Why academics of investigator-initiated studies should consider outsourcing to CROs

Research dri­ven by aca­d­e­mics, the so-called inves­ti­ga­tor-ini­ti­at­ed stud­ies, are clin­i­cal stud­ies ini­ti­at­ed and man­aged by a non-phar­ma­ceu­ti­cal com­pa­ny researcher (e.g., indi­vid­ual inves­ti­ga­tors, insti­tu­tions, col­lab­o­ra­tive study groups or coop­er­a­tive groups) (1). In the USA, the inves­ti­ga­tor-ini­ti­at­ed stud­ies fund­ed by the NIH, aca­d­e­m­ic med­ical cen­ters or vol­un­tary spe­cial­ty groups (char­i­ties) are clas­si­fied as inde­pen­dent stud­ies as these groups are not dri­ven by mon­ey to achieve a suc­cess­ful out­come. These types of tri­als are viewed the gold stan­dard for data and more like­ly to be in the best inter­est of the patient.

They include (1) clin­i­cal inter­ven­tion­al stud­ies (Phase I to IV) of approved and inves­ti­ga­tion­al uses of mar­ket med­ica­tions or med­ical devices or those still in devel­op­ment and (2) clin­i­cal non-inter­ven­tion­al / obser­va­tion­al stud­ies of real-world evidence.

The aca­d­e­mics are respon­si­ble for the legal and reg­u­la­to­ry respon­si­bil­i­ties of the tri­al spon­sor for the con­duct and man­age­ment of the study as defined by all applic­a­ble laws and regulations.

Due to the high price tag for new drugs, the clin­i­cal tri­als are com­mon­ly fund­ed by phar­ma­ceu­ti­cal com­pa­nies. In the USA, the indus­try’s share of total bio­med­ical research increased from near­ly a third in 1980 to near­ly two-thirds in 2000 (2). How­ev­er, one analy­sis of fund­ing source dis­tri­b­u­tion of 119,840 drug tri­als reg­is­tered with clinicaltrials.gov (2005–2017) showed that the pro­por­tion of stud­ies fund­ed by orga­ni­za­tions oth­er than indus­try or NIH has also increased (Fig­ure 1) — main­ly uni­ver­si­ties, hos­pi­tals, and oth­er aca­d­e­m­ic and non-prof­it agen­cies, clas­si­fied here as “oth­er.” Over­all, these insti­tu­tions and NIH fund­ed 47.7% of all reg­is­tered phar­ma­ceu­ti­cal tri­als, while the indus­try fund­ed 52.2% of reg­is­tered stud­ies (big phar­ma 31.0%; small phar­ma 21.2%) (3).

Fig­ure 1: Fund­ing source dis­tri­b­u­tion for all tri­als reg­is­tered with clinicaltrials.gov and con­duct­ed after 1 Jan 1997 until 19 July 2017 (based on the start date data field).

The bias of indus­try spon­sored tri­als can­not be over­looked. One JAMA report of inte­grat­ed data from over 1,100 stud­ies showed that indus­try-spon­sored clin­i­cal tri­als are “sig­nif­i­cant­ly more like­ly to reach con­clu­sions that were favor­able to the spon­sor than were non-indus­try stud­ies”, pos­si­bly because of pub­li­ca­tion bias or selec­tion of an inap­pro­pri­ate com­para­tor to the drug being eval­u­at­ed (Fig­ure 2) (2).

Fig­ure 2: Rela­tion between indus­try spon­sor­ship and study out­come in orig­i­nal research studies.

The inves­ti­ga­tor-ini­ti­at­ed stud­ies are more impar­tial. With­in aca­d­e­m­ic insti­tu­tions, the industry’s involve­ment of activ­i­ties of inves­ti­ga­tor-ini­ti­at­ed stud­ies (e.g., pro­to­col writ­ing, tri­al con­duct, data analy­ses and pub­li­ca­tion) can be min­i­mized / avoid­ed as much as pos­si­ble (4). Even for those stud­ies fund­ed by indus­try but ini­ti­at­ed by the inves­ti­ga­tors, they typ­i­cal­ly have low­er over­head costs, which tend to restrict the indus­try spon­sors to ensur­ing their adher­ence to good clin­i­cal-prac­tice guide­lines and to mon­i­tor­ing the data for seri­ous adverse events, errors, and omis­sions. There­fore, the poten­tial influ­ences from the indus­try on the con­duct of those stud­ies can be also minimized.

As the inves­ti­ga­tor-ini­ti­at­ed stud­ies are large­ly dri­ven by ques­tions that gen­er­al­ly arise beyond the com­ple­tion of Phase III stud­ies that have not been stud­ied dur­ing Phas­es I–III of drug devel­op­ment (1). There­fore, oth­er ben­e­fits of inves­ti­ga­tor-ini­ti­at­ed stud­ies include (1) data gen­er­at­ed in a real-world set­ting, (2) direct appli­ca­tion to the local pop­u­la­tion of the inves­ti­ga­tion site, and (3) pro­vid­ing answers to ques­tions which are not of inter­est or com­mer­cial­ly viable for the industry.

