Document ID: FDA-2011-S-0009-0001
Agency: fda
Document Type: Proposed Rule
Title: Human Subjects Research Protections: Enhancing Protections for Research Subjects and Reducing Burden, Delay, and Ambiguity for Investigators
Posted Date: 2011-07-26T04:00Z

[Federal Register Volume 76, Number 143 (Tuesday, July 26, 2011)]
[Proposed Rules]
[Pages 44512-44531]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2011-18792]

[[Page 44512]]

=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Office of the Secretary

45 CFR Parts 46, 160, and 164

Food and Drug Administration

21 CFR Parts 50 and 56

Human Subjects Research Protections: Enhancing Protections for 
Research Subjects and Reducing Burden, Delay, and Ambiguity for 
Investigators

AGENCIES:  The Office of the Secretary, HHS, and the Food and Drug 
Administration, HHS.

ACTION: Advance notice of proposed rulemaking.

-----------------------------------------------------------------------

SUMMARY: The Office of the Secretary of the Department of Health and 
Human Services (HHS) in coordination with the Office of Science and 
Technology Policy (OSTP) is issuing this advance notice of proposed 
rulemaking (ANPRM) to request comment on how current regulations for 
protecting human subjects who participate in research might be 
modernized and revised to be more effective. This ANPRM seeks comment 
on how to better protect human subjects who are involved in research, 
while facilitating valuable research and reducing burden, delay, and 
ambiguity for investigators.
    The current regulations governing human subjects research were 
developed years ago when research was predominantly conducted at 
universities, colleges, and medical institutions, and each study 
generally took place at only a single site. Although the regulations 
have been amended over the years, they have not kept pace with the 
evolving human research enterprise, the proliferation of multi-site 
clinical trials and observational studies, the expansion of health 
services research, research in the social and behavioral sciences, and 
research involving databases, the Internet, and biological specimen 
repositories, and the use of advanced technologies, such as genomics. 
Revisions to the current human subjects regulations are being 
considered because OSTP and HHS believe these changes would strengthen 
protections for research subjects.

DATES: To be assured consideration, comments must be received at one of 
the addresses provided below, no later than 5 p.m. on September 26, 
2011.

ADDRESSES: You may submit comments, identified by docket ID number HHS-
OPHS-2011-0005, 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 Web page, click on ``Submit a 
Comment'' action and follow the instructions.
     Mail/Hand delivery/Courier [For paper, disk, or CD-ROM 
submissions] to: Jerry Menikoff, M.D., J.D., OHRP, 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: Jerry Menikoff, M.D., J.D., Office for 
Human Research Protections (OHRP), Department of Health and Human 
Services, 1101 Wootton Parkway, Suite 200, Rockville, MD 20852; 
telephone: 240-453-6900 or 1-866-447-4777; facsimile: 301-402-2071; e-
mail: jerry.menikoff@hhs.gov.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background
II. Ensuring Risk-Based Protections
III. Streamlining IRB Review of Multi-Site Studies
IV. Improving Informed Consent
V. Strengthening Data Protections To Minimize Information Risks
VI. Data Collection To Enhance System Oversight
VII. Extension of Federal Regulations
VIII. Clarifying and Harmonizing Regulatory Requirements and Agency 
Guidance
IX. Agency Request for Information

I. Background

    U.S. Federal regulations governing the protection of human subjects 
in research have been in existence for more than three decades. Twenty 
years have passed since the ``Common Rule,'' (codified at Subpart A of 
45 CFR part 46) was adopted by 15 U.S. Federal departments and agencies 
in an effort to promote uniformity, understanding, and compliance with 
human subject protections.\1\
    Existing regulations governing the protection of human subjects in 
Food and Drug Administration (FDA)-regulated research (21 CFR parts 50, 
56, 312, and 812) are separate from the Common Rule but include similar 
requirements.
    The history of contemporary human subjects protections began in 
1947 with the Nuremberg Code, developed for the Nuremberg Military 
Tribunal as standards by which to judge the human experimentation 
conducted by the Nazis. The Code captures many of what are now taken to 
be the basic principles governing the ethical conduct of research 
involving human subjects.
    Similar recommendations were made by the World Medical Association 
in its Declaration of Helsinki: Recommendations Guiding Medical Doctors 
in Biomedical Research Involving Human Subjects, first adopted in 1964 
and subsequently revised many times.
    Basic regulations governing the protection of human subjects in 
research supported or conducted by HHS (then the Department of Health, 
Education and Welfare) were first published in 1974. In the United 
States, a series of highly publicized abuses in research led to the 
enactment of the 1974 National Research Act (Pub. L. 93-348), which 
created the National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research (National Commission). One of the 
charges to the National Commission was to identify the basic ethical 
principles that should underlie the conduct of biomedical and 
behavioral research involving human subjects and to develop guidelines 
to assure that such research is conducted in accordance with those 
principles. In 1979, the National Commission published ``Ethical 
Principles and Guidelines for the Protection of Human Subjects of 
Research,'' also known as the Belmont Report (http://www.hhs.gov/ohrp/policy/belmont.html) which identified three fundamental ethical 
principles for all human subjects research--respect for persons, 
beneficence, and justice.
    Based on the Belmont Report and other work of the National 
Commission, HHS revised and expanded its regulations for the protection 
of human subjects in the late 1970s and early 1980s. The HHS 
regulations are codified at 45 CFR part 46, subparts A through E. The 
statutory authority for the HHS regulations derives from 5 U.S.C. 301; 
42 U.S.C. 300v-1(b); and 42 U.S.C. 289.
    In 1991, 14 other Federal departments and agencies joined HHS in 
adopting a uniform set of rules for the protection of human subjects, 
the ``Common Rule,'' identical to subpart A of 45 CFR part 46 of the 
HHS regulations.
    The Common Rule requires that Federally funded investigators in 
most instances obtain and document the informed consent of research 
subjects, and describes requirements for institutional review board 
(IRB) membership, function, operations, research review, and 
recordkeeping. The regulations also delineate criteria for, and levels 
of, IRB review. Currently, except for human subjects research that

[[Page 44513]]

is determined to be exempt from the regulations, Federally funded 
research involving human subjects is reviewed by an IRB in one of two 
ways: (1) By a convened IRB, or (2) through an expedited review 
process.
    Since the Common Rule was developed, the landscape of research 
activities has changed dramatically, accompanied by a marked increase 
in the volume of research. It is estimated that total spending on 
health-related research and development by the drug industry and the 
Federal government has tripled since 1990.\2\ While traditional 
biomedical research conducted in academic medical centers continues to 
flourish, many studies are now also conducted at community hospitals, 
outpatient clinics, or physician-based practices. Clinical research is 
regularly conducted at multiple institutions across the U.S. and other 
countries. Recruitment firms, bioinformatics specialists, clinical 
trial coordinating centers, protocol developers, data analysts, 
contract research organizations (CROs), data and safety monitoring 
committees, community-based organizations, and other entities have 
joined investigators and sponsors as part of the clinical research 
enterprise.
    Research has also increased, evolved, and diversified in other 
areas, such as national security, crime and crime prevention, 
economics, education, and the environment, using a wide array of 
methodologies in the social sciences and multidisciplinary studies. The 
application of technologies such as functional magnetic resonance 
imaging in neuroscience has led to substantial advances in the 
understanding of human physiology, cognition, and behavior. The advent 
of sophisticated computer software programs, the Internet, and mobile 
technology have created new areas of research activity, particularly 
within the social and behavioral sciences, exponentially increasing the 
amount of information available to researchers, while providing the 
means to access and analyze that information. In many areas of society, 
researchers are being called upon to provide evidence to more 
effectively guide social policy and practices.
    The rapid growth and expansion of human subjects research has led 
to many questions about whether the current regulatory framework is 
adequate and appropriate for the protection of human subjects in the 
21st century. Furthermore, decades of experience have revealed a great 
deal about the functioning--and limitations--of existing regulations, 
and prompted critical evaluations by the Institute of Medicine 
(IOM),\3\ \4\ the U.S. Government Accountability Office,\5\ \6\ \7\ and 
many scholars.\8\ \9\ \10\ Federal consideration of such revisions to 
the regulatory schema, in addition to the issues that suggest a need 
for revision, is not without precedent. In its 2001 concluding report, 
the National Bioethics Advisory Commission (NBAC) made 30 
recommendations that addressed areas including the scope and structure 
of the oversight system, the level of review applied to research, 
emphasizing the informed consent process, documentation and waiver of 
informed consent, protecting privacy and confidentiality, adverse event 
reporting, and review of cooperative or multi-site research 
studies.\11\ NBAC's recommendations are one source for the revisions in 
the Common Rule currently being considered. Addressing these 
considerations now is timely and consistent with the President's 
Executive Order requiring Federal agencies to review existing 
significant regulations to determine whether they should be modified, 
streamlined, expanded, or repealed to make the agency's regulatory 
program more effective or less burdensome in achieving the regulatory 
objective.\12\
    The concerns about the current Common Rule can roughly be 
categorized into seven areas. First, the system has been criticized as 
not adequately calibrating the review process to the risk of research. 
Critics have raised concerns that some IRBs spend considerable time 
reviewing minimal risk research, and that some IRBs have a tendency to 
overestimate the magnitude and probability of reasonably foreseeable 
risks.\13\ Because significantly more research studies require convened 
IRB review, this greater IRB workload diverts time and resources from 
review of research that poses greater risks, theoretically resulting in 
inadequate attention to research that could seriously harm 
subjects.\14\
    Questions have been raised about the appropriateness of the review 
process for social and behavioral research.\15\ \16\ \17\ \18\ The 
nature of the possible risks to subjects is often significantly 
different in many social and behavioral research studies as compared to 
biomedical research, and critics contend that the difference is not 
adequately reflected in the current rules. While physical risks 
generally are the greatest concern in biomedical research, social and 
behavioral studies rarely pose physical risk but may pose psychological 
or informational risks. Some have argued that, particularly given the 
paucity of information suggesting significant risks to subjects in 
certain types of survey and interview-based research, the current 
system over-regulates such research.\19\ \20\ \21\ Further, many 
critics see little evidence that most IRB review of social and 
behavioral research effectively does much to protect research subjects 
from psychological or informational risks.\22\ Over-regulating social 
and behavioral research in general may serve to distract attention from 
attempts to identify those social and behavioral research studies that 
do pose threats to the welfare of subjects and thus do merit 
significant oversight.
    Second, critics have commented about the inefficiencies of review 
by multiple IRBs for multi-site studies, which add bureaucratic 
complexity to the review process and delay initiation of research 
projects without evidence that multiple reviews provide additional 
protections to subjects.\23\ There also has been a concern that the 
current multiple review system might actually be leading to weaker 
protections for subjects than if there were fewer reviews but greater 
responsibility on the part of the IRBs involved.
    Third, questions have been raised about the extent and quality of 
the protections afforded by current informed consent requirements and 
practices. A variety of critics have highlighted problems with consent 
forms. In some research studies, consent forms have become lengthy and 
are often written in highly technical terms.\24\ \25\ \26\ Many also 
claim that consent forms have evolved to protect institutions rather 
than to actually provide salient information to potential human 
subjects.\27\ This is especially problematic if the forms fail to 
include information that is crucial for making a decision about 
participation, including appropriate information about financial 
relationships between researchers and study sponsors, or are written in 
a way that potential subjects are likely to fail to notice such 
information. At the same time, others raise concerns about the rigid 
application of written consent to all forms of research, especially 
research involving surveys, interviews, focus groups, or other similar 
methodologies.\28\ In these types of research, it has been argued that 
written documentation of consent is unnecessary and that answering 
questions should be sufficient to indicate individual consent to 
participate.\29\
    Fourth, increasing use of genetic information, existing (i.e., 
stored) biospecimens, medical records, and administrative claims data 
in research has changed the nature of the risks and

