Re­ports of drug side ef­fects soar five­fold

FDA data­base could warn of dan­ger­ous prod­ucts al­ready on mar­ket

USA TODAY International Edition - - FRONT PAGE - Matthew Wynn MedPage To­day and John Fauber Mil­wau­kee Jour­nal Sen­tinel

More than 1 mil­lion re­ports of drug side ef­fects were filed with the U. S. Food and Drug Ad­min­is­tra­tion in 2015, a five­fold increase since 2004, ac­cord­ing to an anal­y­sis by the Mil­wau­kee Jour

nal Sen­tinel and MedPage To­day. Num­bers aren’t fi­nal for 2016, but they are ex­pected to match that all- time high.

Drugs to treat dis­eases such as rheuma­toid arthri­tis, pso­ri­a­sis, mul­ti­ple scle­ro­sis, a type of cancer and di­a­betes are among those with the great­est num­ber of re­ports. Many of the drugs are for con­di­tions that oc­cur in 1% or less of the pop­u­la­tion, but sev­eral have seen in­creas­ing use.

For years, the FDA’s ad­verseevents sys­tem has been de­rided be­cause of its largely vol­un­tary na­ture — only drug com­pa­nies, not doc­tors or pa­tients, are re­quired to re­port prob­lems. As a re­sult, the sys­tem prob­a­bly was cap­tur­ing only a small per­cent­age of cases.

In re­cent years, the num­ber of re­ports has been mul­ti­ply­ing, prompting more in­de­pen­dent re­searchers and drug com­pa­nies to use the data as a way to de­tect safety prob­lems, the Jour­nal Sen­tinel and MedPage To­day found. But ex­perts say the in­for­ma­tion still is largely un­tapped and — if used more — could be­come an im­por­tant alarm that warns of dan­ger­ous drugs after they hit the mar­ket.

The surge in re­ports could in­di­cate a grow­ing num­ber of harmed pa­tients or more vig­i­lant re­port­ing of ad­verse events, a goal of the FDA. Ex­perts say both prob­a­bly play a role.

Twelve years ago, 206,000 re­ports of side ef­fects from med­i­ca­tions were filed with the FDA — com­plaints as friv­o­lous as flat­u­lence and as se­ri­ous as death.

By 2015, the most re­cent full year of data, the num­ber had grown to 1.2 mil­lion.

The FDA has long dis­cour­aged use of the sys­tem for re­search

pur­poses. When it dis­trib­utes the data­base, it at­taches warn­ings that say the re­ports aren’t ev­i­dence drugs caused the prob­lems listed, that the data can’t be used to es­ti­mate risk and that the in­for­ma­tion should not be used to com­pare drugs.

In 2005, the Gov­ern­ment Ac­count­abil­ity Of­fice estimated the sys­tem cap­tured only 1% to 10% of all ad­verse re­ac­tions. De­spite the ex­plo­sion in re­ports, that re­mains the most re­cent es­ti­mate of how many cases are caught by the sys­tem. STRENGTH IN NUM­BERS The in­creased vol­ume of re­ports has re­searchers, in­surance com­pa­nies and even some phar­ma­ceu­ti­cal groups reimag­in­ing how the data can be used.

“Sheer num­bers have some sci­en­tific weight,” says Thomas Moore, se­nior sci­en­tist at the In­sti­tute for Safe Med­i­ca­tion Prac­tices, a non- profit watch­dog group fo­cused on drug safety. “If 500 peo­ple re­port a prob­lem, it is un­likely that they are all wrong.”

For all its warn­ings about the lim­i­ta­tions of the sys­tem, the FDA it­self has re­lied on the re­ports to guide its ac­tions. Case in point: a patch used to treat mi­graine headaches.

In Septem­ber 2015, the Ze­cu­ity patch was al­lowed on the mar­ket after years of give- and- take with FDA of­fi­cials. The patch, which looks like a large arm­band, re­leased a drug through the skin to fight mi­graines. An early ver­sion failed to get ap­proval after the FDA raised con­cerns that it could “cause se­vere burns and per­ma­nent skin le­sions.”

The patch was re­designed and tested on 58 peo­ple, none of whom re­ported prob­lems. The FDA could have re­quired more clin­i­cal test­ing but in­stead chose to ap­prove the re­designed patch and rely on “post­mar­ket sur­veil­lance.” In other words, the safety of the prod­uct would be linked to re­ports of side ef­fects.

The FDA or­dered Teva, the man­u­fac­turer, to re­port ad­verse events within 15 days of re­ceiv­ing any com­plaint.