For a broad per­spec­tive, inves­ti­ga­tor-ini­ti­at­ed stud­ies offer clin­i­cians an oppor­tu­ni­ty to do all rel­e­vant activ­i­ties of the stud­ies, includ­ing study design, data analy­sis, inter­pre­ta­tion, and data archiv­ing. How­ev­er, ini­ti­at­ing, sus­tain­ing, and tak­ing an inves­ti­ga­tor-ini­ti­at­ed study to real­iza­tion is not easy. While the ben­e­fits of doing an inves­ti­ga­tor-ini­ti­at­ed study are man­i­fold, numer­ous chal­lenges need to be addressed before embark­ing on an inves­ti­ga­tor-ini­ti­at­ed study. These chal­lenges exist, rang­ing from reg­u­la­to­ry sub­mis­sions, con­tin­u­ous mon­i­tor­ing, to per­son­nel train­ing, sta­tis­tics exper­tise, data man­age­ment, and med­ical writing.

Dur­ing the pro­to­col devel­op­ment phase, the poten­tial dif­fi­cul­ties include inad­e­quate / incom­plete lit­er­a­ture search­ing while for­mu­lat­ing a research ques­tion, inad­e­quate train­ing to address eth­i­cal issues, lack of famil­iar­i­ty with basic research method­ol­o­gy, apa­thy toward reg­is­ter­ing the study with a clin­i­cal tri­als reg­istry, and inad­e­quate plan­ning of safe­ty monitoring.

Dur­ing the study phase, the poten­tial dif­fi­cul­ties include inad­e­quate imple­men­ta­tion of meth­ods, non­avail­abil­i­ty of an inter­nal mon­i­tor and qual­i­ty con­trol, inad­e­quate mea­sure to pre­vent dropouts, inad­e­quate archiv­ing facil­i­ty, inad­e­quate man­pow­er to han­dle large data and exe­cute sta­tis­ti­cal analy­sis, and fail­ure to update the study report.
Dur­ing the post-study phase, the pos­si­ble dif­fi­cul­ties include lack of pub­li­ca­tion pol­i­cy at the pro­to­col devel­op­ment state, author­ship dis­putes for mul­ti­cen­tric stud­ies, dis­pute over data own­er­ship, and lack of capa­bil­i­ty for publication.

The most dis­tinct ben­e­fit of out­sourc­ing tasks to a CRO is hav­ing anoth­er pro­fes­sion­al enti­ty con­duct­ing part of or all research activ­i­ties of the stud­ies (5). Qual­i­fied CROs will already have the estab­lished staff in place, expe­ri­ence / equip­ment need­ed, and vital resources pre­pared. It like­ly saves the insti­tu­tion time and mon­ey to estab­lish their own per­son­al and facil­i­ties start­ing from zero. Fast time­li­ness with­out time delays is anoth­er sig­nif­i­cant ben­e­fit of CROs, because they are equipped and pre­pared to ini­ti­ate the work as soon as the con­tract is signed.

Inter­na­tion­al reg­is­tra­tion and mar­ket­ing of med­ica­tion or med­ical device is dif­fi­cult. If the drug or med­ical device being devel­oped is antic­i­pat­ed to be approved inter­na­tion­al­ly, it will be great­ly ben­e­fi­cial to out­source to a CRO that has inter­na­tion­al expe­ri­ence with the approval process in each author­i­ty. The CRO with a data-dri­ven, reli­able and glob­al reg­u­la­to­ry affairs team can help you to meet your targets.

For any aca­d­e­m­ic insti­tu­tions or biotech start-ups, the essen­tials of out­sourc­ing are the same. The first thing, that must be decid­ed, is whether to work with a large full-ser­vice CRO or small­er more spe­cial­ized CROs (6). For inves­ti­ga­tor-ini­ti­at­ed stud­ies or start-ups, there may be a remark­able risk in tak­ing the “easy option” and trust­ing that a big CRO’s exten­sive glob­al resources and capa­bil­i­ties pro­vide assur­ance of suc­cess­ful study con­duct. It is not say­ing that all large CROs are not com­mit­ted to work­ing with aca­d­e­m­ic insti­tu­tions or start-ups, how­ev­er, well defined and devel­oped needs and expec­ta­tions must be under­stood before mak­ing the decision.

ICRC-Wey­er GmbH, as an inte­grat­ed all-phase CRO with a team of mul­ti­dis­ci­pli­nary spe­cial­ists, has exten­sive expe­ri­ence in clin­i­cal and med­ical device stud­ies (includ­ing but not lim­it­ed to inves­ti­ga­tor-imi­tat­ed stud­ies), from study set­up and con­duct to data han­dling, analy­sis and report­ing to all aspects of drug safe­ty with all study phas­es and sub­se­quent­ly with post-mar­ket­ing sur­veil­lance tri­als. All ser­vices can be con­tract­ed as a full-ser­vice pack­age or as func­tion­al ser­vices, based on each customer’s needs.

Liang Gao

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