The FDA: Faster, but not nec­es­sar­i­ly bet­ter. And that could threat­en the agen­cy's brand

Faster FDA drug ap­provals may re­flect less rig­or­ous ev­i­den­tiary stan­dards, a new analy­sis sug­gests.

Jonathan Dar­row BWH

In 1962, the reg­u­la­to­ry scruti­ny of med­i­cines by the FDA in­ten­si­fied in re­ac­tion to thalido­mide, an an­ti-nau­sea drug that gained no­to­ri­ety af­ter its link to se­vere skele­tal birth de­fects. Since then, a flood of in­cen­tives has made the US sys­tem of get­ting drugs ap­proved eas­i­er and the agency seem­ing­ly more flex­i­ble. Reg­u­la­to­ry in­cen­tives — such as fast-track and break­through ther­a­py sta­tus, or­phan drug des­ig­na­tions as well as ac­cel­er­at­ed and con­di­tion­al ap­provals — have di­min­ished re­view times and en­cour­aged the use of sur­ro­gate end­points. And while the in­dus­try has en­cour­aged it, some re­searchers see a down­side.

The analy­sis, con­duct­ed by Jonathan Dar­row and oth­ers and pub­lished in JA­MA on Tues­day, found that that this evo­lu­tion has led to the FDA gen­er­al­ly ac­cept­ing less ro­bust ev­i­dence, all the while short­en­ing its re­view times.

The da­ta show that the clas­sic FDA “gold stan­dard” of ac­cept­ing new drug ap­pli­ca­tions based on at least two piv­otal tri­als has fall­en from 80.6% in 1995-1997 to 52.8% in 2015-2017. Mean­while, med­i­cines bran­dish­ing the “or­phan drug” tag — of­ten sig­nal­ing less rig­or­ous stan­dards — have risen from 18% over the pe­ri­od of 1984 to 1995 to 41% be­tween 2008 and 2018.

FDA drug re­view times have de­clined from more than 3 years in 1983 to less than 1 year in 2017 (al­though the to­tal time to get a drug ready for re­view has re­mained steady), the au­thors high­light­ed.

If drugs ap­proved with less ev­i­dence turn out to be prob­lem­at­ic it may lead to “an ero­sion of the ‘FDA ap­proved’ brand,” Dar­row told Reuters.

Joshua Sharf­stein John Hop­kins

“If the stan­dards are dif­fer­ent than they were in the past, it’s im­por­tant for pa­tients and physi­cians to be aware of that,” Dar­row said in an in­ter­view with the wire ser­vice. “Pa­tients and physi­cians need to fo­cus on the ev­i­dence and not the fact of FDA ap­proval. How big are the ben­e­fits, and how cer­tain are we of the ben­e­fits?”

While some of these new drugs have been re­mark­able ad­vances for de­bil­i­tat­ing and of­ten dead­ly dis­eases, “high prices at the high end or in ex­cess of in­de­pen­dent­ly as­sessed mea­sures of val­ue have cre­at­ed bar­ri­ers to ac­cess,” Joshua Sharf­stein from Johns Hop­kins Bloomberg School of Pub­lic Health point­ed out in a JA­MA ed­i­to­r­i­al in re­sponse to the analy­sis by Dar­row et al.

Over­all, the av­er­age an­nu­al num­ber of new drug ap­provals, in­clud­ing bi­o­log­ics, has see­sawed — from 34 be­tween 1990 and 1999 to 25 from 2000 to 2009 and 41 from 2010 to 2018, au­thors of the analy­sis found. One heart­en­ing da­ta point is the me­di­an an­nu­al num­ber of gener­ics — copy­cat ap­provals ac­cel­er­at­ed from 284 — pri­or to the Gener­ic Drug User Fee Act of 2012 — to 488 be­tween 2013 and 2018.

To ac­com­mo­date the high­er vol­ume of drug man­u­fac­tur­ers, the FDA in 1992 was grant­ed the pow­er to col­lect fees for their re­views. Now, the an­nu­al fees col­lect­ed un­der Pre­scrip­tion Drug User Fee Act (PDU­FA) have jumped from $29 mil­lion in 1993 to $908 mil­lion in 2018, the da­ta showed.

