OHRP letters focus on informed consent issues

Thorough risk descriptions needed

The University of Alabama at Birmingham (UAB) was the most recent in a small list of institutions that received letters of determination from the Office for Human Research Protections (OHRP) of Rockville, MD, about allegations of noncompliance. UAB’s letter was about the SUPPORT study, which randomized premature infants to lower or higher ranges of oxygen levels, and was conducted between 2004 and 2009.

OHRP’s March 7, 2013, letter to Richard B. Marchase, PhD, vice president for research and economic development at UAB, states, “Based on the consent form template and UAB consent forms, we determine that the conduct of this study was in violation of the regulatory requirements for informed consent, stemming from the failure to describe the reasonably foreseeable risks of blindness, neurological damage and death. (As discussed at the end of this letter, participating in the study did have an effect on which infants died, and on which developed blindness.)”

UAB’s media office declined to comment on the letter and study because of pending litigation, but referred IRB Advisor to several letters and editorials, including a New England Journal of Medicine editorial that states, “Through hindsight (and essentially faulting investigators for not informing parents up front of a risk later uncovered by the trial itself), the OHRP investigation has had the effect of damaging the reputation of the investigators and, even worse, casting a pall over the conduct of clinical research to answer important questions in daily practice.”1

OHRP’s top priority is protecting human subjects in research studies, says Ann M. Bradley, press officer, in the Office of the Assistant Secretary for Health, U.S. Department of Health and Human Services.

“OHRP is currently reviewing UAB’s response to its determination letter and will provide further comment when it’s appropriate to do so,” Bradley says.

Another NEJM editorial, by David Magnus, PhD, and Arthur L. Caplan, PhD, said the UAB trial is an example of how comparative effectiveness research can dramatically improve patient care while reducing costs. Prior to the UAB study of oxygen-saturation levels used in very premature infants, the standard of care varied, they write.2

The issues raised by OHRP with the study involve both the study’s risk and the informed consent. SUPPORT investigators believed there was no additional risk to enrolling in the study since the infants would receive levels of oxygen equal to the prevailing standard of care, Magnus and Caplan write.

“Before the study began, there was insufficient evidence to know what oxygen level within the guideline-specified range was best,” they say. “The first problem with the OHRP letter and a good deal of the public outrage that followed is the confusion of the risks of the clinical treatment with the risks of randomization.”

The study’s non-randomized case-control group fared worse than patients enrolled in the study, which would seem to negate the OHRP’s claim that infants enrolled in the study were exposed to greater risk, Magnus and Caplan argue.

Because of these facts, OHRP is mistaken in its assumption that there is increased risk to being enrolled in the trial and, therefore, the investigators did not provide adequate informed consent about that risk, they say.

This kind of faulty logic “poses substantial risk to the conduct of valuable comparative effectiveness research,” the writers conclude.

Additional examples

A review of recent OHRP letters of determination shows additional examples of allegations involving informed consent, risk, and communication of alternatives to research interventions. These include a letter to an Indian hospital in October 2012, in which OHRP alleges in its determination that “subjects were not adequately informed of the alternative procedures or courses of treatment regarding screening for breast cancer or cervical cancer,” and that “subjects were not provided, in writing, with information about the possible alternative of seeking breast or cervical screening outside of the research, as required by HHS regulations at 45 CFR 46.116(a)(4).”

Two letters to U.S. universities, both dated in November 2012, discussed determinations involving inadequate informed consent. One allegation found that the informed consent failed to provide “a description of any reasonably foreseeable risks and discomforts,” and the other letter alleged that the informed consent did not adequately disclose appropriate alternative procedures or courses of treatment that might be advantageous to the subject.

“Specifically, we noted that the informed consent documents of numerous protocols did not include appropriate information regarding the option of obtaining the research intervention outside of the research,” OHRP says in the determination letter.

In each of these cases, OHRP noted the institution’s cooperation with following corrective actions, but to IRB professionals the big question would be how to avoid noncompliance and prevent their institution from being on the receiving end of an OHRP letter of determination.

“Regardless of the amount and type of risk to their research participants, all research team members have a duty to make sure everyone they approach to enroll understands what is involved when they choose to be part of the study,” says Megan A. Foradori, RN, MSN, contractor with Henry M. Jackson Foundation for the Advancement of Military Medicine and research agenda project consultant for the TriService Nursing Research Program in Pittsburgh.

While Foradori says she is unable to comment on specifics of the OHRP letters of determination, she notes that IRBs should look favorably on research teams who can demonstrate that they have gone to great lengths to appropriately explain all factors related to participation.

For instance, in a low-risk study of kidney donor candidates’ decision-making preferences, research nurses who enrolled patients provided a visual aid during informed consent, Foradori explains.

“It’s a schematic of the arms of the study, what was involved at each step for the participant, and the information we would be collecting throughout,” she says. “This not only demonstrated to the participants that we took extra steps to ensure their comprehension, but I believe it also exhibited to our IRB that each participant had a clear understanding of the study protocol, our expectations, and their rights before they enrolled.”

While any research organization that receives an OHRP letter of determination will work hard to answer the allegations and make any corrective actions necessary, this scenario is far from ideal. The best case would be to have policies, procedures, and practices in place that prevent that letter from being sent in the first place. IRBs can assist with this through best practice models, such as using protocol templates that guide investigators through informed consent forms, following regulatory requirements, and from having informed consent experts assist IRBs and investigators with creating and improving the documents.

“OHRP and others concerned with human subjects protections have long urged investigators and institutional review boards to simplify consent forms to focus on essential elements, namely, a description of the study purpose and procedures, the risks and benefits of study participation, and alternatives to research participation, that are required for an enlightened decision about whether to participate,” Bradley says. “The Advanced Notice of Proposed Rulemaking now progressing through HHS would revise the regulations to provide greater specificity about how consent forms should be written and what information they should contain,” Bradley adds. “The goal would be consent forms that are shorter, more readily understood, and less confusing, that contain all key information, and that can serve as an excellent aid to help someone make a good decision about whether to participate in a study.”

Ensuring clearer, simpler informed consent documents is part of the IRB’s role, Foradori notes.

“IRBs, I believe, should take a critical look at the information being provided to potential research participants in submitted protocols,” Foradori says. “And, if there is any indication that there may be room for knowledge gaps, they should require that teams utilize additional tools/methods to clarify the research protocol and resubmit. ”


1. Drazen JM, Solomon CG, Greene MF. Informed consent and SUPPORT. NEJM; Published online: April 17, 2013.

2. Magnus D, Caplan AL. Risk, consent, and SUPPORT. NEJM. Published online: April 18, 2013.