High Risk Research~Spencer Brown, Ph.D., Jose Joglar, M.D., and Paul Pepe, M.D., M.P.H., M.A.C.P., F.A.C.E.P.,F.C.C.M.

Objectives:

At the end of this session, participants should be able to:

1. Compare and differentiate high-risk clinical research between high-risk to research subject and high-risk to investigator/support source.

2. Discuss risk-benefit ratios for high-risk research from the perspective of the subject, and from the perspective of the investigator’s reputation/career status.

3. Discuss process of Institutional Review Board review of high-risk research.

4. Identify means of obtaining intra- and extra-mural support for high-risk research.

Cases for Discussion:

Case 18:

After 9-11, there has been increased interest in understanding potential bio-terrorism agents.  Little is known about the pathophysiology of a relatively uncommon biological agent to infect, cause disease, and means to prevent/control and eradicate the threat posed by this organism if released. 

You are a investigator who is interested in learning what threat would be posed if the organism B. nastybuggicus is released in the subway system in New York city.  

Variation 1.

1. How would you design a study to test the impact of a weaponized strain of B. nastybuggicus.

2. How would you justify the conduct of your study to an IRB?

3. How would you recruit subjects for the study?

4. What is the obligation of the PI to the research subjects if a severe adverse event or death was a result of study participation?

Variation 2.

There is some evidence that organisms related to B. nastybuggicus have limited infectivity if a novel environmental filtration method was used, however this has never been tested on any related organism except in a highly controlled laboratory, and it is unknown if this method would have any effect on B. nastybuggicus.

1. How would you study this device?

2. How would you seek funding for this investigation?

Case 19:

You are a PI in a multi center clinical trial that compares standard intracardiac defibrillator use against a defibrillator with an extra sensor that is designed to measure intracardiac pressures. The study device combines a defibrillator with a heart failure monitoring tool. The initial risk is associated with implanting a second wire inside the cardiac chambers and all the usual risks involved with implanted defibrillators.

The manufacturer decided to use an insulation component that had a history of high failure rate. Within a few months of running the study, you receive some offsite AE reports of some of these sensor wires going bad. The FDA allowed the trial to continue, as well as the IRB.

Should you continue knowing that some of these wires will go bad? You do not think it will endanger the patients when the wire is bad, and the insulation failure risk was disclosed to the subjects. Is the risk now worth it to the patient? Given the newly-appearing failures of the insulation, would you reconsent the enrolled subjects? What would you tell them?

Selected Readings:

Pepe, Paul E., Copass, Michael K., Sopko, George. Clinical trials in the out-of-hospital setting:Rationale and strategies for successful implementation. Critical Care Medicine.January 2009;37(1):S91-S101

Wendler,David., Miller, Franklin G. 2008. Risk-Benefit Analysis and the Net Risks Test. In:The Oxford Textbook of Clinical Research Ethics. ed. Emanuel, E., et al. 503-513. New York: Oxford University Press.