[Federal Register Volume 79, Number 206 (Friday, October 24, 2014)]
[Notices]
[Pages 63629-63634]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2014-25318]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES


Draft Guidance on Disclosing Reasonably Foreseeable Risks in 
Research Evaluating Standards of Care

AGENCY: Office of the Secretary, Office of the Assistant Secretary for 
Health, Office for Human Research Protections, Department of Health and 
Human Services (HHS).

ACTION: Notice.

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SUMMARY: The Department of Health and Human Services (HHS), through the 
Office for Human Research Protections (OHRP) is announcing the 
availability of a draft guidance for the research community entitled 
``Guidance on Disclosing Reasonably Foreseeable Risks in Research 
Evaluating Standards of Care.'' OHRP is specifically addressing what 
risks to subjects are presented by research evaluating or comparing 
risks

[[Page 63630]]

associated with standards of care, and which of these risks are 
reasonably foreseeable and should be disclosed to prospective research 
subjects as part of their informed consent. OHRP is soliciting written 
comments from all interested parties, including, but not limited to IRB 
members, IRB staff, institutional officials, research institutions, 
investigators, research subject advocacy groups, ethicists, the 
regulated community, and the public at large. This draft guidance 
represents OHRP's current thinking on this topic.
    Certain treatments and procedures that are commonly used in health 
care for a given type of disease or condition have come to be known as 
``standards of care.'' Multiple ``standards of care'' involving widely 
differing treatments and risks may be available for the same disease or 
medical condition. Where multiple ``standard of care'' options are 
available for a given disease or condition, the use of the term does 
not imply that the options will produce similar benefits or incur 
similar risks. Furthermore, patients may not find those options equally 
acceptable, nor do physicians always use them interchangeably. 
Importantly there is not necessarily a limit on how different the risks 
from two versions of a standard of care might be. For example, it may 
already be known that one of those versions imposes a significantly 
higher risk of death than the other.
    Adequate knowledge about the effectiveness and risks of standards 
of care and how these standards compare to each other is sometimes 
lacking. In recent years research studies designed to evaluate such 
treatments and procedures have become commonplace. These studies are 
often called ``comparative effectiveness research'' or ``standard of 
care research.''
    As this type of 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 in the 
research community about which risks of the research should be 
determined to be reasonably foreseeable risks of research and how they 
should be described to prospective subjects in the process of informed 
consent. OHRP's interpretation of the HHS research regulations has been 
that if people are being asked to undergo procedures in a research 
study that involve risks that they would not otherwise be exposed to, 
these are `research risks' that people must be informed about. Only in 
that way are they able to make a truly informed decision about whether 
they are willing to participate. For comparative effectiveness or 
standard of care research, OHRP's general position is that the 
reasonably foreseeable risks of research include 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 
subjects would be exposed to outside of the study. This guidance 
addresses these issues in the form of frequently asked questions. OHRP 
will consider comments received before issuing the final guidance 
document.

DATES: Submit written comments by December 23, 2014.

ADDRESSES: Submit written requests for single copies of the draft 
guidance document entitled, Disclosing Reasonably Foreseeable Risks in 
Research Evaluating Standards of Care to the Division of Policy and 
Assurances, Office for Human Research Protections, 1101 Wootton 
Parkway, Suite 200, Rockville, MD 20852. Send one self-addressed 
adhesive label to assist that office in processing your request, or fax 
your request to 301-402- 2071. See the SUPPLEMENTARY INFORMATION 
section for information on electronic access to the draft guidance 
document.
    You may submit comments identified by docket ID number HHS-OPHS-
2014-0005 by one of the following methods:
    Federal eRulemaking Portal: http://www.regulations.gov. Enter the 
above docket ID number in the Enter Keyword or ID field and click on 
``Search.'' On the next page, click the ``Submit a Comment'' action and 
follow the instructions.
    Mail/Hand delivery/Courier [For paper, disk, or CD-ROM 
submissions]: Irene Stith-Coleman, Ph.D., Office for Human Research 
Protections, 1101 Wootton Parkway, Suite 200, Rockville, MD 20852.
    Comments received, including any personal information, will be 
posted without change to http://www.regulations.gov.

