGA each year come directly from general practitioners.
Novartis says it does monitor some of its drugs after they are approved.
‘‘ Novartis Australia conducts postmarketing trials on some medications, however these trials are not designed for the sole purpose of collecting adverse-event data,’’ the spokeswoman said.
Chris Kelman, associate professor in population health at the Australian National University, says the current drug regulatory system is outdated and relies on a process of pre-marketing evaluation, followed by periodic reviews of reported adverse events.
Writing recently in the MedicalJournalof Australia (2007;186(5):249-252), Kelman proposes a new provisional licensing system that would restrict the use of newly approved drugs until post-marketing data is collated and assessed.
‘‘ All applications for new chemical entities would continue to be evaluated by the TGA; however, initial provisional approval would provide a ‘ Caution — New Medicine’ rating for the drug and have expanded requirements for periodic review.
‘‘ Periodic review would be based on accumulated adverse drug reaction reports, recent drug studies, and commissioned Australian observational studies using linked databases. Provisional approval could be upgraded once significant market experience is gained; for example, a medicine could be given a ‘ gold’ safety rating after achieving an agreed benchmark.’’
Hammett says the TGA sometimes requires companies requesting approval for a new drug to provide ongoing surveillance to ensure consumers are not experiencing any unexpected side effects.
However, the requirements do not apply to all new drugs.
‘‘ The 20th version of a blood pressure drug won’t have the same requirements because the side effects profile has already been well established,’’ Hammett says. ‘‘ It’s tailor-made according to the risk of the product.’’
Hammett says the TGA’s swift withdrawal of Prexige shows the current system for reviewing drugs is working.
Prexige is available in more than 50 countries around the world, but Australia is the only country to withdraw the drug. Now other national regulators are asking the TGA to share its data.
Hammett says the TGA had closely monitored the drug, knowing that it was relatively new and belonged to a class of drugs that had previously caused dangerous side effects.
‘‘ The TGA and the Government were aware of that with this drug, and had discussions with the sponsor about an enhanced post-market vigilance program.
‘‘ Novartis, in fact, had a worldwide postmarket safety program in place. They are doing ongoing clinical trials internationally, and are sharing that data with us and that was specifically because there was a concern about this class of drug and we wanted to make sure that we had adequate post-market safety measures in place.
‘‘ The reason Australia has noticed (the problem) so quickly was that we were very vigilant about monitoring this drug when it came onto the PBS,’’ Hammett says.
However, March says regulators will face greater pressure from a public that demands more information about medications they are using.
‘‘ Increasingly we are going to need a more standardised approach to post-marketing surveillance and more transparency,’’ she says. ‘‘ We were quite lucky in some ways in this instance, although the victims and their families certainly were not lucky. The system did work pretty well this time, but we won’t always be so lucky.’’
ARTHRITIS sufferers could be forgiven for thinking they were experiencing deja vu when they picked up the Sunday newspapers last week. Less than three years after one of the most popular arthritis drugs in Australia was withdrawn after being found to increase the risk of heart attack, headlines claimed that yet another arthritis treatment was being recalled after some patients taking the drug died from liver failure.
The Therapeutic Goods Administration had received eight reports of liver damage in patients taking Prexige, a painkiller used by 60,000 Australians to treat osteoarthritis. The reports included two deaths and two people who required liver transplants.
‘‘ The TGA and its expert advisory committee, the Adverse Drug Reactions Advisory Committee, have urgently investigated these reports,’’ the TGA said last Saturday. ‘‘ ADRAC has today recommended the cancellation of the registration of Lumiracoxib (Prexige) due to the severity of the reported side effects associated with this drug.’’
While clinicians applaud the TGA’s quick action in taking Prexige off the shelves, some claim the case raises questions about how drug safety is monitored in Australia.
Prexige was first sold in Australia in November 2005 but was only widely used after it was listed on the Pharmaceutical Benefits Scheme in August 2006.
The TGA and various medical groups were watching the drug closely for any signs of serious side effects. The National Prescribing Service had gone so far as to publicly state that Prexige should not be listed on the PBS.
