Com­pas­sion­ate Use/Ex­pand­ed Ac­cess pro­grams: Three steps to im­prove their im­ple­men­ta­tion for the ben­e­fit of all

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Com­pas­sion­ate Use or Ex­pand­ed Ac­cess is a treat­ment op­tion for pa­tients in des­per­ate need which can be in­de­pen­dent­ly re­quest­ed by a treat­ing physi­cian, pro­vid­ing ac­cess to lo­cal­ly un­li­censed med­ica­tions when all ap­proved treat­ment op­tions have been ex­haust­ed and en­roll­ment in a clin­i­cal tri­al is not pos­si­ble. There is no doubt about the hu­man val­ue of these pro­grams for pa­tients with no oth­er op­tion, and it’s al­so in­creas­ing­ly clear just how ben­e­fi­cial they can be for the en­tire health care ecosys­tem in ad­dress­ing the un­met med­ical needs of pa­tients. But many stake­hold­ers, from gov­ern­ments, health­care in­sti­tu­tions to phar­ma com­pa­nies, are not set up to make the best use of com­pas­sion­ate use. The time to change that is now.

I have been pas­sion­ate about com­pas­sion­ate use pro­grams for many years, but two re­cent events have crys­tal­lized their im­por­tance for me — in­di­cat­ing that we have reached a piv­otal mo­ment where the full po­ten­tial of these pro­grams is there for all to see, if the col­lec­tive will is there to grasp it.

First, in April, the FDA ap­proved a ther­a­py for a rare dis­ease based sole­ly on re­al-world da­ta ob­tained from pa­tients who were part of a com­pas­sion­ate use pro­gram. This was un­prece­dent­ed and shows just how cru­cial da­ta col­lec­tion in com­pas­sion­ate use has be­come to ac­cel­er­ate ap­proval of much-need­ed ther­a­pies, es­pe­cial­ly in rare dis­eases where there are of­ten none or very few treat­ment op­tions.

Sec­ond, my col­leagues and I in­ves­ti­gat­ed fac­tors as­so­ci­at­ed with com­pas­sion­ate use re­quests re­ceived at No­var­tis over a three-year pe­ri­od. The da­ta pub­lished in the Jour­nal of Amer­i­can Med­ical As­so­ci­a­tion (JA­MA) Health Fo­rum showed that of the 31,711 com­pas­sion­ate use re­quests from 110coun­tries, 87% were from high-in­come coun­tries. An even larg­er pro­por­tion – 94% – came from coun­tries with com­pas­sion­ate use reg­u­la­tions made pub­licly avail­able on the in­ter­net, and al­most all (96%) came from coun­tries with a high lev­el of clin­i­cal tri­al ac­tiv­i­ty. While these da­ta clear­ly re­veal vast dis­par­i­ties at the macro­eco­nom­ic lev­el, I be­lieve they al­so shine a light on the path for­ward — for gov­ern­ments, reg­u­la­tors and phar­ma alike.

As a phar­ma ex­ec­u­tive, I am most­ly fo­cused on what com­pa­nies can do to op­ti­mize their com­pas­sion­ate use pro­grams. I’ve been in­volved in this space for well over a decade, and the evo­lu­tion dur­ing this pe­ri­od has been phe­nom­e­nal. At No­var­tis alone, we now re­ceive on av­er­age about 10,000 re­quests every year, with an ap­proval rate of around 95%. We have gar­nered sig­nif­i­cant ex­pe­ri­ence and un­der­stand­ing over time, which we have used to push the bound­aries, pave the path for­ward and im­prove our pro­grams in the fol­low­ing ways:

Find the will be­fore the way

First, there must be a gen­uine de­sire to im­ple­ment and sup­port com­pas­sion­ate use pro­grams — and it must start at the top. Health­care com­pa­nies have a re­spon­si­bil­i­ty to en­able ac­cess to their in­no­v­a­tive med­i­cines to the pa­tients who need them most. At No­var­tis, we are com­mit­ted to help­ing en­sure that our med­i­cines are ac­ces­si­ble to as many pa­tients as pos­si­ble, ir­re­spec­tive of where they come from. We im­ple­ment com­pas­sion­ate use pro­grams be­cause it’s the right thing to do.

