No­var­tis, UCSF re­searchers urge FDA to clean up its messy ad­verse events data­base

A team of re­searchers from No­var­tis, Or­a­cle Health Sci­ences and the Uni­ver­si­ty of Cal­i­for­nia, San Fran­cis­co say the FDA’s ad­verse drug re­ac­tion data­base could be im­proved by group­ing drugs by their chem­i­cal struc­ture and au­tomat­ing cer­tain re­port­ing func­tions.

In a pa­per ap­pear­ing in eLife ear­li­er this month (ti­tled: Re­verse trans­la­tion of ad­verse event re­ports paves the way for de-risk­ing pre­clin­i­cal off-tar­gets) the re­searchers say such changes could help ad­dress sev­er­al ma­jor chal­lenges to in­ter­pret­ing da­ta in FDA’s ad­verse event re­port­ing sys­tem known as FAERS.

Specif­i­cal­ly, the au­thors say that the abil­i­ty to au­to­mat­i­cal­ly map drugs by in­gre­di­ent could make it eas­i­er to iden­ti­fy trends and sift through some of the noise in­her­ent in the open-sub­mis­sion data­base. The au­thors al­so say that in­tro­duc­ing au­toma­tion to the re­ports them­selves could cut down on the num­ber of er­ro­neous or mis­clas­si­fied re­ports.

FAERS cur­rent­ly con­tains well over 8.5 mil­lion re­port­ed ad­verse drug re­ac­tions and is grow­ing at an in­creas­ing rate, with the num­ber of ADRs re­port­ed to FDA ris­ing from less than 100,000 per quar­ter in the late-1990s through the mid-2000s to around 300,000 per quar­ter in 2015.

The ma­jor­i­ty of re­ports to FAERS orig­i­nate from pa­tients (40%) and health­care providers (physi­cians, 25%; oth­er health pro­fes­sion­al, 16%; and phar­ma­cist 5%); the re­main­ing re­ports come from lawyers (3%) or did not iden­ti­fy the re­porter (9%).

Ac­cord­ing to the au­thors, those re­ports match up to just over 7 mil­lion in­di­vid­ual ADRs af­ter ac­count­ing for mul­ti­ple re­ports about the same in­ci­dent and du­pli­cate re­ports.

Too Many Names

One of the biggest fac­tors that com­pli­cates re­search in­to FAERS da­ta is the fact that many drug in­gre­di­ents are sold un­der mul­ti­ple names and in dif­fer­ent for­mu­la­tions.

To get around this, the au­thors ag­gre­gat­ed drugs by their ac­tive in­gre­di­ent, which they say pro­vid­ed stronger drug-ADR sig­nals than by ag­gre­gat­ing based on syn­onym group­ing alone.

This pro­vid­ed the au­thors with a list of 2,729 unique ac­tive in­gre­di­ents. Of those, the au­thors found that a sur­pris­ing 30% had no re­port­ed ADRs and that 90% of the re­port­ed ADRs were at­trib­uted to just un­der half the in­gre­di­ents found in FAERS.

In the case of flu­ox­e­tine, the ac­tive in­gre­di­ent in Prozac, the au­thors found near­ly 400 “syn­onyms” for the drug. Over­all, the au­thors found an av­er­age of 16 syn­onyms per ac­tive in­gre­di­ent in FAERS.

With­out a big­ger pic­ture view of ADRs for drugs with nu­mer­ous syn­onyms, the au­thors say that cer­tain side ef­fects may false­ly ap­pear to be sig­nif­i­cant or in­signif­i­cant. For ex­am­ple, sex­u­al dys­func­tion, a well-known side ef­fect of flu­ox­e­tine, ap­peared to be sta­tis­ti­cal­ly in­signif­i­cant when look­ing on­ly at re­ports for Prozac.

But when look­ing across all ag­gre­gat­ed da­ta for flu­ox­e­tine, the au­thors found that sex­u­al dys­func­tion stood out clear­ly.

Re­port­ing Bias

The au­thors al­so found that re­ports in FAERS dis­pro­por­tion­ate­ly tilt­ed to­wards se­ri­ous or life-threat­en­ing out­comes.

Near­ly 13% of ADRs they iden­ti­fied were to re­port a death, 5% re­port­ed a life-threat­en­ing event, and 34% re­port­ed a hos­pi­tal­iza­tion. But 42% of re­port­ed out­comes fell un­der “oth­er,” which the au­thors say is the on­ly one of FAERS sev­en out­come op­tions that is fit for re­port­ing non-se­ri­ous out­comes.

“It is a fea­ture of re­port­ing in an open sub­mis­sion data­base like FAERS that this ra­tio does not re­flect the true bal­ance be­tween fa­tal and rel­a­tive­ly be­nign drug ADRs, but rather the ra­tio of the ADRs that are thought to mer­it re­port­ing,” the au­thors write.


In many cas­es, the au­thors say that re­porters con­fused ad­verse re­ac­tions with a drug’s in­di­ca­tion.

“Ap­prox­i­mate­ly 5% of all re­ports for any drug de­scribe the drug’s in­di­ca­tion as an ad­verse event,” the au­thors write.

For in­stance, some re­ports iden­ti­fied di­a­betes as a side ef­fect for the drug rosigli­ta­zone, which is used to treat type two di­a­betes.

The au­thors sug­gest that re­porter ed­u­ca­tion could play a role in re­duc­ing the num­ber of re­ports that con­fuse in­di­ca­tion and side ef­fect, as the num­ber of such re­ports be­gan to drop in 2011 when FDA’s 2010 fi­nal rule on ad­verse event re­port­ing went in­to ef­fect.

The au­thors al­so found that oth­er fac­tors, in­clud­ing reg­u­la­to­ry ac­tiv­i­ty and news re­ports can in­flu­ence ad­verse event re­port­ing in ways that can make in­ter­pret­ing trends dif­fi­cult.

In the case of rosigli­ta­zone and an­oth­er re­lat­ed drug, pi­ogli­ta­zone, the au­thors ob­served a sta­tis­ti­cal­ly sig­nif­i­cant sig­nal be­tween both drugs and car­diac events.

But while the au­thors found that the num­ber of heart-re­lat­ed re­ports for rosigli­ta­zone was fair­ly con­stant over time, such re­ports for pi­ogli­ta­zone peaked along­side a pe­ri­od of in­creased scruti­ny of rosigli­ta­zone and re­mained low oth­er­wise.

First pub­lished here. Reg­u­la­to­ry Fo­cus is the flag­ship on­line pub­li­ca­tion of the Reg­u­la­to­ry Af­fairs Pro­fes­sion­als So­ci­ety (RAPS), the largest glob­al or­ga­ni­za­tion of and for those in­volved with the reg­u­la­tion of health­care and re­lat­ed prod­ucts, in­clud­ing med­ical de­vices, phar­ma­ceu­ti­cals, bi­o­log­ics and nu­tri­tion­al prod­ucts. Email for more in­for­ma­tion.

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