FDA drafts guid­ance on demon­strat­ing sub­stan­tial ev­i­dence of ef­fec­tive­ness

The FDA on Thurs­day is­sued draft guid­ance on demon­strat­ing “sub­stan­tial ev­i­dence” of ef­fec­tive­ness for drugs and bi­o­log­ics, ex­pand­ing on decades-old guid­ance is­sued to ad­dress statu­to­ry changes brought on by the Food and Drug Ad­min­is­tra­tion Mod­ern­iza­tion Act of 1997 (FDAMA).

Specif­i­cal­ly, the 18-page draft guid­ance builds on the FDA’s 1998 guid­ance Pro­vid­ing Clin­i­cal Ev­i­dence of Ef­fec­tive­ness for Hu­man Drug and Bi­o­log­i­cal Prod­ucts, which de­tailed the FDA’s ex­pec­ta­tions for ev­i­dence to sup­port the ap­proval of new drugs and bi­o­log­ics or ap­pli­ca­tions for sup­ple­men­tal in­di­ca­tions in light of FDAMA’s clar­i­fi­ca­tion that a sin­gle ad­e­quate and well-con­trolled clin­i­cal tri­al and con­fir­ma­to­ry ev­i­dence can be used to sup­port ap­proval.

While the FDA says its “stan­dard for demon­strat­ing ef­fec­tive­ness has not changed” since the 1998 guid­ance, the agency says that new guid­ance is nec­es­sary to keep up with sci­en­tif­ic ad­vance­ments and changes in drug de­vel­op­ment over the last two decades.

Amy Aber­nethy

“As our sci­en­tif­ic knowl­edge ad­vances, and drugs and bi­o­log­ics with nov­el mech­a­nisms are be­ing de­vel­oped to treat con­di­tions that were pre­vi­ous­ly with­out treat­ments, there is a need for ad­di­tion­al guid­ance on the flex­i­bil­i­ty in the amount and type of ev­i­dence need­ed to es­tab­lish their ef­fec­tive­ness,” said FDA Prin­ci­pal Deputy Com­mis­sion­er Amy Aber­nethy.

With­in the guid­ance, the FDA dis­cuss­es the lev­el of qual­i­ty and the quan­ti­ty of clin­i­cal ev­i­dence need­ed to demon­strate ef­fec­tive­ness and pro­vides ex­am­ples of “cir­cum­stances where ad­di­tion­al flex­i­bil­i­ty may be war­rant­ed,” such as for treat­ments for rare dis­eases or life-threat­en­ing or se­vere­ly de­bil­i­tat­ing con­di­tions where there is an un­met med­ical need.

“There are cir­cum­stances where ev­i­dence gen­er­at­ed us­ing a va­ri­ety of clin­i­cal tri­al de­signs, end­points and sta­tis­ti­cal method­ol­o­gy can sup­port ef­fec­tive­ness, such as in cer­tain drug de­vel­op­ment pro­grams for rare dis­eases,” Aber­nethy said.

In ad­di­tion to the “gold stan­dard” ran­dom­ized, dou­ble-blind­ed, con­trolled su­pe­ri­or­i­ty tri­als, which the FDA says are “re­gard­ed as the most rig­or­ous de­sign,” the guid­ance al­so dis­cuss­es oth­er types of de­signs, in­clud­ing place­bo con­cur­rent con­trol, dose-com­par­i­son con­cur­rent con­trol, no treat­ment con­cur­rent con­trol, ac­tive treat­ment con­cur­rent con­trol and his­tor­i­cal con­trol de­signs.

The guid­ance al­so dis­cuss­es when dif­fer­ent amounts of ev­i­dence are ap­pro­pri­ate to sup­port ap­proval, in­clud­ing two ad­e­quate and well-con­trolled clin­i­cal in­ves­ti­ga­tions or a sin­gle ad­e­quate and well-con­trolled large mul­ti­cen­ter tri­al.

