History of Clinical Trials#

Presenter: Christina Obeid

Founded#

  • Established in 1948 by the United Kingdom Medical Research Council

  • By a professor of Medical Statistics called Sir Austin Bradford Hill

  • The first trial was the streptomycin trial for Tuberculosis

Sir Austin Bradford Hill#

  • Advocates groups to be selected at random around 3 to 5 people at most

  • avoided using the term “randomization” in his 1937 handbook to encourage adoption by skeptical doctors.

MRC Streptomycin trails#

  • Conducted after WW2, when Tuberculosis was the leading cause of death

  • Streptomycin, discovered in 1943 by Albert Schatz and Selman Waksman

  • Proved that bacterium (Mycobacterium tuberculosis) that causes tuberculosis in the labs and animal study

History of Adaptive Trials Designs#

  • Initiated in 1985 with the effectives of extracorporeal membrane oxygenation (ECMO) WAS PUBLISHED BY Robert H. Barlett and colleagues in 1985

ECMO#

  • Procedure for newborns with respiratory failure

  • Faced challenges in terms of getting approval/consent

Play-the-winner#

  • Clinical trial method based on ECMO

  • Introduced by Zelen 1969 and refined Wei and Durham in 1978

  • Treatment success is based on patients’ assignments= e.g. Patient 1 = treatment A or B. If treatment A is successful then the next patient = treatment A, else next patient = treatment B or other

  • Faced challenges in terms of ethical worry in terms of withholding lifesaving treatments

Two-stage approach#

  • Adaptive clinical trials

  • Done by the Bartlett et al. study, Pearl O’Rourke and colleagues

    • 1st stage – equal assigned to ECMO or standard-of-care at until there were 4 deaths observed in either group.

    • 2nd stage - assigned to the more effective treatment until statistical significance was reached.

UK Collaborative#

  • Addressed after criticism of both methods – play-the-winner and two-stage approach

  • Randomized clinical trial using equal allocation between ECMO and the standard control with the maximum sample size of 300 newborns, stopped at 180 newborns due to the sufficient outcome

  • Started from January 1993 to November 1995

Development of Master Protocols#

  • Master protocols – initially developed for oncology

  • Received support from the US Food and Drug Administration (FDA)

  • Adaptable to multiple clinical indications and objectives.

  • Basket and umbrella trials are limited only to oncology but platform trials can expand beyond oncology for research

  • Platform trials e.g.covid 19 platform trials