page 1 Oct. 7, 2002 OHRP letter to: Ronald S. Newvbower, Ph.D(Mass. General Hospital), Lee E. Limbird, Ph.D. (Vanderbilt University), and Robert Kay, MD) (Cleveland Clinic Foundation)
page 2 "OHRP continues to have serious unresolved concerns...trials failed to comply with key requirements of HHS regulations" OHRP requests institutions to investigate further
page 3 Concerns, questions, allegations re: ARMA study design 45 CFR 46.111(a)(1) "excluded a control arm...failed to define...systematic..specific range"
page 4 "study appears to have lacked control group" "insufficient evidence to support any conclusions...low tidal volume intervention" "subjects in ARMA study may have been placed at an increased risk of death in comparison to patients managed... 'standard of care'"
page 5 "exposure to significantly higher..airway pressures....may have contributed further to increased risk of death."
page 6 "Clarify whether investigators or IRB...requested pre-study review and analysis" "Arrange for each site...in the ARMA trial to conduct a review of clinical records"
page 7 "IRB-approved protocol provided theoretical baiss..tidal volume 6mg/kg may have posed greater risk of harm and discomfort in comparison to higher tidal volumes ...less than 12 ml/kg"
page 8 "provide a complete summary of all data collected on all...patients." "study was not adequately monitored; failures in monitoring may have resulted in preventable subject deaths"
page 9 "ARMA protocol provided little substantive discussion: justification for surrogate consent for research involving greater than minimal risk; coercion or undue influence"
page 10 "IRB-approved informed consent...may have failed to adequately describe the purpose of the research....failed to include death as one of the risks of the research."
page 11 "paramount importance...vulnerable population...interventions [must] be designed to provide results and conclusions that would be directly relevant to clinical practice, not simply an answer to a physiologic question. ...failed to provide sufficient justification for.. excluding a control arm maintained on...middle of the normal range"
page 12 FACCT protocol...randomization of either fluid 'liberal' or 'conservative' management strategy. ..actual risks involved...these specific strategies have not been tested in patients previously."
page 13 "lack of control group...there will be insufficient evidence to support any conclusion that either the liberal or conservative fluid management strategy is superior to: individualized 'standard of care'"
page 14 "investigators have stated that there is no standard of care for patients with ALI"
page 15 "please arrange for each site...to conduct a review of the clinical records...please explain the basis for selecting the two experimental groups (low target levels...or high...)"
"Please provide evidence from any human studies that supports the conclusion that the two fluid management strategies selected for the trial are safer or more effective than "standard of care" fluid management"
page 16 "For each individual subject for whom informed consent was obtained and documented, please provide the following information in tabular or spreadsheet format"
page 17 "...outcome variables, please include whether any subject was withdrawn...date of withdrawal, and reason for withdrawal...Please specify how subjects who withdrew ...are being handled in the data analysis."
page 18 FACCT protocol..inclusion criteria allow subjects as young as 13 years to be enrolled in the trial. OHRP is concerned the research may not satisfy requirements of HHS regulations at 45 CFR 46 Subpart D for research involving children."
page 19 "OHRP is concerned that the following statement in the PURPOSE OF THE STUDY section is inaccurate and conflicts with statements made in the FACCT protocol"
page 20 "informed consent document fails to include death as one of the risks of the research...no statement that subjects could have a higher risk of death depending on which experimental group they are assigned to in comparison to each other and in comparison to not entering the trial.."
page 21 "OHRP is concerned...risks section is misleading and minimizes the potential risks"
page 22 ALVEOLI study "appears to have lacked a control group that received either...individualized ventilation management...set at level anywhere along the spectrum...based upon ...complex clinical factors unique to each subject, and expertise...clinical judgment of a team of intensive care physicians--'standard of care'"
page 23 "both groups of experimental subjects in the ALVEOLI study may have been placed at an increased risk of death in comparison to patients managed according to a 'standard of care'"
page 24 "Please clarify whether or not, prior to designing the ALVEOLI study, the ARDSNet investigators conducted a pre-study review and analysis of routine clinical practice within intensive care units of participating ARDSNet institutions.
page 25 "this protocol-mandated tidal volume intervention may compound the risks associated with the experimental PEEP/ FiO ventilation strategies...failure to minimize risks to subjects..."
page 26 Specifies data requested for each subject re: outcome variables
page 27 OHRP is concerned whether additional safeguards were included for subjects who were likely to be vulnerable to coercion or undue influence...were there independent consent monitors?
page 28 Please provide the IRB-approved informed consent documents from each participating ARDSNet institution.
page 29 list of recipients of the letter
List of ARDSNet Centers