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.

Is a pow­er­house Mer­ck team prepar­ing to leap past Roche — and leave Gilead and Bris­tol My­ers be­hind — in the race to TIG­IT dom­i­na­tion?

Roche caused quite a stir at ASCO with its first look at some positive — but not so impressive — data for their combination of Tecentriq with their anti-TIGIT drug tiragolumab. But some analysts believe that Merck is positioned to make a bid — soon — for the lead in the race to a second-wave combo immuno-oncology approach with its own ambitious early-stage program tied to a dominant Keytruda.

Endpoints Premium

Premium subscription required

Unlock this article along with other benefits by subscribing to one of our paid plans.

BiTE® Plat­form and the Evo­lu­tion To­ward Off-The-Shelf Im­muno-On­col­o­gy Ap­proach­es

Despite rapid advances in the field of immuno-oncology that have transformed the cancer treatment landscape, many cancer patients are still left behind.1,2 Not every person has access to innovative therapies designed specifically to treat his or her disease. Many currently available immuno-oncology-based approaches and chemotherapies have brought long-term benefits to some patients — but many patients still need other therapeutic options.3

GSK presents case to ex­pand use of its lu­pus drug in pa­tients with kid­ney dis­ease, but the field is evolv­ing. How long will the mo­nop­oly last?

In 2011, GlaxoSmithKline’s Benlysta became the first biologic to win approval for lupus patients. Nine years on, the British drugmaker has unveiled detailed positive results from a study testing the drug in lupus patients with associated kidney disease — a post-marketing requirement from the initial FDA approval.

Lupus is a drug developer’s nightmare. In the last six decades, there has been just one FDA approval (Benlysta), with the field resembling a graveyard in recent years with a string of failures including UCB and Biogen’s late-stage flop, as well as defeats in Xencor and Sanofi’s programs. One of the main reasons the success has eluded researchers is because lupus, akin to cancer, is not just one disease — it really is a disease of many diseases, noted Al Roy, executive director of Lupus Clinical Investigators Network, an initiative of New York-based Lupus Research Alliance that claims it is the world’s leading private funder of lupus research, in an interview.

Gilead bol­sters its case for block­buster hope­ful fil­go­tinib as FDA pon­ders its de­ci­sion

Before remdesivir soaked up the spotlight amid the coronavirus crisis, Gilead’s filgotinib was the star experimental drug tapped to rake in billions competing with other JAK inhibitors made by rivals including AbbVie and Eli Lilly.

Now, long term data on the drug — discovered by Gilead’s partners at Galapagos and posted as part of a virtual medical conference — have solidified the durability and safety of filgotinib in patients with rheumatoid arthritis, spanning data from three late-stage trials. An FDA decision on the drug is expected this year.

Leen Kawas, Athira CEO (Athira)

Can a small biotech suc­cess­ful­ly tack­le an Ever­est climb like Alzheimer’s? Athi­ra has $85M and some in­flu­en­tial back­ers ready to give it a shot

There haven’t been a lot of big venture rounds for biotech companies looking to run a Phase II study in Alzheimer’s.

The field has been a disaster over the past decade. Amyloid didn’t pan out as a target — going down in a litany of Phase III failures — and is now making its last stand at Biogen. Tau is a comer, but when you look around and all you see is destruction, the idea of backing a startup trying to find complex cocktails to swing the course of this devilishly complicated memory-wasting disease would daunt the pluckiest investors.

Covid-19 roundup: Mod­er­na read­ies to en­ter PhI­II in Ju­ly, As­traZeneca not far be­hind; EU ready to ne­go­ti­ate vac­cine ac­cess with $2.7B fund

Moderna may soon add another first to the Covid-19 vaccine race.

In March, the mRNA biotech was the first company to put a Covid-19 vaccine into humans. Next month, they may become the first company to put their vaccine into the large, late-stage trials that are needed to prove whether the vaccine is effective.

In an interview with JAMA editor Howard Bauchner, NIAID chief Anthony Fauci said that a 30,000-person, Phase III trial for Moderna’s vaccine could start in July. The news comes a week after Moderna began a Phase II study that will enroll several hundred people.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 83,000+ biopharma pros reading Endpoints daily — and it's free.

José Basel­ga finds promise in new class of RNA-mod­i­fy­ing can­cer tar­gets, lock­ing in 3 pre­clin­i­cal pro­grams with $55M

Having dived early into some of the RNA breakthroughs of the last decades — betting on Moderna’s mRNA tech and teaming up with Silence on the siRNA front — AstraZeneca is jumping into a new arena: going after proteins that modify RNA.

Their partner of choice is Accent Therapeutics, which is receiving $55 million in upfront payment to steer a selected preclinical program through to the end of Phase I. After AstraZeneca takes over, the Lexington, MA-based startup has the option to co-develop and co-commercialize in the US — and collect up to $1.1 billion in milestones in the long run. The deal also covers two other potential drug candidates.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 83,000+ biopharma pros reading Endpoints daily — and it's free.

David Meline, incoming Moderna CFO

Am­gen vet David Meline finds a new CFO roost at Mod­er­na, tak­ing a ride on the Covid-19 tiger as de­part­ing ex­ec cash­es out with $12M

We found out a few weeks ago that Moderna CFO Lorence Kim isn’t waiting around to see how the biotech wunderkind makes out in its frantic race to field a messenger RNA vaccine that can quell Covid-19. And now we know who’s stepping on board to take his place in the latest move in the executive suite.

David Meline, who forged his rep during a 6-year run at Amgen, slipped out the exit right after his Q2 “retirement” party in California — presumably virtual — and started the next chapter of his career at a biotech company betting big on revolutionizing the vaccine R&D space.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 83,000+ biopharma pros reading Endpoints daily — and it's free.

UP­DAT­ED: Es­ti­mat­ing a US price tag of $5K per course, remde­sivir is set to make bil­lions for Gilead, says key an­a­lyst

Data on remdesivir — the first drug shown to benefit Covid-19 patients in a randomized, controlled trial setting — may be murky, but its maker Gilead could reap billions from the sales of the failed Ebola therapy, according to an estimate by a prominent Wall Street analyst. However, the forecast, which is based on a $5,000-per-course US price tag, triggered the ire of one top drug price expert.