Now that Sarep­ta has bolt­ed out of the barn, the FDA wants to shut the door

John Jenk­ins, Di­rec­tor, Of­fice of New Drugs

Now that the FDA has capped Sarep­ta’s long and con­tro­ver­sial cam­paign to win an ap­proval for its Duchenne mus­cu­lar dy­s­tro­phy drug with an ac­cel­er­at­ed ap­proval, FDA of­fi­cials would like to send a very clear mes­sage to any oth­er biotech look­ing to slug their way for­ward us­ing the same tac­tics: For­get about it.

In a pre­sen­ta­tion at a sum­mit meet­ing of the Na­tion­al Or­ga­ni­za­tion of Rare Dis­eases on Tues­day, John Jenk­ins, di­rec­tor of the of­fice of new drugs at the Cen­ter for Drug Eval­u­a­tion and Re­search, sin­gled out the eteplirsen case as a new text­book ex­am­ple of what oth­er com­pa­nies should avoid.

“Path tak­en by Sarep­ta NOT a good mod­el for oth­er de­vel­op­ment pro­grams,” de­clared one of Jenk­ins’ talk­ing points un­der a fi­nal sec­tion marked “lessons learned” from eteplirsen and oth­er cas­es.

What fol­lowed was a litany of sins that FDA in­sid­ers have laid at the door of Sarep­ta, which gained the FDA’s stamp of ap­proval to sell Ex­ondys 51 for $300,000 a year, de­spite the heat­ed ob­jec­tions raised by se­nior of­fi­cials over the lack of safe­ty and ef­fi­ca­cy da­ta laced with barb ob­jec­tions over what was pre­sent­ed. In the end, Sarep­ta was able to gain an ap­proval af­ter pa­tient ad­vo­cates and in­flu­en­tial play­ers in Wash­ing­ton DC de­mand­ed it, with lit­tle more than da­ta from a tiny study that was re­peat­ed­ly chal­lenged by re­view­ers but en­dorsed by Janet Wood­cock and per­mit­ted by Com­mis­sion­er Robert Califf.

Jenk­ins had quite a few points to make, and they re­flect­ed the laun­dry list of is­sues that the agency had spot­light­ed to crit­i­cize Sarep­ta re­peat­ed­ly over the course of its re­view and a de­fense of its po­si­tion in light of the biotech’s chal­lenge, plus a few new ones. The FDA, he said, want­ed to make clear that bad­ly planned pro­grams could on­ly de­lay a re­view and OK; as­says, par­tic­u­lar­ly ones that re­ly on in­va­sive pro­ce­dures with chil­dren, need to be well val­i­dat­ed; stud­ies need to be care­ful­ly blind­ed and ran­dom­ized; ev­i­dence of an im­pact on bio­mark­ers has to be care­ful­ly eval­u­at­ed, ex­clud­ing ‘any’ ef­fect that might reg­is­ter, re­view­ers should not be sub­ject­ed to at­tacks, and so on.

Since Sarep­ta won an ap­proval for eteplirsen, there have been some se­ri­ous con­cerns that the FDA has low­ered its stan­dards to the point that more com­pa­nies were like­ly to fol­low suit, wag­ing a lob­by­ing cam­paign to back in­ad­e­quate tri­al re­sults. NYU bioethi­cist Art Ca­plan told End­points re­cent­ly that more de­vel­op­ers are bound to use Sarep­ta as a role mod­el, not­ing that the in­dus­try and reg­u­la­tors need to come up with a new set of rules that could make some sense when it comes to more such pitch­es on the rare dis­ease front.

Jenk­ins, though, wants to hold the line with a more tra­di­tion­al ap­proach, leav­ing Sarep­ta as the ex­cep­tion that could help prove the rule.

Here’s the full man­i­festo:

• A poor­ly planned and ex­e­cut­ed de­vel­op­ment pro­gram for a rare dis­ease mis­us­es valu­able pa­tient re­sources and serves to de­lay ob­tain­ing the knowl­edge re­quired to un­der­stand the ben­e­fits and risks of a drug to sup­port reg­u­la­to­ry re­view and ap­proval

• FDA pro­vides valu­able ad­vice and guid­ance to spon­sors, we can­not re­quire spon­sors to fol­low our ad­vice

Path tak­en by Sarep­ta NOT a good mod­el for oth­er de­vel­op­ment pro­grams

• As­says for bio­mark­ers should be well val­i­dat­ed be­fore use to avoid ob­tain­ing mis­lead­ing in­for­ma­tion and wast­ing clin­i­cal spec­i­mens

• Par­tic­u­lar­ly true when in­va­sive pro­ce­dure re­quired to col­lect tis­sue in chil­dren

• Rig­or­ous blind­ing and con­trol pro­ce­dures should be in place to min­i­mize bias in as­say in­ter­pre­ta­tion

• Pro­to­col should spec­i­fy blind­ing pro­ce­dures, ad­ju­di­ca­tion meth­ods, in­de­pen­dence of read­ers, etc.