FOR FURTHER INFORMATION CONTACT: Irene Stith-Coleman, Ph.D., Office for 
Human Research Protections, Department of Health and Human Services, 
1101 Wootton Parkway, Suite 200, Rockville, MD 20852; phone 240-453-
6900; email Irene.Stith-Coleman@hhs.gov.

SUPPLEMENTARY INFORMATION: 

I. Background

A. HHS Protection of Human Subjects Regulations

    HHS, through OHRP, regulates research involving human subjects 
conducted or supported by HHS. The HHS human subjects protection 
regulations pertain to several different entities, including the 
institutional review board (IRB) charged with reviewing non-exempt 
human subjects research.
    The IRB is an administrative body that takes the form of a board, 
committee, or group, and is responsible for conducting the initial and 
continuing review of research involving human subjects. The IRB must 
have authority to approve, require modification of (in order to secure 
approval), or disapprove all research activities regulated by HHS as 
required by 45 CFR 46.109(a). An IRB's primary purpose in reviewing 
research is to ensure the protection of the rights and welfare of human 
research subjects. In order to approve research, an IRB is required to 
make certain determinations, including that the following 46.111(a)(2) 
criterion is met:

    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 HHS human subjects protections regulations further require that 
an investigator must obtain informed consent from research subjects 
prior to the subjects' participation in the research, unless this 
requirement is waived by the IRB. In this informed consent process, the 
subjects must be provided with ``a description of any reasonably 
foreseeable risks or discomforts to the subject'' as required by 
46.111(a)(4) and 46.116(a)(2).

B. OHRP's Compliance Oversight Investigation of SUPPORT

    On March 7, 2013, OHRP issued a compliance oversight determination 
letter regarding its investigation into ``The Surfactant, Positive 
Pressure, and Oxygenation Randomized Trial'' (SUPPORT) (http://www.hhs.gov/ohrp/detrm_letrs/YR13/mar13a.pdf). OHRP determined that 
certain risks related to the interventions being studied in the SUPPORT 
trial were required by 45 CFR part 46 to be disclosed to the research 
subjects, and that the subjects were not informed of these risks. 
OHRP's view of the SUPPORT trial, as described in this determination 
letter, triggered extensive public discussion regarding (1) what risks 
to subjects are presented by clinical trials studying interventions 
that are standards of care in the clinical

[[Page 63631]]

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 prospective subjects as part of 
obtaining a person's informed consent.
    The critical disagreement in the research community relates to the 
issue of what risks must be disclosed to prospective subjects in a 
research study where participants will be receiving a treatment that is 
different from the treatment they would have received outside the 
study, but still within the range of ``standard of care'' that some 
doctors use for clinical purposes. Multiple ``standards of care'' 
involving widely differing treatments and risks may be available for 
the same disease or medical condition. Where multiple ``standard of 
care'' options are available for a given disease or condition, the use 
of the term does not imply that the options will produce similar 
benefits or incur similar risks. Furthermore, patients may not find 
those options equally acceptable, nor do physicians always use them 
interchangeably. Importantly there is not necessarily a limit on how 
different the risks from two versions of a standard of care might be. 
For example, it may already be known that one of those versions imposes 
a significantly higher risk of death than the other.
    In the SUPPORT trial, an infant had a 50% chance of being assigned 
to the ``lower oxygen'' arm (where the oxygen saturation percentage 
would be maintained between 85% and 89%) or the ``higher oxygen'' range 
(between 91% and 95%). The level of oxygen the infants received was 
chosen by randomization. This design was intended to move these infants 
far enough away from the center value (90%), so that the differences in 
the amount of oxygen the two groups received would allow detection of 
different health outcomes in the groups. Therefore, for the great 
majority of infants in the trial, it is likely that their participation 
altered the level of oxygen they received compared to what they would 
have received had they not participated. Some in the research community 
maintain that because the lower (85% to 89%) and higher (91% to 95%) 
ranges of oxygen saturation provided to the infants were within the 
standard of care range, there were no known risks to participants in 
the study from being randomized to these two oxygen saturation levels. 
OHRP disagrees with this perspective, and maintains that the key issue 
is that the treatment and possible risks infants were exposed to in the 
research were different from the treatment and possible risks they 
would have been exposed to if they had not been in the trial, not that 
the treatment provided in the trial was within the standard of care. 
OHRP's interpretation of the research regulations has been that, if a 
person in a research study is being asked to undergo procedures that 
involve reasonably foreseeable risks that they would not have otherwise 
been exposed to, then that person needs to be told about those risks. 
Only in this way can people make a truly informed decision about 
whether they are willing to participate.
    OHRP has become aware, through the public reaction to OHRP's 
determination letter, of differing perspectives in the scientific, 
research, and ethics communities about these issues and how the 
relevant requirements of the HHS protection of human subjects 
regulations should apply to research studying standard of care 
interventions. This draft guidance is intended to clarify how to apply 
the HHS regulations at 45 CFR part 46 to studies that are designed to 
evaluate one or more standards of care.