Nine months later there were hun­dreds of re­ports of blis­ters, burns, scars and pain. On June 2 of last year, the agency said it was “in­ves­ti­gat­ing the risk of se­ri­ous burns and per­ma­nent scar­ring.” A week later, Teva vol­un­tar­ily pulled the prod­uct.

The com­pany said it worked with the FDA to pin­point a prob­lem but noted that be­cause the root cause was not iden­ti­fied, the prod­uct re­mains off the mar­ket.

Oth­ers say, how­ever, that the vol­un­tary and cum­ber­some na­ture of the sys­tem makes the value of the in­for­ma­tion lim­ited.

“As a physi­cian, I have tried to use it, and it is very, very clumsy,” says Joseph Ross, an as­so­ciate pro­fes­sor of medicine at Yale Univer­sity School of Medicine.

He says the sys­tem pro­vides only a nu­mer­a­tor — the num­ber of ad­verse event re­ports for a drug — with­out estab­lish­ing the de­nom­i­na­tor, the num­ber of peo­ple us­ing that drug.

In its own anal­y­sis, the Jour­nal Sen­tinel and MedPage To­day found that among the 10 drugs that ac­counted for the most re­ports, seven carry “black box” warn­ings, the FDA’s most strin­gent alert for se­ri­ous or po­ten­tially life- threat­en­ing side ef­fects.

The 10 drugs ac­count for one of ev­ery five re­ports filed since 2013. Yet, none is on the top- 10 list of most- pre­scribed drugs as de­ter­mined by IMS Health, a drug mar­ket re­search firm.

“We are con­cerned,” says Michael Carome, deputy di­rec­tor of Pub­lic Cit­i­zen’s Health Re­search Group. “It re­flects that the FDA has al­lowed drugs to come to mar­ket with­out ad­e­quately en­sur­ing safety.”

The FDA doesn’t share that opin­ion. “It’s not al­ways nec­es­sary to wait and go through a tra­di­tional de­vel­op­ment pro­gram be­fore mak­ing a drug avail­able to pa­tients,” says Lyn­d­say Meyer, an FDA spokes­woman.

She says speed­ing up drug ap­proval and de­vel­op­ment goes hand- in- hand with strength­en­ing the ad­verse- event re­port­ing sys­tem. The agency has taken many steps to increase the qual­ity and num­ber of re­ports, she says.

Cou­ple those ac­tions with in­creas­ing con­sumer par­tic­i­pa­tion in the sys­tem, she says, and it’s hardly a sur­prise re­ports would rise so dra­mat­i­cally.

“In fact, we en­cour­age health care providers and the pub­lic to re­port sus­pected ad­verse drug events,” she wrote in a state­ment.

In 2015, the FDA started re­quir­ing com­pa­nies to re­port events elec­tron­i­cally in­stead of on pa­per. That led to an increase in less- se­ri­ous events in the data­base and 300,000 ad­di­tional re­ports — the largest sin­gle- year jump in the pro­gram’s nearly 20- year his­tory.

Pa­tients, too, have in­creas­ingly re­ported prob­lems.

In 2004, just 45,000 re­ports orig­i­nated with con­sumers. In 2013, for the first time, more re­ports orig­i­nated with con­sumers than health pro­fes­sion­als. By 2015, con­sumers ac­counted for 55% of all re­ports. A ‘ VIRTUOUS CIR­CLE’ Brian Over­street runs Ad­vera Health, which an­a­lyzes the data­base for in­surance com­pa­nies, phar­ma­ceu­ti­cal com­pa­nies and other groups.

He says con­sumers are in­creas­ingly likely to re­port cases as part of a “virtuous cir­cle.” Be­cause the sys­tem has more re­ports, it gets more at­ten­tion from the me­dia and the pub­lic. Be­cause it gets more at­ten­tion, con­sumers are more likely to make re­ports, which in turn makes the sys­tem more com­plete.

In some cases, com­pa­nies have started em­brac­ing the once- de­rided FDA data­base.

Den­mark- based Lund­beck, which spe­cial­izes in neu­ro­log­i­cal drugs, used the data to find out what kind of side ef­fects were most com­monly re­ported within a cer­tain class of drugs, says Ash­leigh Duch­ene, a spokes­woman for the com­pany. If a cer­tain kind of side ef­fect keeps crop­ping up, she says, the com­pany’s re­searchers pay spe­cial at­ten­tion to pre­vent­ing that prob­lem.

“It’s that R& D fo­cus for us, see­ing what’s out there,” she says.

“Sheer num­bers have some sci­en­tific weight. If 500 peo­ple re­port a prob­lem, it is un­likely that they are all wrong.” Thomas Moore, In­sti­tute for Safe Med­i­ca­tion Prac­tices


The FDA’s ad­verse- events sys­tem has long been crit­i­cized.

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