[[Page 44514]]

benefits of research participation. Risks related to these types of 
research are not physical but informational (e.g., resulting from the 
unauthorized release of information about subjects). The Privacy Rule 
promulgated under the Health Insurance Portability and Accountability 
Act of 1996 (HIPAA) \30\ addresses some of these informational risks by 
imposing restrictions on how certain identifiable health information 
collected by health plans, healthcare clearinghouses, and certain 
healthcare providers (``covered entities'') may be used and disclosed, 
including for research. In addition, the HIPAA Security Rule requires 
that these entities implement certain administrative, physical, and 
technical safeguards to protect this information when in electronic 
form from unauthorized use or disclosure. However, the HIPAA Rules 
apply only to covered entities (and in certain respects to their 
business associates), and not all investigators are part of a covered 
entity (or business associates of a covered entity). Separate from the 
HIPAA Rules, the Privacy Act of 1974, as amended (5 U.S.C. 552a \31\) 
requires Federal agencies to protect personally identifiable 
information in their possession and control. However, it does not apply 
to non-Federal researchers.
    Fifth, the monitoring and evaluation of the current system for 
protecting human subjects has been criticized.\32\ There is concern 
that current regulations do not provide an ideal mechanism for the 
collection of information that would allow evaluation of the 
effectiveness of the research oversight system in protecting human 
subjects.
    Sixth, concerns have been expressed that the current regulatory 
system does not adequately protect all research subjects.\33\ For 
instance, only some research studies funded by certain Federal agencies 
or those that involve the development of products subject to regulation 
by the FDA, are subject to the Common Rule or similar protections. As a 
result, there are many studies that are not subject to any such Federal 
oversight, even though they may involve substantial risks to the 
subjects.
    Seventh, the multiple, differing regulatory requirements that can 
apply to a single research study have been criticized as complex, 
inconsistent, and lacking in clarity, which results in unwarranted 
variability across institutions and their IRBs in how the requirements 
are interpreted and implemented.\34\ For example, Federal agencies that 
have adopted the Common Rule have issued guidance and developed norms 
of implementation that sometimes differ and may, in certain instances, 
even conflict with guidance from other Common Rule agencies. Similarly, 
the overlapping and sometimes, arguably, inconsistent requirements of 
the Common Rule and the HIPAA Privacy Rule have been criticized as 
being overly complex, causing confusion and frustration among 
investigators, IRBs, and others trying to comply with both sets of 
requirements.\35\
    In response to these various criticisms, we propose changes to the 
following seven aspects of the current regulatory framework. The 
fundamental goal is to enhance the effectiveness of the research 
oversight system by improving the protections for human subjects while 
also reducing burdens, delays, and ambiguity for investigators and 
research subjects.
    1. Refinement of the existing risk-based regulatory framework 
(Section II);
    2. Utilization of a single IRB review of record for domestic sites 
of multi-site studies (Section III);
    3. Improvement of consent forms and the consent process (Section 
IV);
    4. Establishment of mandatory data security and information 
protection standards for all studies that involve identifiable or 
potentially identifiable data (Section V);
    5. Establishment of an improved, more systematic approach for the 
collection and analysis of data on unanticipated problems and adverse 
events (Section VI);
    6. Extension of Federal regulatory protections to all research, 
regardless of funding source, conducted at institutions in the U.S. 
that receive some Federal funding from a Common Rule agency for 
research with human subjects (Section VII); and
    7. Improvement in the harmonization of regulations and related 
agency guidance (Section VIII).
    We believe the proposals we are considering uphold and better 
reflect the ethical principles upon which the Common Rule is based. We 
recognize that this ANPRM is both lengthy and detailed. However this 
level of detail reflects the importance and types of changes that have 
been proposed by the Institute of Medicine (IOM), NBAC, and other 
commentators and are now being considered for adoption. Comment is now 
sought on these proposals and on the broader question of how to 
modernize, simplify, and enhance the current system. The intent is to 
revise the Common Rule \36\ recognizing that other laws and 
regulations, such as the other subparts of the HHS human subjects 
protection regulations (Subparts B, C, and D, which deal with 
particular populations of vulnerable subjects, and Subpart E of 45 CFR 
part 46), FDA regulations, and the HIPAA Privacy Rule most likely will 
be affected and will need to be harmonized, as appropriate, with any 
proposed regulatory changes made to the Common Rule.
    As we consider how the current regulations governing human subjects 
research should be revised, we will take into account the deliberations 
of the Presidential Commission for the Study of Bioethical Issues. We 
will also consider the public comments received on the request for 
information that the Commission issued on March 2, 2011, that sought 
public comment on the current Federal and international standards for 
protecting the health and well-being of participants in scientific 
studies supported by the Federal Government.\37\

II. Ensuring Risk-Based Protections

    Currently, the Common Rule provides for several tiers of 
independent review of research studies, as follows:
    1. The highest level of review, applied to most studies involving 
more than minimal risk and to many studies involving no more than 
minimal risk, is review by a convened IRB.
    2. The next level of review is expedited review.\38\ This generally 
involves review by a single IRB member. A study is eligible for 
expedited review if the research appears on a list published by the 
Secretary of HHS of categories of research eligible for such review, 
and the research is found by the reviewer(s) to involve no more than 
minimal risk.
    3. Certain studies are exempt from IRB review.\39\ The regulations 
specify six ``exemption'' categories; a study must fall within one or 
more of these six categories to be exempted from IRB review altogether. 
Although these studies are not subject to the Common Rule, and no 
review is actually required, guidance issued by the Office for Human 
Research Protection (OHRP) recommends that there be some type of review 
by someone other than the investigator to confirm that the study 
qualifies as exempt, and many institutions do indeed impose such a 
requirement.\40\
    There has been criticism about this regulatory framework for 
reviewing research studies. Although it does attempt to match the level 
of review to the type of risks posed by a study, many argue that it 
does so in a less than ideal manner. For instance, many surveys that 
are unlikely to lead to any harm to subjects nonetheless undergo review 
by a convened IRB.\41\ Further, arguments

[[Page 44515]]

have been made that some of the lines drawn between review categories 
are vague and difficult to apply.\42\ Studies have shown that different 
levels of review are sometimes required by different IRBs for the same 
study.43 44
    In response to these concerns, the IOM report on research 
protections recommended revising the current approach: ``The degree of 
scrutiny, the extent of continuing oversight, and the safety monitoring 
procedures for research proposals should be calibrated to a study's 
degree of risk. Minimal risk studies should be handled diligently, but 
expeditiously, while studies involving high risk should receive the 
extra time and attention they require.'' \45\ The IOM surmised that 
this would reduce burdens that do not translate into meaningful 
protections of human subjects and would limit unnecessary drain on 
resources, enabling IRBs to give more attention to high risk studies 
and critical protection activities while improving the efficiency with 
which research projects are reviewed and overseen.
    This ANPRM describes potential refinements to the current review 
framework intended to ensure that protections are commensurate with the 
level of risk of the research study. Five of the most significant 
changes being considered are summarized below, followed by a more 
detailed explanation of the proposals:
    1. Establishing mandatory data security and information protection 
standards for identifiable information and rules protecting against the 
inappropriate re-identification of de-identified information that is 
collected or generated as part of a research study to minimize 
informational risks and thereby eliminate the need for IRBs to review 
informational risks of the research. For purposes of the Common Rule, 
we are considering adopting the HIPAA standards regarding what 
constitutes individually identifiable information, a limited data set, 
and de-identified information, in order to harmonize these definitions 
and concepts. Since this provision would cover studies currently 
considered ``exempt'' from the current regulations, a change in 
terminology would need to be considered (see Section B(3), below).
    2. Revising the rules for continuing review. Continuing review 
would be eliminated for all minimal risk studies that undergo expedited 
review, unless the reviewer explicitly justifies why continuing review 
would enhance protection of research subjects. For studies initially 
reviewed by a convened IRB, continuing review would not be required, 
unless specifically mandated by the IRB, after the study reaches the 
stage where procedures are limited to either (i) analyzing data (even 
if it is identifiable), or (ii) accessing follow-up clinical data from 
procedures that subjects would undergo as part of standard care for 
their medical condition or disease (such as periodic CT scans to 
monitor whether the subjects' cancers have recurred or progressed).
    3. Revising the regulations regarding expedited review to provide 
for mandatory regular updating of the list of categories of research 
that may be reviewed under this mechanism, creating a presumption that 
studies utilizing only research activities that appear on that list are 
indeed minimal risk, and providing for streamlined document submission 
requirements for review.
    4. Revising the regulations regarding studies currently considered 
exempt to, among other things:
    i. Require that researchers file with the IRB a brief form 
(approximately one page) to register their exempt studies, but 
generally allow the research to commence after the filing;
    ii. Clarify that routine review by an IRB staff member or some 
other person of such minimal risk exempt studies is neither required 
nor even recommended;
    iii. Expand the current category 2 exemption (45 CFR 46.101(b)(2)) 
to include all studies involving educational tests, surveys, 
interviews, and similar procedures so long as the subjects are 
competent adults, without any further qualifications (but subject to 
the data security and information protection standards discussed 
above);
    iv. Add a new category for certain types of behavioral and social 
science research that goes beyond using only survey methodology, but 
nonetheless involves only specified minimal risk procedures, so long as 
the subjects are competent adults (but subject to the data security and 
information protection standards discussed above);
    v. Expand the current category 4 exemption (regarding the 
collection or study of existing data, documents, records and 
biospecimens) (45 CFR 46.101(b)(4)) to include all secondary research 
use of identifiable data and biospecimens that have been collected for 
purposes other than the currently proposed research, provided that 
specified new consent requirements are satisfied. This expanded 
category 4 exemption would apply to the secondary use of identifiable 
data and biospecimens even if such data or biospecimens have not yet 
been collected at the time of the research proposal, and even if 
identifiers are retained by the researcher (instead of requiring at 
least expedited review, as is currently the case); and
    vi. Require random retrospective audits of a sample of exempt 
studies to assess whether the exemptions were being appropriately 
applied.
    5. Generally requiring written consent for research use of any 
biospecimens collected for clinical purposes after the effective date 
of the new rules (such as research with excess pathological specimens). 
Such consent could be obtained by use of a brief standard consent form 
agreeing to generally permit future research. This brief consent could 
be broad enough to cover all biospecimens to be collected related to a 
particular set of encounters with an institution (e.g. hospitalization) 
or even to any biospecimens to be collected at any time by that 
institution. These studies using biospecimens collected for clinical 
purposes would also fall under the expanded and revised exempt 
categories described in (4), above, and thus would not require IRB 
review or any routine administrative review but would be subject to the 
data security and information protection standards discussed above. 
This change would conform the rules for research use of clinically-
collected biospecimens with the rules for biospecimens collected for 
research purposes. The general rule would be that a person needs to 
give consent, in writing, for research use of their biospecimens, 
though that consent need not be study-specific, and could cover open-
ended future research.
    Each of these five proposals and other proposed changes are 
discussed below. We seek comments and recommendations on the specific 
changes being considered.