C. Public Meeting

    On August 28, 2013, a public meeting was held at the HHS Hubert H. 
Humphrey Building to provide an opportunity for broad public 
participation and public comments concerning how the HHS human subjects 
protections requirements should be applied to research studying one or 
more interventions which are used as standard of care treatment in the 
non-research context. HHS specifically requested input regarding how an 
IRB should assess the risks of research involving randomization to one 
of more standard of care interventions, and what reasonably foreseeable 
risks of the research should be disclosed to research subjects in the 
informed consent process. The public meeting and comments were intended 
to assist OHRP in developing guidance regarding what constitutes 
reasonably foreseeable risk in research involving standard of care 
interventions such that the risk is required to be disclosed to 
research subjects. There were 27 oral presentations at the public 
meeting and 72 written comments submitted during the open comment 
period of June 26, 2013 through September 9, 2013.
    The meeting was conducted by HHS officials, including the Director 
of OHRP. The meeting was reserved for presentations of comments, 
recommendations, and data from presenters. The time for each 
presentation was 7 minutes. The allocation of time was based on the 
number of registered presenters. Presenters were scheduled to speak in 
the order in which they registered. Only HHS panel members questioned 
presenters during or at the conclusion of their presentation. The 
meeting was recorded and transcribed. The recording and transcription 
are accessible through the OHRP Web site, http://www.hhs.gov/ohrp/newsroom/rfc/Public%20Meeting%20August%2028,%202013/aug28public.html. 
In addition to materials submitted for discussion at the public 
meeting, individuals were offered the opportunity to submit other 
written comments after the public meeting. All submitted comments were 
considered by HHS during the guidance development phase. A discussion 
of the public comments is below.

II. Discussion of Public Comments

    HHS invited comments at the public meeting regarding how an IRB 
should assess the risks of research involving randomization to one or 
more standard of care interventions, and which research risks should be 
disclosed to subjects in the informed consent process. HHS was 
specifically interested in public input on the following questions:
    1. How should an IRB assess the risks of standard of care 
interventions provided to subjects in the research context?
    a. Under what circumstances should an IRB consider those to be 
risks that may result from the research?
    b. Under what circumstances should an IRB refrain from considering 
those risks as unrelated to the research?
    c. What type of evidence should an IRB evaluate in identifying 
these risks?
    Several commenters presented arguments for always disclosing 
standard of care risks to potential subjects of a clinical trial. Many 
felt that all risks, including those of the standard of care, must be 
disclosed in order to allow subjects and parents of subjects to make a 
fully informed choice to participate in research. Some expressed the 
view that the risks of standard of care interventions are magnified 
when incorporated into a clinical trial, and to mitigate the potential 
harms these commenters recommended mandating data safety monitoring 
plans to detect and identify perceived reasonable foreseeable risk. The 
outcome measures produced from data safety monitoring plans would 
identify the reasonably foreseeable risks of the research.
    Opposing arguments were expressed against incorporating standard of 
care

