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

The Weekend Australian - Travel - - Health -

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

Pic­ture: Vanessa Hunter

Pur­pose: Lyn March says clin­i­cal tri­als are not in­tended to un­cover rare events. Only wider, longer-term use will do that.

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