Robert D. Truog, MD Professor of Medical Ethics, Anaesthesia, & Pediatrics Director of Clinical Ethics, Harvard Medical School Executive Director, Institute for Professionalism & Ethical Practice Senior Associate in Critical Care Medicine, Children’s Hospital Boston

Ethical Issues in Adaptive Clinical

Trials

Adaptive designs: History of ECMO

• Extracorporeal membrane oxygenation is a form of heart-lung bypass for life-threatening cardiac or pulmonary failure

• 1980s: Surgeon Bob Bartlett began to use ECMO for neonatal PPHN with excellent anecdotal results

Adaptive designs: History of ECMO

• But – he realized practices would not change without validation from a randomized controlled trial

• Yet he was conflicted – proving the superiority of ECMO would require him to let some babies die that he believed he could save

Bartlett Article

Bartlett: Play-the-Winner Design

ECMO Survived

CMT Died

10 ECMO: survived

1 CMT: died

Bartlett Article

“The clinical indications for this new and complex treatment remain undefined. Further randomized controlled trials… will be difficult but remain necessary.”

O’Rourke Article

O’Rourke et al, 1989

• Also employed an adaptive design

• Phase I: 50/50 randomization until there are 4 deaths in one arm

• Phase II: Assign all patients to the more successful therapy, until there are 4 deaths in that arm or until statistical significance is achieved

Phase I

ECMO CMT

9 s, 0 d 6 s, 4 d

The Harvard Neonatal ECMO Trial: Results

Phase II 19 s, 1 d

Adaptive Randomization

• In the literature, the trial was criticized from both directions – No patients should have been assigned to CMT – Not enough patients were assigned to CMT

• Perhaps this approach was a good balance – 4 deaths was a psychological “breaking point,”

especially for the nursing staff

• But was it convincing?

The UK Neonatal ECMO Trial

• The existing “RCTs of neonatal ECMO… suggested reductions in mortality but were not conclusive.”

• Because they “used adaptive designs, which may have introduced bias…”

Field et al. UK collaborative randomised trial of neonatal extracorporeal membrane oxygenation. Lancet 1996;348:75-82

The UK Neonatal ECMO Trial

• 1993-1995: 185 neonates randomized to ECMO vs CMT

• Trial stopped early by DSMB, – ECMO survival 60/93 = 65% – CMT survival 38/92 = 41%, p<0.0005

• Were 22 babies unnecessarily “sacrificed”?

Presenter

Presentation Notes

Informed consent – obsession with autonomy – often required, but never sufficient

1) Social & Scientific Value

• Adaptive designs may influence the choice of the outcome variables – Must be one primary outcome of interest – Must be apparent within a short period of

time – May favor use of biomarkers or other

surrogate markers

2) Scientific Validity

• Frequent analysis of data may make confidentiality of data difficult

• Risk of accrual bias – Researchers may be able to guess study trends – May seek to enroll patients who they think will benefit – Subjects may prefer to enroll only in the later stages

of a trial

• Even if a trial is statistically valid, is it important that the validity be “transparent” to clinicians?

Presenter

Presentation Notes

From Jim Ware, RM 679

3) Fair subject selection

• Those who enroll later, benefit more – Subjects who do not understand this may be at a

disadvantage to those who do – Will those with superior understanding seek to

“game” the system? – Does this differ from current approach to Phase 1

trials?

• Investigators may find it more difficult to enroll patients to the arm they believe to be less favorable

4) Favorable risk-benefit ratio

• This is the primary advantage of adaptive designs

• For the investigator: Attempts to mitigate the conflict between clinician and investigator

• For the subject: Attempts to minimize number of subjects assigned to the less-successful therapy

5) Independent Review

• I don’t see any problem here as long as options are clearly defined up-front

– Study modifications made after the study begins could pose problems

6) Informed Consent

• How much do subjects need to understand about the study design to provide informed consent?

• Will they understand that modifications will be based solely on data and not on physician preference?

7) Respect for enrolled subjects

• Informing subjects of study results is increasingly encouraged

• How will subjects with early enrollment in the inferior arm perceive their involvement?

Presenter

Presentation Notes

Informed consent – obsession with autonomy – often required, but never sufficient

Meurer WJ, Lewis RJ, Berry DA. JAMA 2012;307:2377-8

The fundamental dilemma • A dilemma confronts physician-investigators…

• As physicians they are dedicated to caring for their patients…

• As investigators they are dedicated to caring for their research…

• These two commitments conflict whenever an individual physician/investigator comes face to face with an individual patient/subject.

Jay Katz, 1993

The ethical dilemma…

• The goal of research is to acquire generalizable knowledge to improve the health of future patients

• The goal of clinical care is to improve the health of our current patients

• A side-effect of research may be that subjects may be benefitted (or harmed) but it is never the purpose of the research

“Therapeutic Misconception”

• The false belief that the purpose of research is to benefit the patient

• Adaptive designs do not alter the primary goal of the research

• They may favorably impact the risk/benefit ratio, but may increase ethical concerns in other areas

Meurer WJ, Lewis RJ, Berry DA. JAMA 2012;307:2377-8

In my view, adaptive designs are not a “partial remedy for the therapeutic misconception,” but indeed make it even more problematic!