Dear Dr. Menikoff:
On January 22, 2010, AHRP filed a complaint about the design of a multi-site blood storage experiment (RECESS, NCT00991341) sponsored by the National Heart Lung and Blood Institute.
We objected to the trial design because it did not have controls:
“Our concern is that the trial design is unethical because it fails to compare the best current clinical practice–which uses available blood in hospital blood banks–some of which may be new, some old. Transfusing the oldest units first of the available blood that can be up to 42 days old. The protocol instead randomizes patients to receive either old or new blood–depending upon which group they are randomized to–for however many transfusions they need.”
And we objected to the NHLBI-approved informed consent form that fails to disclose to patients that death is the endpoint of interest in this randomized experiment requiring some patients to be transfused with only old blood.
We noted that our request for the citations to four prior clinical trials that the investigators referred to—but failed to post the actual reference on the publicly accessible website (www.clinicaltrials.gov —was declined, suggesting that AHRP make a FOIA request to obtain them.
After obtaining the complete RECESS protocol and obtaining the requested references, AHRP has now come to the opinion that the investigators misrepresented a referenced- Canadian pilot trial. This trial was misleadingly presented in the protocol and RECESS trial web-site suggesting that there is equipoise when there is not:
“A pilot randomized controlled trial in 65 ICU patients of <8 day old blood vs. 15 day old blood actually reported worse outcomes in patients who received <8 day old blood.”
In point of fact, the investigators of this Canadian pilot trial—which compared new (<8 day old blood) to standard practice of using available blood—reported that only 57 patients were eligible for analysis. Further the groups were imbalanced in age and comorbid-conditions, and there were no significant—or even close to significant—findings of harm. Nor did the authors report—as claimed by the NHLBI investigators—that outcomes were worse for patients who received new blood:
“The group receiving red cells _8 days old tended to be older on average (68_8.54 yr versus 63_15.30 yr; P=0.13) and have more co morbid illnesses (85% versus 65%; P= 0.09). “
“In total, 27% of patients in the experimental group died or had a life-threatening complication as compared to 13% in the standard group (P=0.31). There were no differences in prolonged respiratory, cardiovascular, or renal support after randomization (P>0.05).”
“Although we were unable to detect meaningful clinical benefits from the transfusion of RBC stored for less than eight days, we believe that prolonged RBC storage should be further evaluated.”
See: A Pilot Trial Evaluating the Clinical Effects of Prolonged Storage of Red Cells
Paul C. Hebert, MD, Ian Chin-Yee, MD, Dean Fergusson, PhD, Morris Bachman, MD, aymond Martineau, MD, Jennifer Clinch, BSc, MA, Bernhard Olberg, MD_ and the anadian Critical Care Trials Group, Anesth Analg 2005;100:1433–8.
We now challenge the unfounded claim made by the US government sponsored investigators of the RECESS trial that “equipoise exists regarding the effect of RBC storage on patient outcomes.”
Our expert critical care consultants assure us that there is substantial, irrefutable, and well-accepted data to suggest that blood loses function and viability with age consistent with the fact that it is discarded after 42 days in storage. And at least one large study in a premier medical journal (NEJM, 2008) suggests that transfusion with older blood is associated with multiple significantly worse outcomes including death. There is no such comparable data for freshly stored blood—and therefore no equipoise for the study as designed, to compare the effects of transfusing older stored blood vs. newly stored blood.
The RECESS protocol states:
“Perhaps only ICU patients have been studied more carefully with respect to RBC transfusion. A multi-center clinical trial comparing the effects of RBC storage time on clinical outcomes in ICU patients has been funded in Canada. In addition to the different patient population, the Canadian study also differs in that the primary outcome will be mortality and the RBCs in the two arms will be either < 10 day of storage or standard of care. Hence the two studies will be complementary, and between them encompass two of the patient populations accounting for a large share of blood utilization.”
The contrast between the Canadian clinical trial design testing the safety of fresh and stored blood, and the NHLBI design is very revealing because both are examining the same clinical problem.
The Canadian researchers seek to minimize risk for patients by adhering to the ethical principle of human experimentation in testing only an experimental treatment (fresh blood) which is believed to be better than current practice, against current practice.