Ow­ing to the na­ture of the reg­u­la­to­ry and re­im­burse­ment process, there is of­ten a gap of sev­er­al months to years be­tween gen­er­a­tion of ro­bust ef­fi­ca­cy and safe­ty da­ta in tri­als and lo­cal mar­ket­ing au­tho­riza­tion with sub­se­quent lo­cal pa­tient ac­cess. Com­pas­sion­ate use pro­grams en­able the pro­vi­sion of cut­ting-edge ther­a­pies to those who des­per­ate­ly need them dur­ing this win­dow. For com­pa­nies, these pro­grams al­so pro­vide op­por­tu­ni­ties for the col­lec­tion of re­al-world da­ta from a broad­er pa­tient pop­u­la­tion be­yond the clin­i­cal tri­al, and an op­por­tu­ni­ty to en­gage with pa­tient com­mu­ni­ties, of­ten in­valu­able in rare dis­eases.

I be­lieve one of the main rea­sons for our high rate of com­pas­sion­ate use ap­provals is be­cause there’s an un­der­pin­ning phi­los­o­phy where the de­fault is to say ‘yes’, un­less there’s a jus­ti­fied med­ical or sci­en­tif­ic ra­tio­nale not to. Hav­ing this pa­tient-cen­tric mind­set in place and the will­ing­ness to de­ploy re­sources in this area is es­sen­tial.

In­still a ro­bust com­pa­ny pol­i­cy en­abled by an end-to-end re­quest sys­tem

A com­mit­ment to com­pas­sion­ate use means hav­ing the poli­cies, end-to-end process­es, and sys­tems in place to man­age re­quests in a prompt, fair and ef­fi­cient man­ner. The US 21st Cen­tu­ry Cures Act has since 2017 re­quired that phar­ma com­pa­nies de­vel­op­ing in­ves­ti­ga­tion­al drugs (in­clud­ing bi­o­log­ics) make their poli­cies re­gard­ing eval­u­at­ing and re­spond­ing to re­quests read­i­ly and pub­licly avail­able, e.g. on com­pa­ny web­sites.

A cen­tral­ized pol­i­cy and gov­er­nance pro­vide a sol­id foun­da­tion. We have a ded­i­cat­ed group in place act­ing as a Cen­ter of Ex­cel­lence, which has holis­tic over­sight and en­sures all el­e­ments are in place. This al­so in­cludes in­cor­po­rat­ing ad­e­quate guardrails in­to the process, the han­dling of ex­cep­tions, ad­dress­ing ini­tial pe­di­atric use and dos­ing ques­tions (e.g. man­aged with our in­te­grat­ed safe­ty as­sess­ment board), and the use of an ex­ter­nal in­de­pen­dent bioethics ad­vi­so­ry com­mit­tee (IBAC) for se­lect­ed eth­i­cal chal­lenges re­lat­ed to com­pas­sion­ate use.

With the in­creas­ing use of ge­net­ic test­ing and evo­lu­tion of tar­get­ed ther­a­pies, it is im­por­tant to con­sid­er how in­di­vid­ual pa­tient re­quests will be han­dled, es­pe­cial­ly for in­di­ca­tions where the com­pa­ny has no ac­tive or on­go­ing de­vel­op­ment pro­gram.

It’s al­so es­sen­tial to build a user-friend­ly com­pas­sion­ate use re­quest sys­tem — any dif­fi­cul­ties ac­cess­ing or us­ing the sys­tem, or lim­i­ta­tions to who can use it, are like­ly to de­ter treat­ing physi­cians and hin­der the re­ceipt of re­quests.