A. A New Mechanism for Protecting Subjects From Informational Risks

    Most research risks to the individual can be categorized into one 
of three types: physical, psychological, and informational risks. 
(Although there are other harms, such as legal, social, and economic 
harms, these can usually be viewed as variations on those core 
categories.) Physical risks are the most straightforward to 
understand--they are characterized by short term or long term damage to 
the body such as pain, bruising, infection, worsening current disease 
states, long-term symptoms, or even death. Psychological risks can 
include unintentional anxiety and stress including feelings of sadness 
or even depression, feelings of betrayal, and exacerbation of 
underlying psychiatric conditions such as post traumatic stress 
disorder. Psychological risks are not

[[Page 44516]]

necessarily restricted to psychiatric or social and behavioral 
research.
    Informational risks derive from inappropriate use or disclosure of 
information, which could be harmful to the study subjects or groups. 
For instance, disclosure of illegal behavior, substance abuse, or 
chronic illness might jeopardize current or future employment, or cause 
emotional or social harm. In general, informational risks are 
correlated with the nature of the information and the degree of 
identifiability of the information. The majority of unauthorized 
disclosures of identifiable health information from investigators occur 
due to inadequate data security.\46\
    Currently, IRBs evaluate all three categories of risk. IRB review 
or oversight of research posing informational risks may not be the best 
way to minimize the informational risks associated with data on human 
subjects. It is not clear that members have appropriate expertise 
regarding data protections. The current assumption that IRBs are 
responsible for reviewing and adequately addressing informational risks 
appears to lead to inconsistent protections and some cases in which 
there are inadequate protections for the information.\47\ Furthermore, 
review of informational risk is an inefficient use of an IRB's time. 
Standardized data protections, rather than IRB review, may be a more 
effective way to minimize informational risks.
    Accordingly, we are considering mandatory standards for data 
security and information protection whenever data are collected, 
generated, stored, or used. The level of protection required by these 
standards would be calibrated to the level of identifiability of the 
information, which would be based on the standards of identifiability 
under the HIPAA Privacy Rule. (These standards are discussed in detail 
in Section V.) With these standards in place to minimize the 
inappropriate use or disclosure of research information, the criteria 
for IRB approval of studies would be modified so that an IRB would no 
longer be responsible for assessing the adequacy of a study's 
procedures for protecting against informational risks. This change 
would not alter the IRB's role in assuring that the ethical principles 
of respect for persons, beneficence and justice are adequately 
fulfilled.

B. Calibrating the Levels of Review to the Level of Risk

    To improve the link between the type of review and the level of 
risk posed by research studies, we are considering the changes 
described below. Since there would be new mandatory standards for data 
security and information protection to address informational risks, 
only non-informational risks would be considered in determining the 
level of risk posed by research studies.
1. Full Convened IRB Review
    The requirement that research involving greater than minimal risk 
be reviewed by a convened IRB would not be changed from the current 
system. Other changes considered in this ANPRM, such as improvements in 
the ability of IRBs to require better consent forms, may enhance the 
effectiveness of such review.
    With regard to continuing review of such studies, we are 
considering one change. Where the remaining activities in a study are 
limited to either (i) data analysis (even if identifiers are retained) 
or (ii) accessing follow-up clinical data from procedures that subjects 
would undergo as part of standard care for their medical problems (such 
as periodic CT scans to monitor whether the subjects' cancers have 
recurred or progressed), the default would be that no continuing review 
by an IRB would be required. The IRB would have the option to make a 
determination that overrides this default. Researchers would still have 
the current obligations to report various developments (such as 
unanticipated problems, or proposed changes to the study) to the IRB. 
This would be a change from the current rules, which require at least 
expedited IRB review of the activities described in (i) and (ii) 
directly above. By eliminating the requirement for continuing review of 
these activities, this change would allow for more effective use of 
IRBs' time by enabling the IRB to focus on reviewing information that 
is necessary to ensure protections of research subjects.
2. Revise Approach to Expedited Review
    Under the Common Rule, a new research study can receive expedited 
review if the research activities to be conducted appear on the list of 
activities published by the Secretary of HHS that are eligible for such 
review (http://www.hhs.gov/ohrp/policy/expedited98.html), and is found 
by the reviewer(s) to involve no more than minimal risk. For research 
that will receive expedited review, three changes are being considered: 
(1) Revising the criteria that make research studies eligible for 
expedited review, (2) eliminating the requirement of routine annual 
continuing review of expedited studies, and (3) streamlining submission 
requirements.
(a) Eligibility for Expedited Review
    Currently, a reviewer must determine that the study includes only 
research activities that appear in the list promulgated by the 
Secretary as eligible for expedited review, that the study as a whole 
involves no more than minimal risk, and that all of the criteria listed 
in 45 CFR 46.111 are met. We are considering changes in each of these 
three areas:
i. List of Research Activities That Qualify a Study for Expedited 
Review
    We are considering initially updating the current list of research 
activities, which was last updated in 1998. We also are considering 
mandating that a standing Federal panel periodically (such as every 
year or every two years) review and update the list, based on a 
systematic, empirical assessment of the levels of risk. This would 
provide greater clarity about what would be considered to constitute 
minimal risk, and create a process that allows for routinely 
reassessing and updating the list of research activities that would 
qualify as minimal risk.
ii. Determination That the Study Involves No More Than Minimal Risk
    As noted, currently a study can undergo expedited review if all of 
the activities involved appear on the list of eligible research 
activities and the study is found to be minimal risk. The current 
definition of minimal risk encompasses research activities where ``the 
probability and magnitude of harm or discomfort anticipated in the 
research are not greater in and of themselves than those ordinarily 
encountered in daily life or during the performance of routine physical 
or psychological examinations or tests.'' \48\ Since the listed 
activities are ones with which there is a great deal of experience, and 
their risks are well known, it should be a rare instance in which a 
study that uses only the listed activities will, as a whole, pose more 
than minimal risk. Yet many studies which use only those activities--
particularly those in the social and behavioral field--are frequently 
required to undergo review by a convened IRB.\49\ We are accordingly 
considering providing a default presumption in the regulations that a 
study which includes only activities on the list is a minimal risk 
study and should receive expedited review. A reviewer would have the 
option of determining that the study should be reviewed by a convened 
IRB, when that

[[Page 44517]]

conclusion is supported by the specific circumstances of the study.
iii. Determination That the Study Meets All of the 45 CFR 46.111 
Criteria
    Given that a study is eligible for expedited review only if it 
involves minimal risk, and only if its activities are limited to those 
that appear on the published list, it is not clear that the study 
should be required to meet all of the criteria for IRB approval at 45 
CFR 46.111. Currently, before an IRB may approve a research study, 
including research that is being reviewed under an expedited procedure, 
the IRB must find that the following criteria have been satisfied as 
required by 45 CFR 46.111:
    1. Risks to subjects are minimized: (i) By using procedures which 
are consistent with sound research design and which do not 
unnecessarily expose subjects to risk, and (ii) whenever appropriate, 
by using procedures already being performed on the subjects for 
diagnostic or treatment purposes.
    2. 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.
    3. Selection of subjects is equitable. In making this assessment 
the IRB should take into account the purposes of the research and the 
setting in which the research will be conducted and should be 
particularly cognizant of the special problems of research involving 
vulnerable populations, such as children, prisoners, pregnant women, 
mentally disabled persons, or economically or educationally 
disadvantaged persons.
    4. Informed consent will be sought from each prospective subject or 
the subject's legally authorized representative, in accordance with, 
and to the extent required by Sec.  46.116.
    5. Informed consent will be appropriately documented, in accordance 
with, and to the extent required by Sec.  46.117.
    6. When appropriate, the research plan makes adequate provision for 
monitoring the data collected to ensure the safety of subjects.
    7. When appropriate, there are adequate provisions to protect the 
privacy of subjects and to maintain the confidentiality of data.
    8. When some or all of the subjects are likely to be vulnerable to 
coercion or undue influence, such as children, prisoners, pregnant 
women, mentally disabled persons, or economically or educationally 
disadvantaged persons, additional safeguards have been included in the 
study to protect the rights and welfare of these subjects.
    Accordingly, we are considering whether all of those criteria 
should still be required for approval of studies that qualify for 
expedited review, and if not, which ones should not be required.
(b) Eliminating Continuing Review of Expedited Studies
    We believe that annual continuing review of research studies 
involving only activities that are already well-documented to generally 
involve no more than minimal risk may provide little if any added 
protection to subjects, and that it may be preferable for IRB resources 
to be devoted to research that poses greater than minimal risk.
    Accordingly, we are considering changing the default to require no 
continuing review for studies that qualify for expedited review. 
Researchers would still be obligated to obtain IRB approval for changes 
to a study and to report to the IRB unanticipated problems and other 
similar items that are currently required to be reported.
    For any specific study, the reviewer would have the authority to 
make a specific determination and provide a justification about why 
continuing review is appropriate for that minimal risk study, and to 
specify how frequently such review would be required.
(c) Streamlining Documentation Requirements for Expedited Studies
    Under the current Federal regulations, researchers typically must 
submit the same documents including a detailed protocol, informed 
consent documents, and any other supporting documents, regardless of 
whether the study will be reviewed by a convened IRB or be approved by 
the expedited review process. Although it is important to document why 
research qualifies for expedited review, it is unclear whether the time 
and effort expended in such preparation activities result in increased 
benefit in terms of protecting subjects.
    Ideally, standard templates for protocols and consent forms and 
sample versions of those documents that are specifically designed for 
use in the most common types of studies would facilitate expedited 
review. Such forms would need to be carefully designed to eliminate 
those elements that are of relevance only in studies that pose greater 
than minimal risks and to substantially reduce the current burden of 
researchers involved in producing these documents and of the IRB 
members who review them.
    Comments and recommendations are requested on any of the above 
proposals under consideration and on the following specific questions:
    Question 1: Is the current definition of ``minimal risk'' in the 
regulations (45 CFR 46.102(i)--research activities where ``the 
probability and magnitude of harm or discomfort anticipated in the 
research are not greater in and of themselves than those ordinarily 
encountered in daily life or during the performance of routine physical 
or psychological examinations or tests'')--appropriate? If not, how 
should it be changed?
    Question 2: Would the proposals regarding continuing review for 
research that poses no more than minimal risk and qualifies for 
expedited review assure that subjects are adequately protected? What 
specific criteria should be used by IRBs in determining that a study 
that qualifies for expedited initial review should undergo continuing 
review?
    Question 3: For research that poses greater than minimal risk, 
should annual continuing review be required if the remaining study 
activities only include those that could have been approved under 
expedited review or would fall under the revised exempt (Excused) 
category described in section 3, below (e.g., a study in which a 
physical intervention occurred in the first year, all subjects have 
completed that intervention, and only annual written surveys are 
completed for the next five years)?
    Question 4: Should the regulations be changed to indicate that IRBs 
should only consider ``reasonably foreseeable risks or discomforts''?
    Question 5: What criteria can or should be used to determine with 
specificity whether a study's psychological risks or other nonphysical, 
non-information risks, are greater than or less than minimal?
    Question 6: Are there survey instruments or specific types of 
questions that should be classified as greater than minimal risk? How 
should the characteristics of the study population (e.g. mental health 
patients) be taken into consideration in the risk assessment?
    Question 7: What research activities, if any, should be added to 
the published

