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.

A fa­vorite in Alex­ion’s C-suite is leav­ing, and some mighty sur­prised an­a­lysts aren’t the least bit hap­py about it

Analysts hate to lose a biotech CFO they’ve come to trust and admire — especially if they’re being blindsided by a surprise exit.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 59,900+ biopharma pros reading Endpoints daily — and it's free.

David Grainger [file photo]

'Dis­con­nect the bas­tard­s' — one biotech's plan to break can­cer cell­s' uni­fied de­fens­es

Chemotherapy and radiotherapy are the current gladiators of cancer treatment, but they come with well-known limitations and side-effects. The emergence of immunotherapy — a ferocious new titan in oncologist’s toolbox — takes the brakes off the immune system to kill cancer cells with remarkable success in some cases, but the approach is not always effective. What makes certain forms of cancer so resilient? Scientists may have finally pieced together a tantalizing piece of the puzzle, and a new biotech is banking on a new approach to fill the gap.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 59,900+ biopharma pros reading Endpoints daily — and it's free.

While No­var­tis ban­ish­es Zol­gens­ma scan­dal scars — Bio­gen goes on a Spin­raza 'of­fen­sive'

While Novartis painstakingly works to mop up the stench of the data manipulation scandal associated with its expensive gene therapy for spinal muscular atrophy (SMA) Zolgensma— rival Biogen is attempting to expand the use of its SMA therapy, Spinraza. 

The US drugmaker $BIIB secured US approval for Spinraza for use in the often fatal genetic disease in 2016. The approval covered a broad range of patients with infantile-onset (most likely to develop Type 1) SMA. 

Jason Kelly. Mike Blake/Reuters via Adobe

Eye­ing big ther­a­peu­tic push, Gink­go bags $290M to build a cell pro­gram­ming em­pire

Ginkgo Bioworks is on a roll. Days after publicizing a plan to nurture new startups via partnerships with accelerators Y Combinator and Petri, the Boston biotech says it has raised another $290 million for its cell programming platform to reach further and wider.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 59,900+ biopharma pros reading Endpoints daily — and it's free.

UP­DAT­ED: Speak­er Nan­cy Pelosi to un­veil bill for fed­er­al­ly ne­go­ti­at­ed drug prices

After months of buzz from both sides of the aisle, Speaker Nancy Pelosi will today introduce her plan to allow the federal government to negotiate prices for 250 prescription drugs, setting up a showdown with a pharmaceutical industry working overtime to prevent it.

The need to limit drug prices is a rare point of agreement between President Trump and Democrats, although the president has yet to comment on the proposal and will likely face pressure to back a more conservative option or no bill at all. Republican Senator Chuck Grassley is reportedly lobbying his fellow party members on a more modest proposal he negotiated with Democratic Senator Ron Wyden in July.

Jeff Kindler's Cen­trex­ion re­news bid to make pub­lic de­but

Jeffrey Kindler’s plan to take his biotech — which is developing a slate of non-opioid painkillers — public, is back on.

The Boston based company, led by former Pfizer $PFE chief Kindler, originally contemplated a $70 million to $80 million IPO last year— but eventually postponed that strategy. On Wednesday, the company revived its bid to make a public debut in a filing with the SEC — although no pricing details were disclosed.

Zachary Hornby. Boundless

'A fourth rev­o­lu­tion in can­cer ther­a­pies': ARCH-backed Bound­less Bio flash­es big check, makes big­ger promis­es in de­but

It was the cellular equivalent of opening your car door and finding an active, roaring engine in the driver seat.

Scientists learned strands of DNA could occasionally appear outside of its traditional home in the nucleus in the 1970s, when they appeared as little, innocuous circles on microscopes; inexplicable but apparently innate. But not until UC San Diego’s Paul Mischel published his first study in Science in 2014 did researchers realize these circles were not only active but potentially overactive and driving some cancer tumors’ superhuman growth.

It’s fi­nal­ly over: Bio­gen, Ei­sai scrap big Alzheimer’s PhI­I­Is af­ter a pre­dictable BACE cat­a­stro­phe rais­es safe­ty fears

Months after analysts and investors called on Biogen and Eisai to scrap their BACE drug for Alzheimer’s and move on in the wake of a string of late-stage failures and rising safety fears, the partners have called it quits. And they said they were dropping the drug — elenbecestat — after the independent monitoring board raised concerns about…safety.

We don’t know exactly what researchers found in this latest catastrophe, but the companies noted in their release that investigators had determined that the drug was flunking the risk/benefit analysis.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 59,900+ biopharma pros reading Endpoints daily — and it's free.

Mer­ck helps bankroll new part­ner Themis' game plan to fin­ish the chikun­gun­ya race and be­gin on­colyt­ic virus quest

As Themis gears up for a Phase III trial of its chikungunya vaccine, the Vienna-based biotech has closed out €40 million ($44 million) to foot the clinical and manufacturing bills.

Its heavyweight partners at Merck — which signed a pact around a mysterious “blockbuster indication” last month — jumped into the Series D, led by new investors Farallon Capital and Hadean Ventures. Adjuvant Capital also joined, as did current investors Global Health Investment Fund, aws Gruenderfonds, Omnes Capital, Ventech and Wellington Partners Life Sciences.