This guidance, when finalized, will represent the Office for Human Research Protections’ (OHRP’s) current thinking on this topic. This guidance does not create or confer any rights for or on any person and does not operate to bind OHRP or the public.
OHRP guidance should be viewed as recommendations unless specific regulatory requirements are cited. The use of the word must in OHRP guidance means that something is required under the Department of Health and Human Services (HHS) regulations at 45 CFR Part 46. The use of the word should in OHRP guidance means that something is recommended or suggested, but not required. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the OHRP at 240-453-6900 or 866-447-4777, or by email at firstname.lastname@example.org.
Date: October 20, 2014
This guidance pertains to nonexempt research involving human subjects that is designed to evaluate treatments or procedures that are medically recognized standards of care. The guidance applies to such research that is conducted or supported by the Department of Health and Human Services (HHS).
This draft guidance explains how to apply the HHS Regulations at 45 CFR Part 46 to studies that are designed to evaluate one or more standards of care. It discusses whether risks are considered risks of research when one of the purposes of the research is the evaluation or comparison of risks associated with standards of care. It also discusses disclosing certain reasonably foreseeable risks to prospective subjects when seeking their informed consent to participate in such research activities. It explains OHRP’s position that in general the reasonably foreseeable risks of research in a study include the already identified risks of the standards of care being evaluated as a purpose of the research when the risks being evaluated are different from the risks some of the subjects would be exposed to outside of the study. Reasonably foreseeable risks must be described to prospective subjects when seeking their informed consent in accordance with 45 CFR 46.116(a)(2).
The draft guidance addresses the following topics:
What are “standards of care”?
What are “risks of research” in studies evaluating risks associated with standards of care?
When is evaluating a risk in a research study considered to be a “purpose” of the research study?
Are the risks of research associated with the purposes of studies of standards of care “reasonably foreseeable risks” that must be disclosed to prospective subjects in the informed consent process?
This draft guidance focuses on reasonably foreseeable risks of research in studies whose purposes include evaluating risks of treatments or procedures that are medically recognized standards of care. The draft guidance does not address the broader topic of identifying all of the risks in studies designed to evaluate treatments or procedures that are medically recognized standards of care. Moreover, it does not provide a comprehensive review of which of such risks will be reasonably foreseeable. Research studies whose purpose is to evaluate treatments or procedures that are medically recognized standards of care could be designed in a variety of ways that can involve research risks to participants that are not unique to studies of this kind.
This draft guidance also does not address what kinds of information about such research must be disclosed to prospective subjects in the informed consent process under the regulatory provision at 45 CFR 46.116(a)(i), which calls for a “statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject’s participation, a description of the procedures to be followed, and identification of any procedures which are experimental.”
On August 28, 2013, HHS held a meeting to receive public input and comment on how an IRB should assess the risks of research involving randomization to one or more treatments within the standard of care for particular medical conditions, and what reasonably foreseeable risks of the research should be disclosed to research subjects in the informed consent process. The meeting proceedings, the public comments made at the meeting, and written comments from the public submitted to HHS have informed the development of this draft guidance.
The meeting and request for public comment followed the initial compliance oversight determination letter resulting from OHRP’s investigation into”The Surfactant, Positive Pressure, and Oxygenation Randomized Trial'” (SUPPORT) clinical trial (http://www.hhs.gov/ohrp/detrm_letrs/YR13/mar13a.pdf). After its investigation, OHRP determined that research subjects were not adequately informed of certain risks related to the interventions being studied in the SUPPORT trial that HHS regulations for the protection of human subjects require to be disclosed. OHRP's view of the SUPPORT trial, as described in this determination letter, triggered extensive public discussion and raised a number of questions, including: (1) what risks to subjects are presented by clinical trials studying interventions that are standard of care in the clinical treatment context, such that an IRB must evaluate those risks in relation to the anticipated benefits of the research; and (2) how an IRB should assess whether those risks are reasonably foreseeable such that the risks must be described to subjects in the informed consent process. Because of the differing views in the scientific, ethics, and research communities about how HHS regulations for the protection of human subjects should apply to research studying standard of care interventions, OHRP is now issuing this guidance in the hope that this will provide more clarity.