Prexige is a Cox-2 inhibitor, one of the newgeneration non-steroidal anti-inflammatory drugs (NSAIDs) known to cause fewer side effects — such as gastric bleeding — than older anti-inflammatory drugs. However, concerns about Cox-2 inhibitors emerged in September 2004 when pharmaceutical giant Merck withdrew Vioxx, a popular Cox-2 used to treat arthritis, after it was found to increase heart attack and stroke risk.
Then in April 2005, drug company Pfizer withdrew its painkiller Bextra amid concerns that it also was linked to heart disease.
A day before Prexige was listed on the PBS last year, the National Prescribing Service warned there was insufficient information about the drug’s safety. ‘‘ We are warning all GPs that its long-term safety hasn’t been proven yet,’’ a NPS spokesman said.
Clinicians were monitoring the drug for cardiac side effects, but no one expected severe, even fatal, liver damage.
‘‘ We were aware of cardiac risks associated with this class of drugs,’’ said Lynn Weekes, CEO of the National Prescribing Service. ‘‘ But these effects on the liver have really come out of the blue. Some side effects are only really seen over time, when a drug is more widely used.’’
A spokeswoman for Novartis, which makes Prexige, said liver damage was a known but rare side effect of the drug.
Prior to its release, the largest Prexige clinical trial was the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET). TARGET was a one-year trial involving more than 18,000 patients with osteoarthritis that compared a 400mg dose of Prexige to the NSAIDs naproxen (500mg twice-daily) and ibuprofen (800mg three times-daily).
Participants were given a 400mg dose of Prexige once daily for one year.
‘‘ This study demonstrated that Prexige had a superior gastro-intestinal safety profile, providing a significant 79 per cent reduction in serious gastro-intestinal complications in patients not taking aspirin compared with traditional NSAIDs (ibuprofen and naproxen),’’ a Novartis spokeswoman said.
‘‘ No statistically significant difference was seen in liver safety between Prexige and the NSAIDs in this study. In this trial, nine cases were judged as probable or possible druginduced clinical hepatitis: six on Prexige and three on NSAIDs (two on ibuprofen and one on naproxen). All patients recovered fully after treatment was halted.’’
However, some argue the case proves that companies should be required to conduct studies of drugs after they are approved — known as post-marketing studies — because clinical trials will only detect a limited number of side effects.
Lyn March, president of the Australian Rheumatology Association and a rheumatologist at Royal North Shore Hospital, says clinical trials are not set up to test for rare side effects that could occur once a drug is widely used by the public.
‘‘ People who volunteer for trials are generally healthy and trials have exclusion criteria for people who already have underlying health problems. And I would imagine that if people develop health problems, like unusual side effects either from the drug or the placebo, they would be dropped from the trial.’’
The spokeswoman for Novartis said serious liver side effects had been reported rarely for all Cox-2s and non-steroidal antiinflammatories.
The TGA’s principal adviser Rohan Hammett agrees that clinical trials will only detect common side effects, not rare adverse events occuring once a drug is widely used.
With any drug, the pre-registration trials that are done usually involve between 300 and 500 patients. They are designed to pick up major safety problems that occur at a rate of about 1 in 1000 patients. So anything that happens less frequently than that won’t be picked up until the drugs are available on the market.’’
March would like to see additional testing of drugs before they are listed on the PBS.
None of these drugs really gets used widely until they are listed on the PBS. I would definitely support increased pharmacovigilance in some way.’’ Lynn Weekes agrees.
Some side effects are only really seen over time when the drug is more widely used. That’s why post-marketing studies are really essential, not just in terms of a drug’s safety but also usage. There were studies done initially on the drug (Prexige) up to 400mg, and there was no evidence of liver damage.’’
According to the TGA, companies are not routinely required to conduct post-marketing studies. However, the TGA can require
Purpose: Lyn March says clinical trials are not intended to uncover rare events. Only wider, longer-term use will do that.