[[Page 44518]]

list of activities that can be used in a study that qualifies for 
expedited review? Should any of the existing activities on that list be 
removed or revised? For instance, should the following be included as 
minimal risk research activities:
     Allergy skin testing.
     Skin punch biopsy (limited to two per protocol).
     Additional biopsy during a clinical test (e.g., performing 
an extra colonic biopsy in the course of performing a routine 
colonoscopy).
     Glucose tolerance testing among adults.
    Question 8: Should some threshold for radiological exams performed 
for research purposes, that is calibrated to this background level of 
exposure, be identified as involving no more than minimal risk?
    Question 9: How frequently should a mandatory review and update of 
the list of research activities that can qualify for expedited review 
take place? Should the list be revised once a year, every two years, or 
less frequently?
    Question 10: Which, if any, of the current criteria for IRB 
approval under 45 CFR 46.111 should not apply to a study that qualifies 
for expedited review?
    Question 11: What are the advantages of requiring that expedited 
review be conducted by an IRB member? Would it be appropriate to 
instead allow such review to be done by an appropriately trained 
individual, such as the manager of the IRB office, who need not be a 
member of the IRB? If not, what are the disadvantages of relying on a 
non-IRB member to conduct expedited review? If so, what would qualify 
as being ``appropriately trained''? Would the effort to make sure that 
such persons are appropriately trained outweigh the benefits from 
making this change?
    Question 12: Are there other specific changes that could be made to 
reduce the burden imposed on researchers and their staffs in terms of 
meeting the requirements to submit documents to an IRB, without 
decreasing protections to subjects? Are there specific elements that 
can be appropriately eliminated from protocols or consent forms? Which 
other documents that are currently required to be submitted to IRBs can 
be shortened or perhaps appropriately eliminated? Conversely, are there 
specific additions to protocols or consent forms beyond those 
identified in this notice that would meaningfully add to the protection 
of subjects? What entity or organization should develop and disseminate 
such standardized document formats?
    Question 13: Given the problems with the current system regarding 
wide variations in the substance of IRB reviews, would it be 
appropriate to require IRBs to submit periodic reports to OHRP in the 
instances in which they choose to override the defaults described in 
Sections B(1), B(2)(a)(ii), and B(2)(b) above? Should IRBs have to 
report instances in which they require continuing review or convened 
IRB review of a study which involves only activities identified as 
being on the list of those eligible for expedited review? If an IRB 
that chose to override these defaults was required to submit a report 
to OHRP, would this provide useful information about any lack of 
appropriate consistency among IRBs so that clarifying guidance could be 
provided as needed, or provide useful information to OHRP about the 
possible need to revise the expedited review list or the continuing 
review requirements?
3. Moving Away From the Concept of Exempt
    We are considering revising the category of exempt research in ways 
that would both increase protections and broaden the types of studies 
covered. Specifically, although still not subject to IRB review, these 
studies would be subject to the new data security and information 
protection standards described in Section V, and in some cases, 
informed consent would be required as described in Section (c) below. 
Given that these studies would no longer be fully exempt from the 
regulations, they could more accurately be described as ``Excused'' 
from being required to undergo some form of IRB review (which 
terminology we will use hereafter in this ANPRM). (Note: FDA's statute 
requires IRB review and approval of any clinical device investigation. 
21 U.S.C. 360j(g)(3)(A) and (B). Therefore, FDA-regulated studies 
involving specimens will not be eligible for the new Excused category 
and will remain subject to IRB oversight.) The new data security and 
information protection standards make it possible to increase the 
coverage of the Excused category, thereby reducing the burden on 
researchers conducting minimal risk studies, while actually increasing 
the protections for participants.
    Some specific aspects of these changes are described here:
(a) Types of Research Studies That Qualify for the Excused Category
    The existing six exemption categories would be retained as part of 
the new Excused category. The current criteria for defining those 
categories would be reviewed and revised appropriately so that they are 
clear enough that researchers could readily determine whether a study 
qualified to be in these categories. In addition, the following 
significant expansions of the current categories are being considered:
    1. Limitations specified in the current exempt category 2 (research 
involving educational tests, surveys, focus groups, interviews, and 
similar procedures) would no longer be necessary when these studies are 
conducted with competent adults. The current exemption 2 under 45 CFR 
46.101(b)(2) states: ``Research involving the use of educational tests 
(cognitive, diagnostic, aptitude, achievement), survey procedures, 
interview procedures or observation of public behavior, unless: (i) 
Information obtained is recorded in such a manner that human subjects 
can be identified, directly or through identifiers linked to the 
subjects; and (ii) any disclosure of the human subjects' responses 
outside the research could reasonably place the subjects at risk of 
criminal or civil liability or be damaging to the subjects' financial 
standing, employability, or reputation.'' Specifically it is proposed 
that the language that appears after the word ``unless'' in provisions 
(i) and (ii) would be deleted. Thus, research conducted with competent 
adults, that involve educational tests, surveys, focus groups, 
interviews, and similar procedures would qualify for the new Excused 
category, regardless of the nature of the information being collected, 
and regardless of whether data is recorded in such a manner that 
subjects can be identified. It is proposed that the limitations on the 
current category 2 be eliminated since these studies would be conducted 
with competent adults and because these studies would now be subject to 
standard data security and information protection standards. The term 
``competent'' as used here and throughout this ANPRM refers to adults 
who would be able to provide ``legally effective informed consent,'' as 
currently required by 45 CFR 46.116. This concept has been included in 
the Common Rule for decades, and is routinely implemented by 
researchers, generally with little difficulty. For example, researchers 
who currently conduct non-exempt surveys must make determinations 
regarding which subjects to include in their studies, and we are not 
aware of any evidence that suggests making such determinations has been 
a problem.
    2. We are considering whether to include on the list of Excused 
studies certain types of social and behavioral research, conducted with 
competent

[[Page 44519]]

adults, that would involve specified types of benign interventions 
beyond educational tests, surveys, focus groups, interviews, and 
similar procedures, that are commonly used in social and behavioral 
research, that are known to involve virtually no risk to subjects, and 
for which prior review does little to increase protections to subjects. 
These would be methodologies which are very familiar to people in 
everyday life and in which verbal or similar responses would be the 
research data being collected. For example, a researcher might ask 
subjects to watch a video, or read a paragraph or solve puzzles, and 
then ask them some questions to elicit word associations or time 
performance of activities. The specific methodologies might be spelled 
out in regulations, or they might be promulgated via a periodic 
mechanism to announce and update lists similar to the list that is 
published for activities that allow a study to be expedited.
    3. Limitations specified in the current exempt category 4 (research 
involving the use of existing information or biospecimens) would be 
eliminated. The current exemption 4 under 45 CFR 46.101(b)(4) states: 
``Research involving the collection or study of existing data, 
documents, records, pathological specimens, or diagnostic specimens, if 
these sources are publicly available or if the information is recorded 
by the investigator in such a manner that subjects cannot be 
identified, directly or through identifiers linked to the subjects.'' 
Specifically, it is proposed that the category would be revised to 
clarify that the word ``existing'' means collected for purposes other 
than the proposed research and not that all of the data or biospecimens 
need exist at the time the study commenced. In addition, the limitation 
that the researcher cannot record and retain information that 
identifies the subjects would be eliminated. In other words, research 
that only involves the use of data or biospecimens collected for other 
purposes, even if the researcher intends to retain identifiers, would 
now come within the new Excused category, unless there are plans to 
provide individual results back to the subjects. Studies that include a 
plan to provide to subjects individual results from the analysis of 
their biospecimens or data would not qualify for this proposed Excused 
category.
    As described below in Section (c), it is contemplated that certain 
relatively flexible consent requirements would be imposed on some of 
these studies. (See Table 1 at the end of Section V for a summary of 
this proposal.)
(b) Tracking and Auditing Excused Research
    We are considering a mechanism to track Excused research, and to 
audit only a small but appropriate portion of such research, because it 
would still be subject to other regulatory protections, such as the 
proposed data security and information protection standards and certain 
consent requirements. In addition, such a mechanism to track and audit 
Excused research will also enable institutions to assure that the 
research does indeed meet the criteria for inclusion in the Excused 
category. (That is all that an audit would in most cases involve: a 
brief review of the registration form, similar to what many 
institutions currently do when they determine whether a study is 
exempt.) Key to this would be a requirement that researchers register 
their study with an institutional office by completing a brief form. 
This would make the institution aware of the research and identify the 
study's principal investigator. In addition the institution could 
choose to review some of the submissions at the time they are filed 
(and we contemplate that this would only be done in a relatively small 
percentage of the filings) and if deemed appropriate, require that the 
study be sent for expedited review or, in exceptionally rare cases, 
convened IRB review.
    The proposed auditing requirement is intended to encourage 
institutions to use the regulatory flexibility proposed for the Excused 
category of research. Rather than maintaining many institutions' 
current practice of routinely requiring that research that meets the 
current exemption categories undergo some type of review before it is 
permitted to proceed, the proposed auditing requirement would provide 
institutions with information needed to assess their compliance with 
the new Excused category without unnecessarily subjecting all such 
research to either prospective review, or even routine review sometime 
after the study is begun.
(c) Consent Rules for Excused Research
    We are contemplating that the consent practices for studies 
currently designated as exempt would remain in most respects unchanged 
for research falling within the new Excused category, even if some of 
those practices are clarified. For example, oral consent without 
written documentation would continue to be acceptable for many research 
studies involving educational tests, surveys, focus groups, interviews, 
and similar procedures.
    However, we are considering the following revisions to the consent 
rules for the category of Excused research that involves the use of 
pre-existing data or biospecimens as described in Section 3(a)(3) 
above.
    First, written general consent (as described below) would be 
required for the research use of such biospecimens. This would be a 
change from the current rules which allow research without consent when 
a biospecimen is used for research under conditions where the 
researcher does not possess information that would allow them to 
identify the person whose biospecimen is being studied.
    Second, with regard to the researchers' use of pre-existing data 
(i.e. data that were previously collected for purposes other than the 
currently proposed research study):
    a. If the data was originally collected for non-research purposes, 
then, as is currently the rule, written consent would only be required 
if the researcher obtains information that identifies the subjects. 
There would accordingly be no change in the current ability of 
researchers to conduct such research using de-identified data or a 
limited data set, as such terms are used in the HIPAA Rules (see 
Section V), without obtaining consent.
    b. If the data was originally collected for research purposes, then 
consent would be required regardless of whether the researcher obtains 
identifiers. Note that this would be a change with regard to the 
current interpretation of the Common Rule in the case where the 
researcher does not obtain any identifiers. That is, the allowable 
current practice of telling the subjects, during the initial research 
consent, that the data they are providing will be used for one purpose, 
and then after stripping identifiers, allowing it to be used for a new 
purpose to which the subjects never consented, would not be allowed.
    In most instances, the consent requirements described above would 
have been met at the time that the biospecimens or data were initially 
collected, when the subject would have signed a standard, brief general 
consent form allowing for broad, future research. This brief consent 
could be broad enough to cover all data and biospecimens to be 
collected related to a particular set of encounters with an institution 
(e.g. hospitalization) or to any data or biospecimens to be collected 
at anytime by the institution. Importantly, this standardized general 
consent form would permit the subject to say no to all future research. 
In addition, there are likely to be a handful of special categories of 
research with