Ad­di­tion­al­ly, the guid­ance pro­vides ex­am­ples of ap­proach­es based around a sin­gle ad­e­quate and well-con­trolled study:

  • One ad­e­quate and well-con­trolled clin­i­cal in­ves­ti­ga­tion on a new in­di­ca­tion for an ap­proved drug, sup­port­ed by ex­ist­ing ad­e­quate and well-con­trolled clin­i­cal in­ves­ti­ga­tion(s) that demon­strat­ed the ef­fec­tive­ness of the drug for its oth­er, close­ly re­lat­ed ap­proved in­di­ca­tion(s);
  • One ad­e­quate and well-con­trolled clin­i­cal in­ves­ti­ga­tion sup­port­ed by da­ta that pro­vide strong mech­a­nis­tic sup­port;
  • One ad­e­quate and well-con­trolled clin­i­cal in­ves­ti­ga­tion with com­pelling re­sults, sup­port­ed by ad­di­tion­al da­ta from the nat­ur­al his­to­ry of the dis­ease; and
  • One ad­e­quate and well-con­trolled clin­i­cal in­ves­ti­ga­tion of the new drug, sup­port­ed by sci­en­tif­ic knowl­edge about the ef­fec­tive­ness of oth­er drugs in the same phar­ma­co­log­i­cal class.

First pub­lished in Reg­u­la­to­ry Fo­cus™ by the Reg­u­la­to­ry Af­fairs Pro­fes­sion­als So­ci­ety, the largest glob­al or­ga­ni­za­tion of and for those in­volved with the reg­u­la­tion of health­care prod­ucts. 

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.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 70,200+ biopharma pros reading Endpoints daily — and it's free.

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).

How to cap­i­talise on a lean launch

For start-up biotechnology companies and resource stretched pharmaceutical organisations, launching a novel product can be challenging. Lean teams can make setting a launch strategy and achieving your commercial goals seem like a colossal undertaking, but can these barriers be transformed into opportunities that work to your brand’s advantage?
We spoke to Managing Consultant Frances Hendry to find out how Blue Latitude Health partnered with a fledgling subsidiary of a pharmaceutical organisation to launch an innovative product in a
complex market.
What does the launch environment look like for this product?
FH: We started working on the product at Phase II and now we’re going into Phase III trials. There is a significant unmet need in this disease area, and everyone is excited about the launch. However, the organisation is still evolving and the team is quite small – naturally this causes a little turbulence.

Wuhan virus out­break trig­gers in­evitable small-biotech ral­ly

Every few years, a public health crisis (think Ebola, Zika) spurred by a rogue pathogen triggers a small-biotech rally, as drugmakers emerge from the woodwork with ambitious plans to treat the mounting outbreak. In most cases, that enthusiasm never quite delivers.

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.

Brex­it fears, Wood­ford woes over­shad­owed UK biotech and cut 2019 fi­nanc­ing by al­most half

The venture tide might have subsided, the IPO window may be closing and certain listed biotechs may be having a tough time amid Neil Woodford’s well-publicized demised, but there’s still plenty to celebrate in the UK BioIndustry Association’s eyes.

Overall investment in UK biotech last year fell from the record-breaking £2.2 billion levels of 2018 to £1.3 billion — including £679 million in venture capital, a meager £64 million in IPOs plus £596 million when you add up all public financings, according to a new report from the BIA.

Blue­print Med­i­cines po­ten­tial­ly de­lays Ay­vak­it de­ci­sion; Con­trol beats treat­ment in mesothe­lioma tri­al

→ Blueprint Medicines filed an amendment to its application to get the gastrointestinal stromal tumor (GIST) drug Ayvakit approved in fourth-line GIST, the company disclosed in the prospectus for a new $325 million public offering.  Blueprint got a big accelerated OK on the drug this month in a particular mutation, but because the FDA decided to split their review in two, they didn’t hear on fourth-line GIST. They were supposed to hear before February 14, but this amendment could push that date back by 3 months. Blueprint wrote that the amendment is designed to allow the company to comply with the FDA’s request for data from the Phase III Voyage trial before they give a judgment.

Io­n­is, Akcea boost­ed by a pos­i­tive PhII for their No­var­tis castoff car­dio drug — and they plan to push ahead in­to piv­otals

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.

Hal Barron and Emma Walmsley, GSK

GSK’s ‘break­through’ BC­MA can­cer drug gets a pri­or­i­ty re­view — and a big win for the on­col­o­gy R&D team

After largely whiffing the past 2 years on the pharma R&D front, GlaxoSmithKline research chief Hal Barron has seized boasting rights to a key win that puts them back in the cancer drug development game.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 70,200+ biopharma pros reading Endpoints daily — and it's free.

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

Update: Nominations open through end of day, Monday, January 27

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.