• In many cas­es, ran­dom­ized con­trolled clin­i­cal tri­als rep­re­sent the fastest way to de­ter­mine if a drug is ef­fec­tive

• Ran­dom­ize as ear­ly as pos­si­ble in de­vel­op­ment to avoid po­ten­tial­ly mis­lead­ing and un­in­ter­pretable find­ings from open-la­bel tri­als

• Em­ploy meth­ods to lim­it time on place­bo (e.g., dose-re­sponse, de­layed start, ran­dom­ized with­draw­al, in­ter­im analy­sis)

• Re­port ear­ly tri­al re­sults ac­cu­rate­ly, post hoc analy­ses of failed tri­als are gen­er­al­ly hy­poth­e­sis gen­er­at­ing for next tri­al, not ev­i­dence to sup­port ap­proval

• Knowl­edge of nat­ur­al his­to­ry of dis­ease crit­i­cal to in­tel­li­gent de­sign of clin­i­cal tri­als

• Con­duct nat­ur­al his­to­ry tri­als be­fore clin­i­cal tri­als be­gin

• If a nat­ur­al his­to­ry ex­ter­nal con­trol group is pro­posed, it should be iden­ti­fied prospec­tive­ly to en­sure com­pa­ra­bil­i­ty to treat­ment group

• Nat­ur­al his­to­ry ex­ter­nal con­trol group cre­at­ed post hoc is very dif­fi­cult to in­ter­pret, un­less ef­fect of test drug is very large, due to known and un­known con­found­ing

• Use of ac­cel­er­at­ed ap­proval path­way should be prospec­tive­ly planned, NOT as a “res­cue” for a failed pro­gram

• Spon­sor and FDA should agree on the sur­ro­gate and drug ef­fect con­sid­ered “rea­son­ably like­ly” to pre­dict clin­i­cal ben­e­fit be­fore un­blind­ing da­ta

• “Any” ef­fect of a drug on a bio­mark­er is not a ba­sis for AA

• Ide­al­ly, the con­fir­ma­to­ry tri­al to fur­ther de­fine clin­i­cal ben­e­fit should be start­ed be­fore AA is grant­ed to en­sure the tri­al will be com­plet­ed in a time­ly man­ner

• FDA wel­comes the en­gage­ment of pa­tients and care­givers in help­ing to de­sign de­vel­op­ment pro­grams that will re­sult in drugs that pro­vide mean­ing­ful clin­i­cal ben­e­fit to those with dis­ease

• Ap­proval de­ci­sions must be based on da­ta from ad­e­quate and well-con­trolled clin­i­cal tri­als, which may in­clude PROs and oth­er pa­tient-de­rived mea­sures

• Ex­pe­ri­ence of pa­tients en­rolled in tri­als can be very help­ful; dis­cor­dant re­sults be­tween tri­al da­ta and pa­tient anec­dotes are very hard to rec­on­cile

• FDA re­view­ers are com­mit­ted to fa­cil­i­tat­ing de­vel­op­ment of ef­fec­tive and safe drugs for rare dis­eases

• Up­hold­ing statu­to­ry stan­dards for ap­proval in face of hopes and de­sires of pa­tients, fam­i­lies, spon­sors, and in­vestors is a very dif­fi­cult job

• Per­son­al at­tacks on FDA re­view­ers cre­ates an at­mos­phere of dis­trust and iso­la­tion rather than col­lab­o­ra­tion

• Re­cruit­ment and re­ten­tion of qual­i­fied re­view staff is very chal­leng­ing in such an en­vi­ron­ment

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The biotech sector has come down firmly from the highs of February as negative sentiment takes hold. The sector had a major boost of optimism from the success of the COVID-19 vaccines, making investors keenly aware of the potential of biopharma R&D engines. But from early this year, clinical trial, regulatory and access setbacks have reminded investors of the sector’s inherent risks.

RBC Capital Markets recently surveyed investors to take the temperature of the market, a mix of specialists/generalists and long-only/ long-short investment strategies. Heading into the second half of the year, investors mostly see the sector as undervalued (49%), a large change from the first half of the year when only 20% rated it as undervalued. Around 41% of investors now believe that biotech will underperform the S&P500 in the second half of 2021. Despite that view, 54% plan to maintain their position in the market and 41% still plan to increase their holdings.

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Pascal Soriot, AstraZeneca CEO (via Getty images)

UP­DAT­ED: FDA slaps As­traZeneca's MCL-1 can­cer drug with a hold af­ter safe­ty is­sue — 2 years af­ter Am­gen axed a trou­bled ri­val

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Leen Kawas (L) has resigned as CEO of Athira and will be replaced by COO Mark Litton

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Mark Litton, the company’s COO since June 2019 and a longtime biotech executive, has been named full-time CEO. Kawas, meanwhile, will no longer have ties to the company except for owning a few hundred thousand shares.

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Sen. Richard Durbin (D-IL, foreground) and Sen. Richard Blumenthal (D-CT) (Patrick Semansky/AP Images)

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