[[Page 44520]]

biospecimens that, given the unique concerns they might raise for a 
significant segment of the public, would be dealt with by check-off 
boxes allowing subjects to separately say yes or no to that particular 
type of research (e.g., perhaps creating a cell line, or reproductive 
research). Participation in a research study (such as a clinical trial) 
could not be conditioned on agreeing to allow future open-ended 
research using a biospecimen. With regard to the secondary research use 
of pre-existing data, on those occasions when oral consent was 
acceptable under the regulations for the initial data collection, it is 
envisioned that subjects would have typically provided their oral 
consent for future research at the time of the initial data collection; 
a written consent form would not have to be signed in that 
circumstance. Table 1 at the end of Section V illustrates the consent 
requirements for pre-existing data in the context of the data security 
and information protection requirements which would also apply.
    Third, these changes would only be applied prospectively, not 
retrospectively. In other words, they would only apply to biospecimens 
and data that are collected after the effective date of the new rules.
    And fourth, there would be rules (to be determined) that would 
allow for waiver of consent under specified circumstances, though those 
conditions would not necessarily be the same as those for other types 
of research.
(d) Overall Consequences for Current Review Practices
    The proposal for changes described in sections (a) through (c) 
above would eliminate the current practice of not allowing researchers 
to begin conducting such minimal risk studies until a reviewer has 
determined the study does indeed meet the criteria for being exempt. 
Such delay is not currently required by the Common Rule, and appears to 
slow research without adding significant protection to subjects. 
Instead, under the plan being considered, researchers would file with 
their institution or IRB a brief registration form (about one page 
long) that provides essential information about the study, including, 
for example, information about who will be the principal investigator, 
and the purpose of the study. The researchers would then be authorized 
to begin conducting the study after the filing (unless the institution 
chose to review that filing and determined that the research did not 
qualify as Excused). It would be made clear that the regulations would 
not require, and in fact, would discourage, having each of these 
registration forms undergo a comprehensive administrative review prior 
to commencing the study or even afterward.
    Comments and recommendations are requested on any of the above 
proposals under consideration and on the following specific questions:
    Question 14: Are these expansions in the types of studies that 
would qualify for this Excused category appropriate? Would these 
changes be likely to discourage individuals from participating in 
research? Might these changes result in inappropriately reduced 
protections for research subjects, or diminished attention to the 
principles of respect for persons, beneficence, and justice?
    Question 15: Beyond the expansions under consideration, are there 
other types of research studies that should qualify for the Excused 
category? Are there specific types of studies that are being considered 
for inclusion in these expansions, that should not be included because 
they should undergo prospective review for ethical or other reasons 
before a researcher is allowed to commence the research?
    Question 16: Should research involving surveys and related 
methodologies qualify for the Excused category only if they do not 
involve topics that are emotionally charged, such as sexual or physical 
abuse? If so, what entity should be responsible for determining whether 
a topic is or is not emotionally charged?
    Question 17: What specific social and behavioral research 
methodologies should fall within the Excused category? Under what 
circumstances, if any, should a study qualify for the Excused category 
if the study involves a form of deception (and if so, how should 
``deception'' be defined)?
    Question 18: Currently some IRBs make determinations regarding 
whether clinical results should be returned to study participants. How 
should such determinations be made if the study now fits in the Excused 
category? Can standard algorithms be developed for when test results 
should be provided to participants and when they should not (e.g., if 
they can be clinically interpreted, they must be given to the 
participants?).
    Question 19: Regarding the Excused category, should there be a 
brief waiting period (e.g. one week) before a researcher may commence 
research after submitting the one-page registration form, to allow 
institutions to look at the forms and determine if some studies should 
not be Excused?
    Question 20: The term ``Excused'' may not be the ideal term to 
describe the studies that will come within the proposed revision of the 
current category of exempt studies, given that these studies will be 
subject to some protections that are actually greater than those that 
currently exist. Might a term such as ``Registered'' better emphasize 
that these studies will in fact be subject to a variety of requirements 
designed to protect participants? We welcome other suggestions for 
alternative labels that might be more appropriate.
    Question 21: Is it appropriate to require institutions holding a 
Federalwide Assurance to conduct retrospective audits of a percentage 
of the Excused studies to make sure they qualify for inclusion in this 
category? Should the regulations specify a necessary minimum percentage 
of studies to be audited in order to satisfy the regulatory 
requirements? Should some other method besides a random selection be 
used to determine which Excused studies would be audited?
    Question 22: Are retrospective audit mechanisms sufficient to 
provide adequate protections to subjects, as compared to having 
research undergo some type of review prior to a researcher receiving 
permission to begin a study? Might this new audit mechanism end up 
producing a greater burden than the current system? Do researchers 
possess the objectivity and expertise to make an initial assessment of 
whether their research qualifies for the Excused category? By allowing 
researchers to make their own determinations, without prospective 
independent review, will protections for some subjects be 
inappropriately weakened? If allowing researchers to make such 
determinations without independent review would generally be 
acceptable, are there nonetheless specific categories of studies 
included in the proposed expansion for which this change would 
inappropriately weaken protections for subjects? And will the use of a 
one-page registration form give institutions sufficient information to 
enable them to appropriately conduct the audits?
    Question 23: Under what circumstances should it be permissible to 
waive consent for research involving the collection and study of 
existing data and biospecimens as described in Section 3(a)(3) above? 
Should the rules for waiving consent be different if the information or 
biospecimens were originally collected for research purposes or non-
research purposes? Should a request to waive informed consent trigger a 
requirement for IRB review?

[[Page 44521]]

    Question 24: The Common Rule has been criticized for 
inappropriately being applied to--and inhibiting research in-- certain 
activities, including quality improvement, public health activities, 
and program evaluation studies. 50 51 52 Regarding quality 
improvement, for example, these activities are in many instances 
conducted by health care and other organizations under clear legal 
authority to change internal operating procedures to increase safety or 
otherwise improve performance, often without the consent of staff or 
clients, followed by monitoring or evaluation of the effects. It is far 
from clear that the Common Rule was intended to apply to such 
activities, nor that having it apply produces any meaningful benefits 
to the public. Indeed, its application to such activities, and 
requiring IRB review and compliance with informed consent requirements, 
might have a chilling effect on the ability to learn from, and conduct, 
important types of innovation. We seek comment on whether and, if so, 
how, the Common Rule should be changed to clarify whether or not 
oversight of quality improvement, program evaluation studies, or public 
health activities are covered. Are there specific types of these 
studies for which the existing rules (even after the changes proposed 
in this Notice) are inappropriate? If so, should this problem be 
addressed through modifications to the exemption (Excused) categories, 
or by changing the definition of ``research'' used in the Common Rule 
to exclude some of these studies, or a combination of both? And if the 
definition of research were to be changed, how should the activities to 
be excluded be defined (e.g., ``quality improvement'' or ``program 
evaluation'')? Are there some such activities that should not be 
excluded from being subject to the Common Rule because the protections 
provided by that rule are appropriate and no similar protections are 
provided by other regulations? With regard to quality improvement 
activities, might it be useful to adopt the distinction made by the 
HIPAA Privacy Rule (45 CFR 164.501(1)), which distinguishes between 
``health care operations'' and ``research'' activities, defining 
``health care operations'' to include ``conducting quality assessment 
and improvement activities, including outcomes evaluation and 
development of clinical guidelines, provided that the obtaining of 
generalizable knowledge is not the primary purpose of any studies 
resulting from such activities''?
    Question 25: Are there certain fields of study whose usual methods 
of inquiry were not intended to or should not be covered by the Common 
Rule (such as classics, history, languages, literature, and journalism) 
because they do not create generalizable knowledge and may be more 
appropriately covered by ethical codes that differ from the ethical 
principles embodied in the Common Rule? If so, what are those fields, 
and how should those methods of inquiry be identified? Should the 
Common Rule be revised to explicitly state that those activities are 
not subject to its requirements?
    Question 26: The current exempt category 5 applies to certain 
research and demonstration projects that are designed to study or 
evaluate public benefit or service programs. Is the circumstance that a 
particular demonstration project generates ``broad'' knowledge 
incorrectly being used as a reason to prevent certain activities 
(including section 1115 waivers under Medicaid) from qualifying for 
exempt category 5? If so, how should this exemption (as part of the new 
category of Excused research) best be revised to assure that it will no 
longer be misinterpreted or misapplied? Would broadening the 
interpretation of the exemption result in inappropriately increased 
risks to participants in research? If so, how could such risks be 
mitigated? Also, is there a need to update or otherwise revise the 
``OPRR Guidance on 45 CFR 46.101(b)(5)''?
    Question 27: The Common Rule currently states (45 CFR 46.111(a)(2)) 
that an 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 the research risks 
that fall within the purview of its responsibility.'' Do IRBs correctly 
interpret this provision as meaning that while they should be 
evaluating risks to the individual subjects participating in a study, 
it is not part of their mandate to evaluate policy issues such as how 
groups of persons or institutions, for example, might object to 
conducting a study because the possible results of the study might be 
disagreeable to them? \53\ If that is not how the provision is 
typically interpreted, is there a need to clarify its meaning?
    Question 28: For research that requires IRB approval, the Common 
Rule does not currently require that the researcher always be allowed 
some form of appeal of a decision (e.g., disapproval of a project). 
Some institutions have voluntarily chosen to provide appeal mechanisms 
in some instances, by, for example, allowing the researcher to present 
the project to a different IRB, or by having it reviewed by a special 
``appeal'' IRB that is composed of members chosen from among the 
membership of the institution's other IRBs. Should the Common Rule 
include a requirement that every institution must provide an 
appropriate appeal mechanism? If so, what should be considered 
acceptable appeal mechanisms? Should such appeal mechanisms, or 
different ones, be available for appeals asserting that the 
investigation is not research, or that the research does not require 
IRB approval?
    Question 29: As noted above, IRBs sometimes engage in activities 
beyond those that are required by the regulations. For example, an IRB 
might review some studies for the purpose of determining whether or not 
they qualify for exemption (the new Excused category), or might review 
studies involving the analysis of data that is publicly available. 
Would it be helpful, in furtherance of increased transparency, to 
require that each time an IRB takes such an action, it must 
specifically identify that activity as one that is not required by the 
regulations?