[[Page 63632]]

risks for clinical intervention as risks of standard of care or 
comparative effectiveness research. Many commenters stated that it is 
inaccurate to describe standard of care intervention risks as research 
risks, and that good evidence of such risks is often lacking; they 
pointed out that many widely used medical practices are based on 
clinician judgments alone. Proponents of this view expressed the 
opinion that IRBs should not require standard of care risks to be 
disclosed as research risks, but rather, indicated that standard of 
care inventions should be addressed in the clinical treatment consent 
prior to enrolling potential subjects in the clinical trial.
    Response: OHRP agrees that to the extent participation in a 
clinical trial does not impose risks that are different from those to 
which a subject would have been exposed had they not been in the trial, 
those risks should not be considered risks attributable to the 
research. The key issue is not whether an intervention provided to 
subjects is within a standard of care, but whether the treatment a 
subject receives (and thus the risks they are exposed to) is different 
from that which these subjects would have been exposed to outside of 
the research study. The risks that result from such a difference in 
treatment are risks derived from participation in the research study. 
Patients randomized to different standards of care in a comparative 
effectiveness trial should accordingly be made aware of the risks of 
the standards of care that are being compared. OHRP agrees that the 
distinction between receiving clinical care and participating in 
research must be made clear to subjects.
    2. What factors should an IRB consider in determining that the 
research-related risks of standard of care interventions, provided to 
research subjects in the research context, are reasonably foreseeable 
and therefore required to be disclosed to subjects?
    Many commenters recommended first defining the term ``standard of 
care'' prior to defining the term ``reasonably foreseeable risk.'' 
Various commenters stated that the term ``standard of care'' is used to 
refer to a medically recognized standard of care that has been accepted 
by medical experts as a proper treatment or procedure for a given 
disease or condition, and been widely used by healthcare professionals. 
These commenters pointed to the need for an evidentiary basis for a 
given standard of care, and felt that whether it was acquired through 
publication, through conduct of randomized clinical trials, or through 
expert opinion, the basis for assessing standard of care may vary 
throughout the medical community, and therefore the research and other 
evidence regarding the associated risks of a standard of care being 
evaluated may vary as well.
    The varying definitions for ``reasonably foreseeable risk'' 
presented in the comments were representative of the lack of consensus 
of the interpretation of the term among the experts in the medical and 
clinical research community.
    Several commenters identified a number of kinds of standards and 
quantitative measures to help define reasonably foreseeable risks. The 
proposed levels of evidence offered by the commenters included clinical 
trial evidence, peer and literature review analysis, professional prior 
experience, risk and benefit ratio analyses and baseline risks of the 
identified population. A few commenters expressed the view that 
reasonably foreseeable risks are those risks supported in peer reviewed 
medical literature that occur in 5% of the patients or that hold p-
values of less than 0.10 in one or more trials.
    One comment stated, ``events for which one can hypothesize a 
plausible risk but which have not been shown to be caused by the 
intervention should not be classified as reasonably foreseeable.'' 
Other commenters were opposed to attempting a suggested definition.
    There was an overall agreement among the commenters about 
disclosing research risks of standard of care treatment to the 
prospective participants, but disagreement on where in the informed 
consent document this information should be disclosed.
    Response: OHRP believes that all research and other evidence 
underlying medically recognized standards of care should be given 
appropriate consideration in determining whether risks are reasonably 
foreseeable. The draft guidance does not address specific quantitative 
approaches to evaluating or identifying reasonably foreseeable risk. 
With regard to which risks should be considered ``reasonably 
foreseeable,'' OHRP concluded that at a minimum, identified risks 
associated with a standard of care that are being evaluated as a 
purpose of the research, should certainly be considered ``reasonably 
foreseeable.'' A core purpose of the Common Rule is to allow 
prospective subjects to make informed decisions about whether to 
participate in research. If a specific risk has been identified as 
significant enough that it is important for the Federal government to 
spend taxpayer money to better understand the extent or nature of that 
risk, then that risk is one that prospective subjects should be made 
aware of so that they can decide if they want to be exposed to it. It 
would be seem inappropriate to have both the federal agency funding a 
study and the researchers conducting it aware of an identified risk, 
and yet not disclose that risk to the very subjects who would be 
exposed to it, while at the same time claiming that their ``informed'' 
consent to participation has been obtained in a very meaningful way.
    3. How should randomization be considered in research studying one 
or more interventions within the standards of care? Should the 
randomization procedure itself be considered to present a risk to the 
subjects? Why or why not? If so, is the risk presented by randomization 
more than minimal risk? Should an IRB be allowed to waive informed 
consent for research involving randomization of subjects to one or more 
standard of care interventions? Why or why not?
    Many commenters felt that randomization alone does not pose a 
research risk, while others disagreed. In certain instances, some 
commenters said that randomization can impose harms to research 
subjects. One commenter stated that ``if a research study involves 
random assignment of two different interventions that are sometimes 
used for treating an acute stroke, and death and neurological 
impairment are the primary endpoints being measured in the study, such 
research should be considered to present much greater than minimal risk 
to subjects.'' A subset of commenters expressed that such outcomes 
should be made clear in the informed consent process and document. One 
commenter stated ``research involving randomization to one or more 
standard of care interventions should follow the same requirements for 
informed consent as other research studies and should not be assumed to 
involve no more than minimal risk.''
    Some commenters recommended that clinical trials involving 
randomization should not be permitted to waive informed consent for 
subjects involving standard of care interventions. One commenter 
suggested that the use of randomization with waiver of consent deprives 
subjects of the trust inherent in the doctor-patient relationship.
    A small subset of commenters cited the loss of autonomy of the 
research participant by incorporating randomization in a protocol. When 
people are randomly assigned to one of a number of different standards 
of care, they forego the ability to choose which standard of care they 
prefer.

