AHRP Complaint Results in Research Protocol Change

In response to complaints filed by the Alliance for Human Research Protection (January 20, 2010)  and another (January 28)  in which we raised concerns about the ethics and safety for human subjects in a federally sponsored (NIH), blood storage experiment, an investigation by the federal Office of Human Research Protections has resulted in protocol revisions to the RECESS trial.

Below, a letter from OHRP’s Director of Compliance and Oversight to AHRP, acknowledges the validity of our concerns, indicating that the protocol has been revised:

"OHRP shared your concerns and discussed them with the National Heart Lung and Blood Institute.  They appreciated the concerns and have revised the protocol to address them.  In specific, the protocol has been revised to indicate that sites will not be allowed to maintain a special inventory of RBC units stored ≥ 21 days for the study, or specifically order units that would be stored ≥ 21 days by the expected date of surgery."

The RECESS experiment seeks to answer the question whether new blood is safer than old stored blood. Current practice uses whatever stored blood is available–some may be new, some old.   The importance of including a current best practice control arm in human trials cannot be overstated: it provides a safety measure for patients which is mandated by the Declaration of Helsinki.

When testing two experimental medical procedures without a best practice comparator–especially when severely ill patients are the subjects and death is the endpoint–will likely result in more preventable deaths and serious injuries.

AHRP believes that testing two experimental treatments with death as the endpoint–without a current practice control arm–may be justified for an animal study, but should never be done in humans–especially in vulnerable critically ill people.

The protocol revisions described in the OHRP letter (below) meet our request, ensuring that:
 "subjects assigned to the old blood arm would never be getting blood that is older than they would have gotten had they not participated in the study…The RECESS protocol was also revised to include more frequent monitoring and analysis of adverse events."

This is the second time that a complaint by AHRP filed with the federal regulatory agency about a major, multi-site experiment–designed and conducted under the auspices of the National Heart Lung and Blood Institute–has led to changes to conform with medical ethics standards:

In July, 2003, the OHRP validated our criticism about flagrant violations of the informed consent requirements in the ARDSNet lung ventilation experiments.

Among the numerous substantive informed consent violations noted by OHRP:
the ARDSNet consent documents failed to describe the purpose of the research, the nature of the experimental design, or to disclose the risks and alternative standard treatment. OHRP’s letter acknowledged:
"at nearly all study sites the informed consent failed to include death as one of the risks of the research, calling it "misleading and inaccurate."

As a result of that AHRP complaint, the ARDSNet informed consent documents were revised to disclose the experimental nature and risks.

Vera Hassner Sharav

—–Original Message—–

From: Borror, Kristina C (HHS/OPHS) [mailto:Kristina.Borror@hhs.gov]
Sent: Monday, April 05, 2010 8:43 AM
To: veracare@ahrp.org
Cc: Menikoff, Jerry (HHS/OPHS); Carome, Michael A (HHS/OPHS)
Subject: FW: An Ethically Dubious Blood Experiment: RECESS
Importance: High

Dear Ms. Sharav:

The Office for Human Research Protections (OHRP) has received your January 22, 2010 email regarding your concerns about the Red Cell Storage Duration Study (RECESS).

OHRP has responsibility for oversight of compliance with the U.S. Department of Health and Human Services (HHS) regulations for the protection of human research subjects (see 45 CFR Part 46 at http://www.dhhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).  In carrying out this responsibility, OHRP evaluates, at OHRP’s discretion, substantive allegations of noncompliance involving human subject research projects conducted or supported by HHS or that are otherwise subject to the regulations (see OHRP memorandum dated October 14, 2009 at http://www.hhs.gov/ohrp/compliance/ohrpcomp.pdf for an explanation of OHRP’s jurisdiction).

OHRP shared your concerns and discussed them with the National Heart Lung and Blood Institute.  They appreciated the concerns and have revised the protocol to address them.  In specific, the protocol has been revised to indicate that sites will not be allowed to maintain a special inventory of RBC units stored ≥ 21 days for the study, or specifically order units that would be stored ≥ 21 days by the expected date of surgery. 

After potential subjects have provided informed consent, eligibility will be determined based on the trial’s inclusion/exclusion criteria. Consenting, eligible subjects will be enrolled in the study and will be considered for randomization. Prior to surgery but no earlier than one calendar day before surgery, a study staff member will contact the institution’s transfusion service to determine whether both of the following criteria are met.
*    The transfusion service has enough suitable units stored ≤ 10 days to meet the crossmatch request for this subject.
*    The general inventory of the transfusion service has enough suitable units stored ≥ 21 days to meet the crossmatch request for this subject. In other words, the crossmatch request would be filled with RBC units stored ≥ 21 days if issued according to standard inventory management (oldest product released first).

If these criteria are both met, the study staff member will immediately randomize the subject. If there is not sufficient inventory to meet both criteria, the subject will not be randomized and his or her participation in the study will end.  Therefore, subjects assigned to the old blood arm would never be getting blood that is older than they would have gotten had they not participated in the study.

Because of these changes, more subjects will need to be enrolled to reach the goal of 1434 evaluable subjects.  The protocol has revised the inclusion criteria to expand the pool of potentially eligible cardiac surgery patients.  The RECESS protocol was also revised to include more frequent monitoring and analysis of adverse events.

As a result, OHRP anticipates no further involvement in this matter.  

OHRP appreciates your concern about the protection of human research subjects.

Sincerely,
Kristina C. Borror, Ph.D.
Director
Division of Compliance Oversight
Office for Human Research Protections
1101 Wootton Parkway, Suite 200
The Tower Building
Rockville, MD 20852
email: kristina.borror@hhs.gov
Phone: (240) 453-8132
Fax: (240) 453-6909