This draft guidance document focuses on research studies whose purposes include evaluating risks of treatments or procedures that are medically recognized standards of care, and clarifies OHRP’s interpretation that certain risks of standards of care generally must be disclosed to prospective subjects as reasonably foreseeable risks of research when seeking their informed consent in accordance with 45 CFR 46.116(a)(2). It does not encompass all of the reasonably foreseeable risks of research that should be disclosed, but rather focuses on certain reasonably foreseeable risks that are associated with a purpose of the research. OHRP is seeking public comments on this draft guidance. OHRP will take these comments into consideration before issuing a final guidance document on this topic.
The general public, IRBs, investigators, research administrators and other relevant institutional officials and funding agencies that may be responsible for review or oversight of human subjects research conducted or supported by HHS.
The HHS regulations include the following provision regarding the requirement for IRBs to evaluate and identify the risks of research in order to approve the research:
Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result. In evaluating risks and benefits, the IRB should consider only those risks and benefits that may result from the research (as distinguished from risks and benefits of therapies subjects would receive even if not participating in the research). The IRB should not consider possible long-range effects of applying knowledge gained in the research (for example, the possible effects of the research on public policy) as among those research risks that fall within the purview of its responsibility. (45 CFR 46.111(a)(2)) (emphasis added)
The HHS regulations for the protection of human subjects (45 CFR part 46) also include the following provision regarding the disclosure of information about the reasonably foreseeable risks of the research in the process of obtaining the informed consent of the subjects:
(a). Basic elements of informed consent. Except as provided in paragraph (c) or (d) of this section, in seeking informed consent the following information shall be provided to each subject:”
(2) A description of any reasonably foreseeable risks or discomforts to the subject;” (45 CFR 46.116(a)(2))
Advances in healthcare interventions have led to an increasing number of treatments and procedures that are available to clinicians and their patients as medically recognized standards of care. Adequate knowledge about the effectiveness and risks of standards of care is sometimes lacking, and in recent years research studies designed to evaluate such treatments and procedures have become commonplace. Many of these standards of care are based on some degree of evidence and expert opinion, but often they are not based on rigorous and robust clinical trials. Sometimes there is more than one standard of care being used to treat the same medical condition.
Research studies that are designed to evaluate two or more standards of care are often referred to as “comparative effectiveness research” or studies of “the standard of care.” Research comparisons of different standards of care for the same condition are conducted for various reasons, including assessing possible differences in outcomes, risks and benefits between two standards of care. In such studies it is reasonable to expect that one standard of care may be found to be better or worse than another. This may be especially true when a study is designed to target a particular risk for evaluation. The risks associated with the standards of care being compared may differ substantially from each other, as is commonly the case with different accepted ways of treating a medical problem.
For example, in a study comparing two standards of care in which one involves surgery and the other involves drug treatment, the qualities of the risks are quite different from each other. In addition, standards of care being compared in a study can potentially pose different levels or amounts of risk, and the research can involve greater than minimal risk for research subjects. For example, one surgical procedure might offer the prospect of a better result than another, but also involve a greater risk of a particular bad outcome. The merits of devoting the resources needed to carry out such studies, and the ethical justification for asking prospective subjects to agree to participate in them, depend on there being real uncertainty about the outcomes of the studies in terms of meaningful differences in harms or benefits that may result from receiving one standard of care versus another. In some cases there is little or no existing evidence from prior clinical trials directly comparing the risks and benefits of specific different standards of care.
As comparative effectiveness research has become more common, so, too, have questions about how the HHS human subject protection regulations (45 CFR Part 46) apply to such research. There is uncertainty among some people about which risks should be determined to be reasonably foreseeable risks and how they should be described to prospective subjects in the process of informed consent. OHRP’s general position is that in research studies designed to evaluate the risks of standards of care: (1) the risks of standards of care that at least some subjects would be exposed to by participating in a research study that are different from the risks of therapies the subjects would be exposed to outside the study are risks of the research that the IRB must consider when evaluating the research (45 CFR 46.111(a)(2)); and, (2) the identified risks the research proposes to evaluate as one of the purposes of the study are reasonably foreseeable risks that generally must be disclosed to prospective subjects when seeking their informed consent (45 CFR 46.116(a)(2)).