[[Page 63633]]

    However, other comments indicated that consent could be waived for 
standard of care trials. One commenter stated, ``waivers of consent for 
randomization are appropriate, ethically defensible and necessary in 
the case of comparing two standards of care interventions in some 
cases'' and that ``waiving consent requires active and innovative ways 
to engage the community and reach patients.''
    In addition to the ethical defensibility for waiver of consent, one 
commenter expressed that there is nothing inherent in randomization 
that should preclude consideration of a waiver. ``Most research 
involving prospective randomization seems likely to require informed 
consent; because it seems unlikely that the research would meet the 
46.116 requirement that the IRB finds that the research couldn't 
feasibly be carried out without a waiver of consent. However, the IRB 
should be allowed to waive informed consent for any research that does 
meet all the waiver criteria.''
    Others comments stressed that waiver of consent does not eliminate 
the duty to communicate with the research participant about the risks 
and benefits of a study. A few commenters expressed that potential 
research participants should be informed of randomization but that 
there is no reasonable evidence that randomization increases risk. 
However, the lack of evidence regarding the risk of randomization does 
not justify the use or prohibition of waiver of informed consent.
    Response: The draft guidance treats randomization no differently 
than any other mechanism by which a research subject may be assigned to 
a particular treatment. The underlying question, as discussed above, is 
whether, in the study, a subject will be assigned to a treatment whose 
risks may be different from the risks they would have been exposed to 
outside of the trial. If that happens--whether it is by randomization 
or some other study design (e.g., all of the subjects could be assigned 
to the same treatment, with no randomization at all)--then those 
differences in risks are risks relating to participating in the 
research. Thus, in this sense, there are no ``special'' or unique risks 
to randomization. The thing that matters is whether participating in 
the study may expose a subject to risks that are different from those 
they would otherwise have been exposed to.
    4. How, and to what extent, does uncertainty about risk within the 
standard of care affect the answers to these questions? What if the 
risk significantly varies within the standard of care?
    One commenter stated that the fact that there is uncertainty about 
differences in the proposed primary and secondary outcomes between two 
or more groups receiving different interventions being tested in a 
clinical trial is one reason that such research involves foreseeable 
risks to the subjects. If there were no such uncertainty, there would 
be no reasonable basis for conducting the research in the first place, 
and it would be unethical to do so. Others felt that uncertainty alone 
does not affect the risks of standard of care research to a research 
subject because risks of the standard of care do not affect research 
risk, regardless of the magnitude or certainty of the risks of the 
standard of care.
    Other comments in this area addressed models for research risk 
disclosure, such as a transparency model in which investigators would 
``explain to potential research participants what scientists and 
physicians think they know, commonly believe and the basis for such 
knowledge and beliefs.''
    Response: The draft guidance does not address the issue of 
uncertainty of risk associated with standard of care or comparative 
effectiveness research overall. However, the guidance does indicate 