Crit­ics have ad­mon­ished the slid­ing door be­tween ex­ec­u­tives in the bio­phar­ma­ceu­ti­cal in­dus­try and the FDA, and un­der­score that the trans­ac­tion­al in­ter­ac­tion be­tween the agency and the in­dus­try does not bode well for an in­de­pen­dent, un­bi­ased re­view of prod­ucts.

2019 Trin­i­ty Drug In­dex Eval­u­ates Ac­tu­al Com­mer­cial Per­for­mance of Nov­el Drugs Ap­proved in 2016

Fewer Approvals, but Neurology Rivals Oncology and Sees Major Innovations

This report, the fourth in our Trinity Drug Index series, outlines key themes and emerging trends in the industry as we progress towards a new world of targeted and innovative products. It provides a comprehensive evaluation of the performance of novel drugs approved by the FDA in 2016, scoring each on its commercial performance, therapeutic value, and R&D investment (Table 1: Drug ranking – Ratings on a 1-5 scale).

UP­DAT­ED: FDA’s golodirsen CRL: Sarep­ta’s Duchenne drugs are dan­ger­ous to pa­tients, of­fer­ing on­ly a small ben­e­fit. And where's that con­fir­ma­to­ry tri­al?

Back last summer, Sarepta CEO Doug Ingram told Duchenne MD families and investors that the FDA’s shock rejection of their second Duchenne MD drug golodirsen was due to some concerns regulators raised about the risk of infection and the possibility of kidney toxicity. But when pressed to release the letter for all to see, he declined, according to a report from BioPharmaDive, saying that kind of move “might not look like we’re being as respectful as we’d like to be.”

He went on to assure everyone that he hadn’t misrepresented the CRL.

But Ingram’s public remarks didn’t include everything in the letter, which — following the FDA’s surprise about-face and unexplained approval — has now been posted on the FDA’s website and broadly circulated on Twitter early Wednesday.

The CRL raises plenty of fresh questions about why the FDA abruptly decided to reverse itself and hand out an OK for a drug a senior regulator at the FDA believed — 5 months ago, when he wrote the letter — is dangerous to patients. It also puts the spotlight back on Sarepta $SRPT, which failed to launch a confirmatory study of eteplirsen, which was only approved after a heated internal controversy at the FDA. Ellis Unger, director of CDER’s Office of Drug Evaluation I, notes that study could have clarified quite a lot about the benefit and risks associated with their drugs — which can cost as much as a million dollars per patient per year, depending on weight.

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Things are no different, as the coronavirus outbreak in Wuhan, China takes hold. There have been close to 300 confirmed human infections in China, and at least four deaths. Coronaviruses are a large family of viruses, which include MERS and SARS. On Tuesday, the CDC reported the virus was detected in a US traveler returning from Wuhan.

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Late last year Novartis abandoned a cardio drug from Ionis’ spinoff Akcea just after the pharma giant snapped up inclisiran, going the RNAi way in guarding against heart disease in the $9.7 billion Medco buyout.

Now the pharma goliath — which is headed down the PCSK9 road with a drug it believes can be used in a mass population — can get a clearer picture of just what they gave up.

Akcea $AKCA and the mother company $IONS put out a statement early Wednesday saying that their Phase II study of AKCEA-APOCIII-LR delivered solid efficacy data, with the high dose clearly outperforming placebo in significantly reducing triglycerides as a means to cutting the risk of cardiovascular disease. In addition, investigators concluded that the drug slashed apoC-III, very low-density lipoprotein and remnant cholesterol while boosting “good” HDL levels.

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Who are the young bio­phar­ma lead­ers shap­ing the in­dus­try? Nom­i­nate them for End­points' spe­cial re­port

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Two years ago, when we did our first Endpoints 20-under-40, we profiled a set of up-and-comers who promised to help reshape the industry as we know it. Now we’re back and once again looking for the top 20 biopharma professionals under the age of 40. We’ll be profiling folks who have accomplished a lot at a young age but seem on the verge of accomplishing so much more.