III. Streamlining IRB Review of Multi-Site Studies

    Currently, a substantial amount of research takes place by means of 
multi-site studies wherein a single research study is conducted at 
numerous institutions. Multi-site studies are particularly common in 
clinical trials, survey epidemiology, and education contexts. While the 
Common Rule does require that each institution engaged in a multi-site 
research study obtain IRB approval of the study, it does not require 
that a separate local IRB at each institution conduct such review. 
(Note: While the Common Rule does not require local IRB review by each 
institution engaged in a multi-site research study, the statute that 
pertains to FDA's regulation of device investigations requires sponsors 
to submit the protocol to the ``local institutional review committee 
which has been established in accordance with regulations of the 
Secretary to supervise clinical testing of devices in the facilities 
where the proposed clinical testing is to be conducted.'' The only 
statutory exception is if a local IRB does not exist or its review is 
determined to be ``inadequate'' (21 U.S.C. 360j(g)(3)(A)). Accordingly, 
the change proposed in this ANPRM regarding the use of one IRB of 
record for multi-site studies would not apply to FDA-regulated device 
studies.) However, in many cases, a local IRB for each institution does 
independently review the research protocol, informed consent

[[Page 44522]]

documents and other materials, sometimes resulting in hundreds of 
reviews for one study. When any one of these IRBs requires changes to 
the research protocol that are adopted for the entire study, 
investigators must re-submit the revised protocol to all of the 
reviewing IRBs. This process can take many months and can significantly 
delay the initiation of research projects. Separately, there are 
reports showing that there can be widely differing outcomes regarding 
the level of review required from IRB to IRB, even for identical 
studies.\54\
    The choice to have multi-site research reviewed by a central IRB, 
or by an IRB at another institution, is voluntary. In practice, most 
institutions have been reluctant to replace review by their local IRBs 
with review by a central IRB.55 56 Participants in two 
meetings on alternative IRB models that OHRP co-sponsored in November 
2005 and November 2006 indicated that one of the key factors 
influencing institutions' decisions about this issue is OHRP's current 
practice of enforcing compliance with the Common Rule through the 
institutions that were engaged in human subjects research, even in 
circumstances when the regulatory violation is directly related to the 
responsibilities of an external IRB.\57\
    Many commentators\58\ claim that multiple IRB reviews do not 
enhance the protection of human subjects and may, in fact, divert 
valuable resources from more detailed reviews of other studies. 
Relevant local contextual issues (e.g., investigator competence, site 
suitability) pertinent to most clinical studies can be addressed 
through mechanisms other than local IRB review. For research where 
local perspectives might be distinctly important (e.g., in relation to 
certain kinds of vulnerable populations targeted for recruitment) local 
IRB review could be limited to such consideration(s), but again, IRB 
review is not the only mechanism for addressing such issues. The 
evaluation of a study's social value, scientific validity, and risks 
and benefits, and the adequacy of the informed consent document and 
process generally do not require the unique perspective of a local IRB.
    To respond to this concern, central IRBs have been developed. The 
National Cancer Institute created a central IRB for adult research 
studies in 2001 and a central pediatric oncology IRB in 2004. 
Similarly, the Department of Veterans Affairs has required review of 
certain multi-site protocols by a single national IRB since 2008. Also, 
certain groups of private institutions have joined together to develop 
their own central IRBs. These central IRBs reduce the workload for 
local IRBs and may minimize institutional conflicts of interest. Since 
2006, FDA has endorsed the use of a centralized IRB review process in 
multi-site clinical trials of investigational new drugs and has issued 
guidance intended to assist sponsors, institutions, IRBs, and clinical 
investigators on its implementation.\59\
    Public comment is requested on the feasibility, advantages, and 
disadvantages of mandating that all domestic sites in a multi-site 
study rely upon a single IRB as their IRB of record for that study. 
(This would apply regardless of whether the study underwent convened 
review or expedited review.) This proposal would only affect which IRB 
would be designated as the IRB of record for institutional compliance 
with the IRB review requirements of the Common Rule. It would not 
relieve any site of its other obligations under the regulations to 
protect human subjects. Nor would it prohibit institutions from 
choosing, for their own purposes, to conduct additional internal ethics 
reviews, though such reviews would no longer have any regulatory status 
in terms of compliance with the Common Rule (and could be discouraged). 
To address institutions' concerns about OHRP's practice of enforcing 
compliance with 45 CFR part 46 through the institutions that are 
engaged in human subjects research, appropriate accompanying changes 
would be made in enforcement procedures to hold external IRBs directly 
accountable for compliance with certain regulatory requirements (see, 
e.g., the proposal on IRB accountability released by OHRP in 2009, at 
http://www.hhs.gov/ohrp/newsroom/rfc/com030509.html)
    This change is being considered only for domestic sites in multi-
site studies. In most cases, independent local IRB reviews of 
international sites are appropriate because it might be difficult for 
an IRB in the U.S. to adequately evaluate local conditions in a foreign 
country that could play an important role in the ethical evaluation of 
the study.
    Comments and recommendations are requested on the following:
    Question 30: What are the advantages and disadvantages of 
mandating, as opposed to simply encouraging, one IRB of record for 
domestic multi-site research studies?
    Question 31: How does local IRB review of research add to the 
protection of human subjects in multi-site research studies? How would 
mandating one IRB of record impair consideration of valuable local 
knowledge that enhances protection of human subjects? Should the public 
be concerned that a centralized IRB may not have adequate knowledge of 
an institution's specific perspective or the needs of their population, 
or that a centralized IRB may not share an institution's views or 
interpretations on certain ethical issues?
    Question 32: To what extent are concerns about regulatory and legal 
liability contributing to institutions' decisions to rely on local IRB 
review for multi-site research? Would the changes we are considering 
adequately address these concerns?
    Question 33: How significant are the inefficiencies created by 
local IRB review of multi-site studies?
    Question 34: If there were only one IRB of record for multi-site 
studies, how should the IRB of record be selected? How could 
inappropriate forms of ``IRB shopping''--intentionally selecting an IRB 
that is likely to approve the study without proper scrutiny--be 
prevented?

IV. Improving Informed Consent

    Currently, under the Common Rule and FDA regulations, investigators 
generally must obtain and document the subjects' informed consent to 
participate in research.\60\ The regulations currently require that the 
consent forms include at least eight specific items of information. 
Various aspects of the consent forms have been heavily criticized, as 
has the amount of time IRBs devote to editing and revising consent 
forms.
    In addition, consent forms may frequently fail to include some of 
the most important pieces of information that a person would need in 
order to make an ``enlightened decision'' (to quote the Nuremberg Code) 
to enroll in a research study.\61\ Instead of presenting the 
information in a way that is most helpful to prospective subjects--such 
as explaining why someone might want to choose not to enroll--the forms 
often function as sales documents, instead of as genuine aids to good 
decision-making.\62\
    While the regulations have changed in only relatively modest ways 
since 1974, the average length of consent forms has been increasing 
since then,\63\ and the forms have become excessively long and 
legalistic, even for relatively routine and low risk research 
studies.\64\ For example, it is not uncommon for the documents to 
stretch to 15 or even 30 pages in length. Moreover, studies have shown 
that the reading level of many of these documents is above the desired 
8th grade level. 65 66 67 Length and high reading levels may 
inhibit people from reading the full document and from understanding 
relevant information.

[[Page 44523]]

    Further, some have argued that the requirements for obtaining 
waivers of informed consent or waivers of documentation of informed 
consent are confusing and inflexible, which leads to inconsistent 
application.\68\ These problems may not be inherent in the language of 
the Common Rule, but there may be some changes to the regulations or 
clarifications as to how to interpret and implement such regulations 
that could improve informed consent documents and process.

A. Improving Consent Forms

    We are considering a number of modifications to the regulations to 
improve consent forms, including (1) prescribing appropriate content 
that must be included in consent forms, with greater specificity than 
is provided in the current regulations; (2) restricting content that 
would be inappropriate to include in consent forms; (3) limiting the 
acceptable length of various sections of a consent form; (4) 
prescribing how information should be presented in consent forms, such 
as information that should be included at the very beginning of the 
consent form, or types of information that should be included in 
appendices and not in the main body of the consent form; (5) reducing 
institutional ``boilerplate'' in consent forms (that is, standard 
language that does little to genuinely inform subjects, and often is 
intended to primarily protect institutions from lawsuits); and (6) 
making available standardized consent form templates, the use of which 
could satisfy applicable regulatory provisions.
    Comments and recommendations are requested on the following:
    Question 35: What factors contribute to the excessive length and 
complexity of informed consent forms, and how might they be addressed?
    Question 36: What additional information, if any, should be 
required by the regulations to assure that consent forms appropriately 
describe to subjects, in concise and clear language, alternatives to 
participating in the research study and why it may or may not be in 
their best interests to participate? What modifications or deletions to 
the required elements would be appropriate?
    Question 37: Would the contemplated modifications improve the 
quality of consent forms? If not, what changes would do so?
    Question 38: Should the regulations require that, for certain types 
of studies, investigators assess how well potential research subjects 
comprehend the information provided to them before they are allowed to 
sign the consent form?
    Question 39: If changes are made to the informed consent 
requirements of the Common Rule, would any conforming changes need to 
be made to the authorization requirements of the HIPAA Privacy Rule?
    Question 40: Would informed consent be improved if the regulations 
included additional requirements regarding the consent process, and if 
so, what should be required? For example, should investigators be 
required to disclose in consent forms certain information about the 
financial relationships they have with study sponsors?

B. Waiver of Informed Consent or Documentation of Informed Consent in 
Primary Data Collection

    Currently the Common Rule permits an IRB to waive the requirements 
for obtaining informed consent under two sets of circumstances (45 CFR 
46.116 (c) or (d)).\69\ The most common set of circumstances requires 
that four specific criteria be satisfied (45 CFR 46.116(d)). Many 
commentators have argued that these conditions for waiver of consent 
are vague and applied haphazardly at different institutions. 
70 71 In response to these concerns, the Secretary's 
Advisory Committee on Human Research Protections (SACHRP), through its 
Subcommittee on Subpart A, developed several recommendations regarding 
the interpretation of these waiver criteria.\72\
    IRBs, under the Common Rule (45 CFR 46.117(c)), also may waive the 
requirement for the investigator to obtain a signed consent form for 
some or all subjects. The current criteria for such a waiver may not be 
flexible enough for dealing with a variety of circumstances, such as 
when Federally-sponsored research is conducted in an international 
setting where for cultural or historical reasons signing documents may 
be viewed as offensive and problematic. It is worth noting that for 
studies that only involve surveys, focus groups, and interviews with 
competent adults, there will usually be no need to apply the waiver of 
documentation criteria provided at 45 CFR 46.117(c). Such studies will 
generally qualify for the new Excused category, with only oral consent 
required.
    Comments and recommendations are requested on the following:
    Question 41: What changes to the regulations would clarify the 
current four criteria for waiver of informed consent and facilitate 
their consistent application?
    Question 42: In circumstances where the regulations would permit 
oral consent, what information should investigators be required to 
provide to prospective subjects? Are all of the elements of informed 
consent included at 45 CFR 46.116 necessary to be conveyed, or are some 
elements unnecessary? If some elements should not be required for oral 
consent, which ones are unnecessary?
    Question 43: Are there additional circumstances under which it 
should be permissible to waive the usual requirements for obtaining or 
documenting informed consent?
    Question 44: Are there types of research involving surveys, focus 
groups, or other similar procedures in which oral consent without 
documentation should not be permitted? What principles or criteria 
distinguish these cases?