that when one of the purposes of the research is the evaluation or 
comparison of risks associated with standards of care, and the risks of 
the standard of care received by the subjects are different from those 
risks the subjects would be exposed to outside of the research, then 
these risks should be considered to be reasonably foreseeable.
    5. Under what circumstances do potential risks qualify as 
reasonably foreseeable risks? For example, is it sufficient that there 
be a documented belief in the medical community that a particular 
intervention within the standard of care increases the risk of harm, or 
is it necessary that there be published studies identifying the risk?
    Comments focused on methods to evaluate and identify reasonably 
foreseeable risks, and recommended that the phrases ``reasonably 
foreseeable'' and ``all imaginable'' risks need to be clarified among 
the research community. To assist, one commenter recommended that a 
body of annotated examples, analogous to case law, needed to be created 
for IRBs to use as precedent to evaluate clinical trials. Another 
commenter recommended that IRBs need experts who can evaluate the 
actual risks to subjects.
    Several comments recommended various criteria for identifying 
reasonably foreseeable risks, such as credible evidence, reported 
safety concerns, and ``significant documented belief'' in the medical 
community that a particular intervention would increases the risk of 
harm. Other comments added biological plausibility and clinical 
experience as qualifiers. All submitted comments concurred with the 
need to further evaluate the determination of reasonably foreseeable 
risk.
    Response: As discussed above, the guidance concludes that if 
evaluating a particular risk associated with a standard of care is a 
purpose of the research, then in general that particular risk should be 
considered to be ``reasonably foreseeable.'' 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).
    OHRP recognizes that the available evidence regarding the risks of 
specific standards of care will vary, and may include evidence from one 
or more clinical trials, other research studies, the opinion of 
clinical experts, and the history of clinical practice, all of which 
are taken into account in the formulation of standard of practice 
guidelines. In any case, if a particular identified risk is considered 
significant enough to constitute a rationale for conducting the study, 
then this should in almost all cases imply the conclusion that the risk 
is ``reasonably foreseeable'' for the purposes of these regulations, 
and that it would be mistaken to claim that informed consent was 
obtained if prospective subjects were not made aware of that risk.
General Comments
    Some commenters expressed views not directly related to the 
questions asked by OHRP. Specifically, several commenters made remarks 
directly related to the SUPPORT trial. In addition, other issues of 
concern focused on cluster randomization, consent waivers based on the 
research's potential for public health benefit, and rigorous research 
evaluations. Although the commenters disagreed with specific aspects of 
these topics, they agreed that these issues are growing concerns among 
the research community and should be discussed further.

III. Electronic Access

    Persons with access to the Internet may obtain the draft guidance 
document on OHRP's Web site at http://www.hhs.gov/ohrp/newsroom/rfc/index.html or on the Federal

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Rulemaking Portal at http://www.regulations.gov/.

    Dated: October 21, 2014.
Wanda K. Jones,
Acting Assistant Secretary for Health.
[FR Doc. 2014-25318 Filed 10-23-14; 8:45 am]
BILLING CODE 4150-36-P