Ac­cel­er­at­ing To­ward Hu­man Rel­e­vant Non­clin­i­cal Test Meth­ods

In No­vem­ber of 1937, ed­i­tors from JA­MA mag­a­zine penned a scathing let­ter about the Unit­ed States’ in­abil­i­ty to pro­tect pa­tients from tox­ins that mas­quer­ade as ther­a­peu­tics, say­ing the drug de­vel­op­ment process was in dire need of laws with “com­mon sci­en­tif­ic de­cen­cy.” In the pre­ced­ing months, the na­tion had been riv­et­ed by the sud­den deaths of near­ly 100 peo­ple af­ter tak­ing elixir sul­fanil­amide. Ac­cord­ing to a con­gres­sion­al re­port, the elixir had been giv­en to pa­tients de­spite hav­ing on­ly been “test­ed for its fla­vor but not its ef­fect on hu­man life.” Up un­til this point, drug man­u­fac­tur­ers were not re­quired to test ther­a­peu­tics be­fore send­ing them to mar­ket.

Un­der pres­sure, con­gress passed the 1938 Fed­er­al Food, Drug, and Cos­met­ics Act (FD­CA) which man­dat­ed that drug de­vel­op­ers demon­strate the safe­ty of new drugs through an­i­mal test­ing. An­i­mals have since been the last line of de­fense, tasked with suss­ing out which com­pounds a hu­man can and can­not tol­er­ate by show­ing first-hand the ill ef­fects of tox­ic chem­i­cals.

The bill that called for an­i­mal test­ing is not sur­pris­ing. At the time, the on­ly way for re­searchers to tru­ly in­ves­ti­gate a new drug’s phar­ma­co­tox­i­col­o­gy was to ei­ther take the drug them­selves or else give it to an­i­mals as prox­ies. How­ev­er, in the near­ly 80 years since the elixir sul­fanil­amide dis­as­ter, sci­ence has ad­vanced and with it, a grow­ing skep­ti­cism of an­i­mal mod­els has de­vel­oped.

Though an­i­mal mod­els have played a piv­otal role in the evo­lu­tion of mod­ern phar­ma­ceu­ti­cal de­vel­op­ment, they’re no longer a gold stan­dard. Too of­ten, they clas­si­fy tox­ic drugs as safe, on­ly to be re­vealed as dan­ger­ous through the agony of pa­tients. Ad­vanced mod­el sys­tems have been de­vel­oped that more ac­cu­rate­ly em­u­late hu­man tis­sue and ap­pear to be high­ly sen­si­tive in­di­ca­tors of drug tox­i­c­i­ty—all with­out the eth­i­cal and fi­nan­cial bur­dens that come with an­i­mal test­ing.

It’s against this back­drop that the FDA Mod­ern­iza­tion Act was de­vel­oped, an amend­ment to the FD­CA that elim­i­nates the man­date for pre­clin­i­cal an­i­mal test­ing. If en­act­ed, it would be the lat­est in a glob­al move­ment to im­prove pa­tient and con­sumer safe­ty by di­vest­ing from an­i­mal test­ing.

A Glob­al Move­ment

The use of an­i­mal mod­els in re­search is pro­lif­ic and for good rea­son. It is ex­ceed­ing­ly dif­fi­cult and im­por­tant to study how chem­i­cals be­have in com­plex, mul­ti­or­gan sys­tems. The tran­sit of a com­pound from one or­gan to an­oth­er may change it, af­fect­ing its phar­ma­co­log­i­cal prop­er­ties and po­ten­tial­ly ren­der­ing it tox­ic. An­i­mals, and par­tic­u­lar­ly mam­mals, pos­sess the same or­gans that hu­mans do and can thus be a close ap­prox­i­ma­tion of the hu­man body.

How­ev­er, an­i­mal-mod­els are far from per­fect and come with a host of eth­i­cal con­cerns. Even with mul­ti­ple lay­ers of reg­u­la­tion in place, sto­ries abound of an­i­mal abuse and suf­fer­ing. With no suit­able al­ter­na­tive, re­searchers have per­sist­ed with the mantra that we should re­fine, re­duce, and re­place ex­per­i­men­ta­tion on an­i­mals wher­ev­er pos­si­ble.

To that end, new mod­el sys­tems have been de­vel­oped that close­ly re­sem­ble hu­man tis­sues and may help to re­duce and re­place an­i­mals in pre­clin­i­cal screen­ing. For ex­am­ple, syn­thet­ic hu­man skin—formed from do­nat­ed tis­sue—has been val­i­dat­ed as a strong pre­clin­i­cal mod­el for as­sess­ing skin ir­ri­ta­tion and dam­age caused by cos­met­ics, negat­ing the need for an­i­mal test­ing.