C. Strengthening Consent Protections Related to Reuse or Additional 
Analysis of Existing Data and Biospecimens

    Critics of the existing rules have observed that the current 
requirements for informed consent for future research with pre-existing 
data and biospecimens are confusing and consume substantial amounts of 
researchers' and IRBs' time and resources. Under the Common Rule and 
the HIPAA Privacy Rule, if identifiers are removed, specimens and data 
that have been collected for purposes other than the proposed research 
can be used without any requirement for informed consent or a HIPAA 
authorization. When these identifiers have not been removed, under the 
Common Rule, investigators may be allowed in certain situations to 
obtain a general consent for future research with existing biospecimens 
and other information stored in databases. Conversely, the Department's 
current interpretation of the HIPAA Privacy Rule requires that 
authorizations for research be study-specific. Thus, the Privacy Rule 
currently has not been interpreted to permit general authorizations for 
future unspecified research uses of health information. Importantly, 
the HHS Office for Civil Rights (OCR) has recently sought and is 
currently reviewing public comment on the extent to which a single 
general authorization may cover a range of future research uses of an 
individual's health information (see 75 FR 40868, 40893 available at 
http://www.hhs.gov/ocr/privacy/hipaa/understanding/coveredentities/nprmhitech.pdf).
    Because biospecimens and data that have been collected for clinical 
use or purposes other than for the proposed research are often an 
important source of information and material for investigators, and the 
reuse of existing data and materials can be an efficient

[[Page 44524]]

mechanism for conducting research without presenting additional 
physical or psychological risks to the individual, it seems prudent to 
consider changes to current regulations. As the IOM recently stated in 
Beyond the HIPAA Privacy Rule: Enhancing Privacy, Improving Health 
Through Research, it is important to ``facilitate important health 
research by maximizing the usefulness of patient data associated with 
biospecimens banks and in research databases, thereby allowing novel 
hypotheses to be tested with existing data and materials as knowledge 
and technology improve.'' \73\
    Some critics, including potential and former research subjects, 
object to research performed on a person's biospecimens without 
consent. This was recently highlighted in the book, The Immortal Life 
of Henrietta Lacks. \74\ Conversely, investigators are concerned that 
the need for informed consent for every use of a biospecimen will 
greatly inhibit research.75 76 77 They worry that obtaining 
individual consent for each separate research study will create 
unmanageable logistical demands, making valuable research impossible. 
They also worry that research will be skewed by individuals who refuse 
consent, undermining the scientific validity of the research. An 
accumulating body of data indicates that while most individuals want to 
be able to decide whether their biospecimens are available for 
research, they often do not desire to have control over which specific 
researchers use their samples, for which diseases, at which 
institutions.78 79 80
    The potential changes to the consent rules that were described in 
detail in Section II(B)(3)(c) (in the discussion of revising the rules 
for exempt studies) are being considered to strengthen and align 
consent protections, simultaneously addressing the concerns of 
individuals, while ensuring the pursuit of important research.
    Comments and recommendations are requested on any of the above 
proposals under consideration and on the following specific questions:
    Question 45: Under what circumstances should future research use of 
data initially collected for non-research purposes require informed 
consent? Should consent requirements vary based on the likelihood of 
identifying a research subject? Are there other circumstances in which 
it should not be necessary to obtain additional consent for the 
research use of currently available data that were collected for a 
purpose other than the currently proposed research?
    Question 46: Under what circumstances should unanticipated future 
analysis of data that were collected for a different research purpose 
be permitted without consent? Should consent requirements vary based on 
the likelihood of identifying a research subject?
    Question 47: Should there be a change to the current practice of 
allowing research on biospecimens that have been collected outside of a 
research study (i.e. ``left-over'' tissue following surgery) without 
consent, as long as the subject's identity is never disclosed to the 
investigator?
    Question 48: What, if any, are the circumstances in which it would 
be appropriate to waive the requirement to obtain consent for 
additional analysis of biospecimens?
    Question 49: Is it desirable to implement the use of a 
standardized, general consent form to permit future research on 
biospecimens and data? Are there other options that should be 
considered, such as a public education campaign combined with a 
notification and opt-out process?
    Question 50: What is the best method for providing individuals with 
a meaningful opportunity to choose not to consent to certain types of 
future research that might pose particular concerns for substantial 
numbers of research subjects beyond those presented by the usual 
research involving biospecimens? How should the consent categories that 
might be contained in the standardized consent form be defined (e.g. an 
option to say yes-or-no to future research in general, as well as a 
more specific option to say yes-or-no to certain specified types of 
research)? Should individuals have the option of identifying their own 
categories of research that they would either permit or disallow?
    Question 51: If the requirement to obtain consent for all research 
uses of biospecimens is implemented, how should it be applied to 
biospecimens that are collected outside of the U.S. but are to be used 
in research supported by a Common Rule agency? Should there be 
different rules for that setting, and if so, what should they be? 
Should they be based on the relevant requirements in the countries 
where the biospecimens were collected?
    Question 52: Should the new consent rules be applied only 
prospectively, that is, should previously existing biospecimens and 
data sets be ``grandfathered'' under the prior regulatory requirements? 
If so, what are the operational issues with doing so?
    Question 53: In cases in which consent for future research use is 
not obtained at the time of collection, should there be a presumption 
that obtaining consent for the secondary analysis of existing 
biospecimens or identifiable data would be deemed impracticable, such 
that consent could be waived, when more than a specified threshold 
number of individuals are involved? (SACHRP provided the Secretary with 
recommendations on this issue.\81\) If so, what threshold number should 
constitute impracticability? Is the number of potential human subjects 
the only measure of impracticability?

V. Strengthening Data Protections To Minimize Information Risks

    Collection of identifiable data, as well as secondary analyses of 
such data, poses informational risks. The assurance that identifiable 
information will be safeguarded is important for an individual's 
willingness to participate in research. Further, we recognize that 
there is an increasing belief that what constitutes ``identifiable'' 
and ``de-identified'' data is fluid; rapidly evolving advances in 
technology coupled with the increasing volume of data readily available 
may soon allow identification of an individual from data that is 
currently considered de-identified. In this sense, much of what is 
currently considered de-identified is also potentially identifiable 
data.
    While there are currently some regulatory approaches that can be 
used to safeguard and maintain the confidentiality of research 
participants' information, such protections are limited in scope. The 
HIPAA Privacy and Security Rules generally require safeguards for 
individually identifiable health information and place limits and 
conditions on the use and disclosure of such information. However, the 
Rules only apply to researchers if they are part of a HIPAA covered 
entity (e.g., a covered health care provider or health plan) and, to a 
certain extent, to researchers that are business associates of a 
covered entity.
    Separate from the HIPAA Rules, the Privacy Act of 1974, as amended 
(5 U.S.C. 552a \82\) binds Federal agencies to protect personally 
identifiable information in their possession and control. It prohibits 
the disclosure (without prior consent or notice) of records that are 
retrieved by personal identifiers. In addition, there are other Federal 
privacy provisions that may need to be considered, but all have a 
limited scope. For example, Title 5 of the E-Government Act,\83\ 
entitled the ``Confidential Information Protection and Statistical 
Efficiency Act of 2002,''(CIPSEA) provides additional protections for 
confidential statistical

[[Page 44525]]

information collected by the Federal government. However, neither the 
Privacy Act nor CIPSEA generally apply to grant-funded investigators 
who are neither Federal employees nor contractors. (An additional 
example is the Department of Justice's set of regulations for 
protecting information collected in certain research and other 
programs, at 28 CFR part 22.)
    Furthermore, none of these statutes was written with an eye toward 
the advances that have come in genetic and information technologies 
that make complete de-identification of biospecimens impossible and re-
identification of sensitive health data easier. Certificates of 
confidentiality may be issued upon request through the authority of HHS 
(section 301(d) of the Public Health Service Act (42 U.S.C. 241(d)) to 
any investigator conducting IRB-approved research that involves the 
collection of sensitive and identifiable information. However, 
certificates of confidentiality do not require investigators to refuse 
to disclose identifying information; rather, they convey the legal 
right to refuse to disclose. Certificates of confidentiality also do 
not protect against unauthorized or accidental disclosures of 
identifiable private information due to inadequate data security 
procedures. The National Institute of Justice (NIJ) provides a 
different model for privacy protection: all NIJ-funded investigators 
collecting identifying information must apply for a privacy certificate 
and are required to keep identifiable data confidential (28 CFR part 
22).
    Consequently, other fundamental protections for research 
participants may be warranted beyond updating the requirements for 
independent review and informed consent currently provided by the 
Common Rule. As noted above (Section II(A)), a solution we are 
considering is to mandate data security and information protection 
standards that would apply to all research that collected, stored, 
analyzed or otherwise reused identifiable or potentially identifiable 
information. This would include research with biospecimens, survey 
data, and research using administrative records as well as secondary 
analysis of the data. However, we are considering applying these new 
protections only to prospective collections of data and biospecimens 
after the implementation of any changes to the Common Rule and not 
retrospectively to research involving existing data, including stored 
biospecimens and their subsequent analysis. Further, it is envisioned 
that these data security and information protection standards would be 
scaled appropriately to the level of identifiability of the data.
    While the discussion below focuses on these data security and 
information protection standards, we also are interested in whether 
there are other changes that might be made to the Common Rule, such as 
appropriate limitations on researchers' disclosure of identifiable or 
potentially identifiable information, that would strengthen, and create 
more uniformity in, the promises of confidentiality that currently 
exist for human subjects.