1. What are “standards of care”?
In this guidance, the term “standard of care” is used to refer to medically recognized standards of care. Medically recognized standards of care are treatments or procedures that have been accepted by medical experts as appropriate treatments or procedures for a given type of disease or condition and are commonly used by healthcare professionals. The medical recognition of standards of care is typically represented by publication in a peer-reviewed journal or some form of recognition by a professional medical society. The evidentiary bases for these recognized standards of care vary. Clinical practice guidelines, which represent standards of care, are based on evidence that may include one or more properly randomized controlled trials, cohort or case-controlled analytical studies, or opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees. Consequently, the amount and quality of existing evidence on the risks associated with the standards of care being evaluated in proposed studies varies significantly from study to study. The standard of care being evaluated may be a treatment or procedure involving an intervention or interaction with the human subject, or a procedure for obtaining information about that subject. This guidance focuses on how the HHS regulations for the protection of human subjects in research apply to research whose purposes include evaluating risks of such standards of care.
2. What are “risks of research” in studies evaluating risks associated with standards of care?
The HHS regulations refer to the risks of research by stating:
In evaluating risks and benefits, the IRB should consider only those risks and benefits that may result from the research (as distinguished from risks and benefits of therapies subjects would receive even if not participating in the research…. (45 CFR 46.111(a)(2)).
The term “risk” refers to the likelihood that research harms or discomforts will occur, and to the nature and magnitude of those harms or discomforts. The risks of research in a study include those risks of therapies that some participating subjects would face that are or could be different from the risks of therapies they would have faced without participating in the research study.
In standard of care studies, OHRP generally considers the risks of a specific standard of care being evaluated to be risks of research if (1) a standard of care that at least some of the individual subjects will be assigned to receive will be different from the standard of care that they would have received if they were not participating in the study, and (2) there might be different risks associated with those standards of care. Therefore, in such studies, the possible differences in risk being evaluated are considered risks of the research. In fact, studies designed to evaluate the risks of standards of care often hypothesize that the risks associated with one standard of care being evaluated might be different from the risks associated with another standard of care. The particular risks that the subjects will be exposed to because of being assigned to a specific standard of care are risks the subjects will be exposed to for the sake of the research.
When a research study assigns the specific version of the accepted standards of care to be used, it is almost certain that at least some of the subjects will receive a different standard of care than they would have received if not participating in the research. Indeed, in the common study design where subjects are randomized equally between two treatments, approximately half of the subjects will be assigned to a treatment different from what they would have otherwise received.
It is equally important to recognize that the risks of the research do not include the risks that are created by the medical condition for which the person is being treated, or the risks associated with any available standard of care treatment that they would receive for that condition outside of the research.
Thus, if an observational study compares two standards of care that are chosen by individuals with a given medical condition in consultation with their clinical care providers, and the research plan does not assign subjects to any specific standard of care, then the risks of the standards of care are not risks of research. In this case, the risks of the standards of care are the same risks that the subjects would have been exposed to without participating in the research study. Exposure to the risks of the standard of care occurs as a matter of clinical care in this example, and not because of study participation. The only risks of the study are those associated with the research data collection and analyses of that data.
3. When is evaluating a risk in a research study considered to be a “purpose” of the research study?
The purposes of research are the aims or objectives that determine the design of the research study and provide the scientific and ethical justification for carrying it out. The evaluation of a risk is considered a purpose of the research when a research study is designed and conducted in order to ascertain the existence, extent or nature of a particular harm. If a study is designed to discover the degree to which that particular harm will or will not occur, the possibility of that harm occurring is clearly foreseen by those responsible for the design and conduct of the study. The risks should accordingly be disclosed to the people who are being asked to be exposed to that risk as subjects in the study.
