What should parents be told before their premature infants participate in a clinical study?
For the second time in four months, the consumer group Public Citizen is alleging that a large, federally funded study of premature infants is ethically flawed.
Both complaints raise a big issue that's certain to get more attention beyond these particular studies: What's the ethically right way to do research on the validity of the usual care that doctors provide every day.
The U.S. Department of Health and Human Services will host an unusual forum on that question next Wednesday — stimulated by the sharp questions raised by Public Citizen.
This time around, the group is focusing on a study called TOP, short for Transfusion of Prematures. The project hopes to enroll more than 1,800 severely premature infants to test when blood transfusions should be given to treat anemia, a common and serious problem for tiny newborns.
The study randomly assigns preemies to one group that will get transfusions when their anemia is relatively mild or another that will wait until the disorder is severe. Researchers want to see which approach is better at reducing deaths and brain damage.
The study is very similar in approach to a 2010 trial called SUPPORT, which tested two different regimens for providing oxygen to 1,300 premature infants to see which one was less likely to cause blindness while avoiding death. That's not surprising, since both studies are being conducted by the same federally sponsored Neonatal Research Network involving many of the same institutions.
As in its criticism of the earlier SUPPORT study, Public Citizen says the TOP investigators aren't informing parents of the risks to their infants compared to usual care, when preemies' treatment is tailored to each situation. The group also criticizes the design of the TOP study, which does not set up a comparison group that receives usual, customized care.
In a 20-page letter to Health and Human Services Secretary Kathleen Sebelius, Public Citizen calls for an immediate halt to the study "due to the serious deficiencies in the consent forms and unresolved questions about the ethics of the study design."
The National Institutes of Health is defending the study — just as National Institutes of Health Director Francis Collins in June defended SUPPORT.
The TOP study of anemia and transfusion timing "is an important study that adheres to the highest ethical and clinical standards," the NIH says in an email to Shots.
"NIH is committed to ensuring that prospective research participants — and the people who speak for and love them — are given clear, complete and accurate information about the risks and benefits of participating in research," the statement continues.
It notes that the consent forms provided to parents at the 19 medical centers in the TOP study were all approved by their federally required Institutional Review Boards.
But that's one of the points of contention raised by Public Citizen's complaint.
The group says IRBs weren't given enough information to judge whether the proposed study is ethical. Its letter to Sebelius says ethics committees weren't told how much transfusion practices in the trial "deviate from the usual care ... and the risks thereby posed by these deviations."
The complaint also alleges that a committee set up to monitor the TOP study as it unfolds can't do the job because there's no comparison group of infants receiving "usual care." Such "data safety and monitoring boards" are charged with reviewing what happens to research subjects during the study, and are empowered to call a halt if some are doing significantly worse (or better) than others, or patients outside the study.
But the brunt of Public Citizen's criticism is that parents being asked to enroll their infants in TOP are not being told the whole story of the risks they might face. For instance, consent forms do not tell parents about the results of two previous studies of the when-to-transfuse question, which suggested that infants who got transfused late had higher incidence of death, brain injury and need for emergency transfusions.
Public Citizen notes that consent forms contain statements such as "This study does not carry any additional risk to your baby," "There are no known risks at this time to participation in this study," and risks "are exactly the same risks that exist in current medical practice."
The consumer group says parents should be told that if their infants are in the study, they will not get the individualized care tailored for their situation.
Ethicist George Annas of Boston University, who will speak at next week's forum, agrees on this point.
"You have to make sure parents understand what you're asking them to do," Annas tells Shots. "The primary thing is you're giving up your right to a physician who makes decisions based on what he or she thinks is in the best interest of your child rather than flipping a coin."
The stakes in sorting out these issues are high. That's why Collins entered the fray in June, disavowing a ruling by an HHS ethics panel that criticized the SUPPORT study. Dozens of medical researchers and ethicists have also rallied around the SUPPORT investigators.
But an editorial in this week's Nature strongly sides with the critics of SUPPORT and those who say full informed consent shouldn't be fudged when doing studies that test standard practices.
"Such 'standard of care' trials are likely to become more widespread," the editorial notes, "after being mandated in the 2010 health care law."