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.

Con­fla­tion

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 news@raps.org for more in­for­ma­tion.

Lessons for biotech and phar­ma from a doc­tor who chased his own cure

After being struck by a rare disease as a healthy third year medical student, David Fajgenbaum began an arduous journey chasing his own cure. Amidst the hustle of this year’s JP Morgan conference, the digital trials platform Medable partnered with Endpoints Studio to share Dr. Fajgenbaum’s story with the drug development industry.

What follows is an edited transcript of the conversation between Medable CEO Dr. Michelle Longmire and Dr. Fajgenbaum, and it is full of lessons for biotech executives charged with bringing the next generation of medicines to patients.

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The VC crowd took a step back last year, but nevertheless maintained a furious pace of new investments in therapeutic tech platforms and biotech startups. And the top 100 players completely dominated the megabillions game.

Just looking at the number of deals done by each of the top 100, OrbiMed came in at the top, with 20, followed by Alexandria (18), Perceptive (16) and the ubiquitous RA Capital at 16. It’s impossible to say exactly how much they invested in total — those numbers are only rarely provided — but it is clear from the numbers assembled by Chris Dokomajilar at DealForma who’s most likely to be found sitting at the table during the go-go days of biotech investing.

Dokomajilar tracked $14.06 billion in biotech venture investing last year, a dip from the frenzied pace of $16.02 billion in 2018 and more than $10 billion higher than he recorded for 2010, as the economy was recovering from a profound economic crisis.

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Mass spectrometry is a tool designed to measure with profound accuracy the mass of a single molecule. Typically, mass spectrometers can be used to identify unknown compounds, to quantify known compounds, and to determine the structure and chemical properties of molecules.

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While there’s no proof yet that fapilavir, or favipiravir, is the cure that patients and physicians are yearning for, it stands out for a unique constellation of qualities. It’s been commercially available in Japan for several years (unlike Gilead’s experimental remdesivir) yet it’s new to China (unlike the malaria drug chloroquine phosphate). Perhaps more importantly, a domestic biotech — Zhejiang Hisun Pharma — owns the rights to manufacture and market the drug, preempting any concerns about patents.

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His alleged partners-in-crime included Ara Aprahamian, a former sales and marketing executive at Taro Pharmaceutical Industries, who was also indicted in Philadelphia earlier this month for price-fixing and bid-rigging.

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The list of the 11 block­busters-to-be in line for a 2020 launch high­light agony and ec­sta­sy of drug R&D

For all the talk about unmet medical need and patients first and so on, the key criteria investors watch for any new drug in the pipelines is peak sales projection. Are you going to hit the blockbuster mark, at $1 billion-plus, or are you going to be an also-ran in the sales department?

Of course, analysts’ peak sales projections by themselves are of limited value in many cases. When the PCSK9 drugs started arriving 5 years ago, Repatha was billed as a $2.5 billion peak earner. They’re nowhere near that, with new competition threatening current levels. And if Biogen’s controversial Alzheimer’s drug aducanumab (submission planned but not on the list) is approved, per chance, will payers cover it?

Maybe not. And then those $10 billion in peak sales assumptions would go straight down the drain.

But, analysts are analysts, and peak sales projections have to be factored in when assessing the top experimental drugs up for a launch in the year ahead.

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On Friday, AstraZeneca posted fourth-quarter sales of $6.25 billion, just shy of Wall Street estimates. Nearly $1.2 billion of that product revenue came from China.

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