In the context of research evaluating standards of care, the evaluation of the risks in studies comparing standards of care that OHRP generally considers to be identified as “purposes” of the research should be limited to evaluating those risks that are sufficiently important to justify the conduct of the study. The purposes of such studies should not be construed as necessarily including each and every one of the outcomes that may be measured as part of the study, but that are not part of the fundamental reasons for conducting the study. Nor is the evaluation of any risk that is simply unknown or unrecognized to be considered a purpose of a research study. Only if the research study is deliberately designed to provide evidence about a particular identified risk is the evaluation of that risk to be considered a purpose of the research. For example, if a research study is designed to include enough subjects to enable the analysis of the data to draw statistically significant conclusions about a particular risk, this would be a basis for considering the evaluation of that risk to be a purpose of the research.
4. Are the risks of research associated with the purposes of studies of standards of care “reasonably foreseeable risks” that must be disclosed to prospective subjects in the informed consent process?
The HHS regulations require that prospective subjects must be informed of the reasonably foreseeable risks of the research, so that they can take this into account in deciding whether or not to participate. Individuals being asked to consent to participate in such a research study may have preferences with respect to risks to which they might be willing to be exposed. The regulations include the following requirement for the disclosure of risks as part of the informed consent process:
(2) A description of any reasonably foreseeable risks or discomforts to the subject; (45 CFR 46.116(a)(2))
If evaluating a particular risk of research associated with a standard of care is a purpose of the research, then in general OHRP considers that particular risk to be “reasonably foreseeable.” Such reasonably foreseeable risks must be disclosed as risks in the informed consent process in accordance with the regulatory requirements of 45 CFR 46.116(a)(2).
Just as with research evaluations of the risks of experimental treatments or procedures, if the rationale for evaluating a risk associated with a standard of care is sufficient to warrant conducting the research, then OHRP’s view is that, in general, the research risk being evaluated has been recognized as a sufficiently possible outcome so as to make it a “reasonably foreseeable” risk, and the regulatory provision applies. If researchers design and conduct a study for the purpose of evaluating a particular risk, then that risk is significant enough that it should be disclosed to the prospective subjects who are actually exposed to it. Prospective subjects ought to be informed of a particular risk that they may be exposed to, if a research study is evaluating that risk and the subjects could avoid it if they were to decide not to participate.
Consider this hypothetical example: It is known that treatment using surgery and radiation has a high likelihood of curing a particular form of childhood cancer, but that the radiation produces a significant risk of other cancers developing later in the child’s life. Consequently, some doctors treating children with this cancer use a smaller amount of radiation. Both amounts of radiation are consistent with clinical care guidelines and considered to be within the standard of care. There is little evidence available comparing the outcomes of the two treatments in terms of their cure rates or the development of later cancers. A randomized clinical trial is proposed with subjects to be assigned to treatment with the higher or lower amount of radiation to compare the effectiveness of the two treatments in curing the current cancer and how often later cancers occur. Parents should receive and evaluate appropriate information before deciding whether to permit their child to participate in this greater-than-minimal-risk study. This decision is important and consequential. They should be told about the reasonably foreseeable risks of the study, that the treatment with the larger amount of radiation poses a possibly increased risk of cancer in later life, and that the treatment with the smaller amount of radiation poses a possibly increased risk of the original cancer not being cured.
In summary, if a research study examining standards of care includes as a purpose evaluating identified risks associated with those standards of care, the identified risks associated with the standards of care being evaluated that are different from the risks of standards of care at least some of the subjects would be exposed to outside of the research study are generally considered by OHRP to be reasonably foreseeable risks of research. Reasonably foreseeable risks must be described to prospective subjects when seeking their informed consent (45 CFR 46.116(a)(2)). All standards of care do not pose identical risks, either in terms of the nature or the degree of the risks, and individuals often may have reasons to prefer the risks of one standard of care over the risks of another. Disclosing the reasonably foreseeable risks of research to prospective subjects recognizes the ethical obligation to give prospective subjects sufficient information to make a knowledgeable decision about whether or not to participate. This reflects the ethical principle of respect for persons, which recognizes the importance of giving individuals sufficient information during the informed consent process to make a considered judgment about whether to participate in research that could affect their health or wellbeing—for better or worse.
If you have specific questions about how to apply this guidance, please contact OHRP by phone at (866) 447-4777 (toll-free within the United States) or (240) 453-6900, or by e-mail at email@example.com.