Quantifying the risks of non-oncology phase I research in healthy volunteers: meta-analysis of phase I studies

Abstract

ObjeCtiveTo quantify the frequency and seriousness of adverse events in non-oncology phase I studies with healthy participants.

The Bial 10-2474 Phase 1 Study-A Drug Development Perspective and Recommendations for Future First-in-Human Trials

“…In Emmanuel's review of safety experience in Pfizer's phase 1 units, of 11 028 participants exposed to active drug from 2004 to 2011, there were 255 severe AEs and a total of 34 SAEs, 11 of which were related to study drug and 7 to study procedures. No deaths or life‐threatening events occurred …”

Ethical considerations and challenges in first-in-human research

“…Although enrollment rates of women in early-phase trials have been increasing, women are still considered an underrepresented group. 77,103 Of note, exclusion of women should still be taken into consideration and would be ethically appropriate should evidence demonstrate or suspect an increased trial-related risk in female individuals.…”

“…First, risk-benefit justification is crucial in the involvement of healthy subjects in FIH trials because they have more to lose than patients and the benefits to them are none existent while adverse events are common. [75][76][77] Safety/toxicity analysis and management plans for unexpected adverse events must be undertaken with the greatest precaution possible as trials involving healthy subjects should ideally be very safe. Any reasonably expected serious or life-threatening adverse event from a proposed experimental intervention could serve to disqualify any other 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 ethical justification for the conduct of research in healthy subjects.…”

The pharmaceutical industry needs more clinical pharmacologists

“…Clinical pharmacology phase I clinical trials are generally safe with a very low incidence of serious, drug‐related adverse events . However, the first‐in‐man studies with TGN1412 in 2006 and in 2016 with BIA 10‐2474, in which one healthy subject died and another four suffered brain damage, serve as a reminder that phase I trials are not without risk.…”