In rec­og­niz­ing the val­ue of these non-an­i­mal mod­els, 41 coun­tries have banned the sale of cos­met­ics that were de­vel­oped us­ing an­i­mal test­ing. Mul­ti­ple US states have en­act­ed sim­i­lar state-lev­el bans, and, just this year, The Hu­mane Cos­met­ics Act was in­tro­duced for con­gres­sion­al con­sid­er­a­tion. If en­act­ed, this bill could sig­nif­i­cant­ly re­duce the glob­al use of an­i­mals in cos­met­ic test­ing.

Cur­tail­ing an­i­mal us­age in en­vi­ron­men­tal and ther­a­peu­tic tox­i­col­o­gy has been slow­er, but progress has been made. The EPA re­cent­ly an­nounced plans to se­vere­ly re­duce an­i­mal us­age when screen­ing new chem­i­cals, and the NIH has sig­naled in­tent to sub­stan­tial­ly de­crease the use of pri­mates in its re­search.

These are the rum­blings of change that fore­shad­ow a fu­ture with­out an­i­mal test­ing. But, to re­al­ize that po­ten­tial, we’ll need to con­tin­ue to in­vest in the de­vel­op­ment of ad­vanced mod­el sys­tems like or­gan-on-a-chip (or­gan-chips) tech­nol­o­gy and leg­is­la­tion such as the FDA Mod­ern­iza­tion Act.

Or­gan-Chips and The FDA Mod­ern­iza­tion Act

Among its stip­u­la­tions, the FDA Mod­ern­iza­tion Act would al­low re­searchers to use the most ac­cu­rate mod­el sys­tems when as­sess­ing a new com­pound’s safe­ty, elim­i­nat­ing the re­quire­ment that all drugs be test­ed in an­i­mals be­fore clin­i­cal tri­als.

Fu­el for this bill has come from a grow­ing body of ev­i­dence show­ing that or­gan-chips can pro­duce high­ly sen­si­tive and ac­cu­rate mod­els for test­ing drug tox­i­c­i­ty. Gen­er­al­ly, or­gan-chips are in vit­ro sys­tems that com­bine bio­me­chan­i­cal forces and het­ero­ge­neous hu­man cell pop­u­la­tions in a 3D tis­sue ar­chi­tec­ture to mim­ic spe­cif­ic tis­sue units.

In a re­cent study, re­searchers from Em­u­late de­scribed a large study in which 780 Liv­er-Chips were test­ed for their abil­i­ty to iden­ti­fy tox­ic com­pounds. No­tably, each tox­in used in this study had been clas­si­fied as safe in an­i­mal stud­ies, on­ly show­ing tox­i­c­i­ty once giv­en to pa­tients. Un­like an­i­mal mod­els, these or­gan-chips cor­rect­ly iden­ti­fied the com­pounds’ tox­i­c­i­ty with a sen­si­tiv­i­ty of 87%.

These promis­ing re­sults sug­gest that or­gan-chips may one day re­place an­i­mal mod­els. Much more re­search is need­ed be­fore that day comes. But, for now, or­gan-chips can be ef­fec­tive­ly used to en­sure that an­i­mals are not wast­ed on drugs that are des­tined to fail. Re­searchers can in­te­grate or­gan-chips pri­or to an­i­mal test­ing as a fil­ter against tox­ic com­pounds, en­sur­ing that an­i­mals are on­ly used to test the most promis­ing can­di­dates. The FDA Mod­ern­iza­tion Act en­cour­ages this in­te­gra­tion and paves the way for mod­els like or­gan-chips to po­ten­tial­ly re­place an­i­mals al­to­geth­er.

A Law with Com­mon Sci­en­tif­ic De­cen­cy

The tides of change are in full swing. We see a trend of glob­al di­vest­ment from the use of an­i­mals in cos­met­ics test­ing, and a grow­ing move­ment to re­duce and re­place an­i­mals in ther­a­peu­tic and chem­i­cal screen­ing. By em­brac­ing mod­ern tech­nol­o­gy and ever more ac­cu­rate in vit­ro mod­el sys­tems, the FDA Mod­ern­iza­tion Act is a law that brings us an­oth­er step clos­er to com­mon sci­en­tif­ic de­cen­cy and a more hu­mane fu­ture.