Risks are minimized in the Canadian trial by exposing patients only to therapies that may benefit them; and by inclusion of a control arm (current practice) ensuring for adequate safety monitoring during the trial. This is particularly important in such vulnerable critically ill subjects, when significant harm such as death is the endpoint of interest. After all, research is, by definition, an exploration into the unknown. It is possible that both experimental arms (fresh vs. old blood) may prove to be more harmful than current practice. In this situation, without a “standard of care” control for comparison, patients could potentially continue to be enrolled in the face of significant harm from both experimental arms.
The US researchers seek to maximize trial outcome differences rather than safety—they do so by testing two experimental treatments—one believed beneficial the other harmful—without testing current practice.
Such trial designs—with one arm believed to be potentially harmful—put some patients unjustifiably at increased risk of death (contrast this with the Canadian trial design). Moreover, because the NHLB study lacks controls, no firm conclusions about changing current practice can be made on the basis of this or other such studies–nor do such studies provide a necessary comparator for adequately monitoring patient safety during the trial.
The Canadian study design is both scientifically more rigorous and ethically legitimate: whereas the NHLBI designed RECESS protocol is unacceptable. Testing two experimental treatments in vulnerable critically ill subjects with death as the endpoint may be justified for an animal study, but should never be done in humans.
AHRP asks the National Heart, Lung, and Blood Institute to stop sponsoring or conducting clinical trial designs that exclude current practice arms from their multi-site trials—as such trials put some patients at increased risk of death. Two examples: the blood storage (RECESS) trial and the mechanical lung ventilation trial (ARDSNET).
The disparity between the RECESS investigators’ claim and the actual reported findings of the Canadian pilot trial raises concerns, possibly explaining why the prior trial citations were not disclosed on www.clinicaltrials.gov, the publicly accessible website, and why our request for the citations was deemed to require a FOIA request.
Additionally, AHRP is concerned that blood will need to be aged in order to meet the protocol requirements that 6 units of >21 day old and 6 units of < ten day old blood banked blood be on hand in the Blood Bank before patients can be randomized:
“Before the subject is randomized, the study coordinator will contact the institution¹s Blood Bank to notify the Blood Bank staff of a potential RECESS subject, the subject¹s planned date of surgery, and the subject¹s ABO and Rh blood type. The Blood Bank staff will determine whether they expect to be able to support the subject with RBC units of the appropriate storage age during and after the surgery, no matter which treatment group the subject is randomized to. The Blood Bank must expect to be able to provide six suitable products that have been stored <10 days and six suitable products that have been stored >21 days in inventory by the time the surgery is expected to take place. If the Blood Bank anticipates difficulty in providing both longer and shorter storage age products during and after the surgery, the subject will not be randomized.”
Furthermore, if the Blood Bank runs out of the appropriate inventory for an enrolled patient, the protocol states:
“…it may take one to two days to create an inventory for a randomized subject, inability to adhere to the randomized treatment for pre-operative transfusions will be reported, but not considered a protocol violation. Institutional processing standards will be maintained for all study subjects. Frozen products and deglycerolized products are not allowed.”
How will the Blood Bank “create an inventory” of blood for a randomized subject?
The deliberate aging of blood is most problematic: blood is a valuable, scarce resource.
Deliberately aging blood will result in less available blood overall because more blood will likely expire before its safe use. In addition, since blood looses function and viability with age it is not a desirable feature to build into a protocol to let it get older without using it if needed.
Will this protocol require using the Red Cross blood bank to obtain enough old and new blood?
Has the Red Cross approved this use of their scarce blood resources?
If so, will informed consent be obtained from volunteers who normally donate blood to save lives at the Red Cross and also from the sponsoring hospital volunteers who also usually give blood to save lives?
AHRP believes that blood donors have a right to know and a right to refuse to donate their blood particularly for controversial research purposes.
Vera Hassner Sharav
To: Jerry Menikoff MD (firstname.lastname@example.org); Michael Carome MD
Cc: Francis.Collins@nih.hhs.gov; Margaret Hamburg (MargaretAHamburg@aol.com); Joshua Sharfstein MD (email@example.com); Kathleen.Sebelius@hhs.gov