We launched an on­line re­quest sys­tem in De­cem­ber 2019 to stream­line re­quest man­age­ment. It’s sim­ple and can be used by physi­cians any­where in the world. Treat­ing physi­cians can sub­mit and han­dle a re­quest through any desk­top or mo­bile de­vice. In gen­er­al, it en­ables a speedy turn­around time — most re­view out­comes are pro­vid­ed with­in five work­ing days, en­sur­ing the pa­tient and treat­ing physi­cian do not lose a lot of time.

Part­ner with oth­ers and share your find­ings

We be­lieve open­ness and part­ner­ships are vi­tal pieces of the puz­zle. The da­ta from our JA­MA analy­sis was lim­it­ed to the ex­pe­ri­ence of a sin­gle com­pa­ny, and re­sults may dif­fer across oth­er or­ga­ni­za­tions. In light of this, we would wel­come sim­i­lar da­ta analy­sis from our in­dus­try peers and reg­u­la­tors to help in­form and en­rich the over­all knowl­edge base in this space.

There are on­go­ing best-prac­tice col­lab­o­ra­tions be­tween mul­ti­ple stake­hold­ers — in­clud­ing phar­ma com­pa­nies, pa­tient groups, reg­u­la­tors, gov­ern­ments, health­care pro­fes­sion­als, ven­dors and acad­e­mia — to en­sure that pa­tient ac­cess needs in com­pas­sion­ate use are ad­dressed holis­ti­cal­ly. It is im­por­tant to be a part of these con­ver­sa­tions and col­lab­o­ra­tions to en­sure di­verse per­spec­tives and ex­pe­ri­ences are con­sid­ered in the de­vel­op­ment of so­lu­tions to help ad­dress pa­tient ac­cess needs glob­al­ly.

There has been so much progress al­ready, but there’s still a lot that could be done to im­prove the im­ple­men­ta­tion of com­pas­sion­ate use pro­grams around the world. The best way for­ward is to­geth­er, for the ul­ti­mate ben­e­fit of pa­tients.

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For anyone who’s been following discussions about the safety alarms surrounding the adeno-associated viruses (AAV) commonly used to deliver gene therapy, Astellas should be a familiar name.

The Japanese pharma — which bought out Audentes Therapeutics near the end of 2019 and later built a gene therapy unit around the acquisition — rocked the field when it reported three patient deaths in a trial testing AT132, the lead program from Audentes designed to treat a rare muscle disease called X-linked myotubular myopathy (XLMTM).

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Big questions remain — questions that can have big implications about the future of AAV gene therapies.

Bernhardt Zeiher did not imagine any of it when he first joined Astellas as the therapeutic area leader in inflammation, immunology and infectious diseases. But his ascent to chief medical officer and head of development coincided almost exactly with Astellas’ big move into gene therapy, putting him often in the driver’s seat to grapple with the setbacks.

As Zeiher prepares to retire next month after a 12-year tenure — leaving the unfinished tasks to his successor, a seasoned cancer drug developer — he chatted with Endpoints News, in part, to discuss the effort to understand what happened, lessons learned and the criticism along the way.

The transcript has been lightly edited for length and clarity.

Endpoints: I want to also ask you a bit about the gene therapy efforts you’ve been working on. Astellas has really been at the forefront of discovering the safety concerns associated with AAV gene therapy. What’s that been like for you?

Zeiher: Well, I have to admit, it’s been a bit of a roller coaster. We acquired Audentes. Huge amount of enthusiasm. What we saw with AT132 — that was the lead program in XLMTM — was just remarkable efficacy. I mean, kids who went from being on ventilators, not able to eat for themselves, sit up, do things like that, to off ventilators, walking, you know, really — one investigator called it this Lazarus-like effect. It was just really dramatic efficacy. And then to have the safety events that occurred. So they actually occurred within that first year of the acquisition. So we had the three patient deaths. Me and my organization became very, very much involved. In fact, Ed Conner, who had been the chief medical officer, he left after some of the deaths, but I stepped in as the kind of acting chief medical officer, we had another chief medical officer who was involved, and then we had a fourth death, and I became acting again for a period of time.

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