A. Consistently Characterizing Information With Respect to Potential 
for Identification

    Currently, the HIPAA Privacy Rule's standards for identifiable and 
de-identified information are not aligned with what is considered human 
subjects research under the Common Rule. Under the Common Rule research 
does not involve ``human subjects'' if the investigator does not obtain 
data about individuals through an interaction or intervention or obtain 
identifiable private information about individuals.\84\ Under the 
regulatory definition of human subject, ``private information'' is 
described as ``information about behavior that occurs in a context in 
which the individual can reasonably expect that no observation or 
recording is taking place, and information which has been provided for 
specific purposes by an individual and which the individual can 
reasonably expect will not be made public (for example, a medical 
record).'' Private information is not considered to be identifiable 
under the Common Rule if the identity of the subject is not or may not 
be ``readily ascertained'' by the investigator from the information. 
Under the HIPAA Privacy Rule, health information is de-identified and 
thus exempt from the Rule, if it neither identifies nor provides a 
reasonable basis to identify an individual.
    The HIPAA Privacy Rule provides two ways to de-identify 
information: (1) A formal determination by a qualified expert that the 
risk is very small that an individual could be identified; or (2) the 
removal of all 18 specified identifiers of the individual and of the 
individual's relatives, household members, and employers, as long as 
the covered entity has no actual knowledge that the remaining 
information could be used to identify the individual (45 CFR 
164.514(b)). Under these rules, some information that is not considered 
identifiable under the Common Rule may be considered identifiable for 
purposes of the HIPAA Privacy Rule, such as dates of service or zip 
codes. However, to accommodate investigators' need to have access to 
data elements such as these, the Privacy Rule also provides for a 
limited data set to be used for research purposes, which is data that 
has been stripped of direct identifiers but that may retain certain 
elements, such as dates of service and zip codes (45 CFR 
164.514(e)(2)). Because a limited data set is not considered fully de-
identified, the Privacy Rule requires that a covered entity enter into 
a data use agreement with the investigator to prohibit the re-
identification of the information and to otherwise protect the 
information.
    We are considering adopting the HIPAA standards for purposes of the 
Common Rule regarding what constitutes individually identifiable 
information, a limited data set, and de-identified information, in 
order to address inconsistencies regarding these definitions and 
concepts between the HIPAA Privacy Rule and the Common Rule. 
Furthermore, in light of emerging technologies and evolving 
informational risks, it might be advisable to evaluate the set of 
identifiers that must be removed for a data set to be considered ``de-
identified'' under both human subjects regulations and the HIPAA 
Privacy Rule. Table 1 in Section II illustrates how the HIPAA Privacy 
Rule's standards of identifiability would apply to the Excused category 
of research involving pre-existing information or biospecimens.
    Regardless of what information is removed, it is possible to 
extract DNA from a biospecimen itself and potentially link it to 
otherwise available data to identify individuals. Consequently, we are 
considering categorizing all research involving the primary collection 
of biospecimens as well as storage and secondary analysis of existing 
biospecimens as research involving identifiable information (see Table 
1, at the end of this section).
    Comments and recommendations are requested on the following:
    Question 54: Will use of the HIPAA Privacy Rule's standards for 
identifiable and de-identified information, and limited data sets, 
facilitate the implementation of the data security and information 
protection provisions being considered? Are the HIPAA standards, which 
were designed for dealing with health information, appropriate for use 
in all types of research studies, including social and behavioral 
research? If the HIPAA standards are not appropriate for all studies, 
what standards would be more appropriate?
    Question 55: What mechanism should be used to regularly evaluate 
and to recommend updates to what is

[[Page 44526]]

considered de-identified information? Beyond the mere passage of time, 
should certain types of triggering events such as evolutions in 
technology or the development of new security risks also be used to 
demonstrate that it is appropriate to reevaluate what constitutes de-
identified information?
    Question 56: DNA extracted from de-identified biospecimens can be 
sequenced and analyzed in other ways, with the results sometimes being 
linked to other available data than may allow a researcher to identify 
the persons whose specimens were being studied. How should Federal 
regulations manage the risks associated with the possibility of 
identification of such biospecimens? Should a human biospecimen be 
considered identifiable in and of itself? What are the advantages and 
disadvantages of considering all future research with biospecimens to 
be research with identifiable information?
    Question 57: Should some types of genomic data be considered 
identifiable and, if so, which types (e.g., genome-wide SNP analyses or 
whole genome sequences)?

B. Standards for Data Security and Information Protection

    The goal of information protection is to prevent breach of 
confidentiality through unauthorized access, inappropriate disclosure, 
or re-identification at either the individual or in some cases the 
subgroup level. Information that contains direct identifiers of 
individuals poses a greater informational risk than does a limited data 
set, which in turn poses a greater informational risk than de-
identified information.
    As discussed in Section II(A), the majority of unauthorized 
disclosures of identifiable health information from investigators occur 
due to inadequate data security.\85\ IRB review or oversight of 
research posing informational risks may not be the best way to minimize 
the informational risks associated with data on human subjects. 
Instead, informational risks may be best mitigated through compliance 
with stringent standards for data security and information protection 
that are effectively enforced through mechanisms such as periodic 
random audits.
    We are considering three specific requirements that could 
strengthen the protections for research studies that pose informational 
risks. First, research involving the collection and use of identifiable 
data, as well as data in limited data set form, could be required to 
adhere to data security standards modeled on the HIPAA Security 
Rule.\86\ In particular, for research involving individually 
identifiable information, all biospecimens, and limited data sets, data 
security standards could require the use of reasonable and appropriate 
encryption for data maintained or transmitted in electronic form and 
strong physical safeguards for information maintained in paper form, 
audit trails, and access controls that allow only authorized personnel 
to have access to the information. Further, investigators would be 
required to adhere to breach notification standards modeled on those 
applied to HIPAA covered entities for breaches of individually 
identifiable health information.\87\ For research using limited data 
sets or de-identified information, investigators would be strictly 
prohibited from attempting to re-identify the subjects of the 
information. Requiring that investigators implement and adhere to these 
standard data security and information protection measures would lessen 
the need for investigators to enter into data use agreements to protect 
the limited data set, as is currently required under the HIPAA Privacy 
Rule. Because these mandatory protections would apply to all research 
studies, it should not be necessary for IRBs to review studies posing 
only informational risks or to consider informational risks in studies 
involving other risks to human subjects.
    Second, data could be considered de-identified or in limited data 
set form even if investigators see the identifiers but do not record 
them in the permanent research file. To de-identify information or 
create limited data sets, many investigators have established complex 
procedures for having ``trusted third parties'' remove identifiers 
prior to passing on information to an investigator for a study. This 
adds another level of complexity and suggests that third parties are 
more trusted to protect information than investigators. If 
investigators adhere to the standards for data security and information 
protection there may be less need for these complex third party 
relationships.
    Third, to strengthen the enforcement mechanisms under the Common 
Rule, we are considering providing for periodic random retrospective 
audits, and additional enforcement tools.
    Comments and recommendations are requested on any of the above 
proposals under consideration and on the following specific questions:
    Question 58: Should the new data security and information 
protection standards apply not just prospectively to data and 
biospecimens that are collected after the implementation of new rules, 
but instead to all data and biospecimens? Would the administrative 
burden of applying the rule to all data and biospecimens be 
substantially greater than applying it only prospectively to newly 
collected information and biospecimens? How should the new standards be 
enforced?
    Question 59: Would study subjects be sufficiently protected from 
informational risks if investigators are required to adhere to a strict 
set of data security and information protection standards modeled on 
the HIPAA Rules? Are such standards appropriate not just for studies 
involving health information, but for all types of studies, including 
social and behavioral research? Or might a better system employ 
different standards for different types of research? (We note that the 
HIPAA Rules would allow subjects to authorize researchers to disclose 
the subjects' identities, in circumstances where investigators wish to 
publicly recognize their subjects in published reports, and the 
subjects appreciate that recognition.)
    Question 60: Is there a need for additional standardized data 
security and information protection requirements that would apply to 
the phase of research that involves data gathering through an 
interaction or intervention with an individual (e.g. during the 
administration of a survey)?
    Question 61: Are there additional data security and information 
protection standards that should be considered? Should such mandatory 
standards be modeled on those used by the Federal government (for 
instance, the National Institute of Standards and Technology recently 
issued a ``Guide to Protecting the Confidentiality of Personally 
Identifiable Information.'')?
    Question 62: If investigators are subject to data security and 
information protection requirements modeled on the HIPAA Rules, is it 
then acceptable for HIPAA covered entities to disclose limited data 
sets to investigators for research purposes without obtaining data use 
agreements?
    Question 63: Given the concerns raised by some that even with the 
removal of the 18 HIPAA identifiers, re-identification of de-identified 
datasets is possible, should there be an absolute prohibition against 
re-identifying de-identified data?
    Question 64: For research involving de-identified data, is the 
proposed prohibition against a researcher re-identifying such data a 
sufficient protection, or should there in some instances be 
requirements preventing the researcher from disclosing the de-
identified data to, for example, third

[[Page 44527]]

parties who might not be subject to these rules?
    Question 65: Should registration with the institution be required 
for analysis of de-identified datasets, as was proposed in Section 
II(B)(3) for Excused research, so as to permit auditing for 
unauthorized re-identification?
    Question 66: What entity or entities at an institution conducting 
research should be given the oversight authority to conduct the audits, 
and to make sure that these standards with regard to data security are 
being complied with? Should an institution have flexibility to 
determine which entity or entities will have this oversight 
responsibility for their institution?

    Table 1--Proposal for the Excused Category of Research Involving Pre-Existing Information or Biospecimens
----------------------------------------------------------------------------------------------------------------
                                                                                              De-identified
                                             Identifiable         Limited data set (as       information (as
                                         information and all      defined in the HIPAA     defined in the HIPAA
                                             biospecimens            Privacy Rule)            Privacy Rule)
----------------------------------------------------------------------------------------------------------------
Written consent required for future    Yes, which could be      No consent required....  No consent required.
 research with material collected for   obtained in connection
 non-research purposes?.                with the initial
                                        collection.
Consent for future research with       Yes. Consent for future  Yes. Same rule as for    Yes. Same rule as for
 material collected for research        research typically       ``Identifiable           ``Identifiable
 purposes?.                             obtained at the same     Information and All      Information and All
                                        time as consent for      Biospecimens''.          Biospecimens.''
                                        initial research
                                        (which, for data,
                                        could be oral when
                                        oral consent was
                                        permissible for the
                                        initial collection).
Standardized Data Protections?*......  Yes. Protections would   Yes. Same rule as for    Yes. Protection would
                                        include encryption,      ``Identifiable           include prohibition on
                                        use only by authorized   Information and All      re-identification.
                                        personnel with audit     Biospecimens'' plus a
                                        tracing, prompt breach   prohibition against re-
                                        notification, and        identification.
                                        periodic retrospective
                                        random audits.
Registration of research with IRB or   Yes....................  Yes....................  No.
 research office?.
Prior Review by IRB or research        No, unless               No.....................  No.
 office?                                investigators plan to
                                        re-contact subjects
                                        with their individual
                                        research results.
----------------------------------------------------------------------------------------------------------------
* These data protections are discussed in the context of secondary research uses of biospecimens and data, which
  present mostly informational risks, rather than physical risks, to participants. However, as indicated
  elsewhere in this ANPRM, informational risks will always be present where data and biospecimens are collected,
  thus requiring these data protections to be applied to any such research.

VI. Data Collection To Enhance System Oversight

    Research agencies collect various types of safety data with the 
common goal of protecting human subjects. However, individual agency 
requirements for reporting such data vary. This has resulted in 
variations between agencies regarding their policies and requirements 
for the reporting of such data. For example, the Common Rule does not 
require investigators to report ``adverse events'', but rather 
references ``unanticipated problems involving risks to subjects or 
others.'' The relationship of ``unanticipated problems'' to ``adverse 
events'' historically has been unclear. Furthermore, there are some 
agencies that do require the reporting of many ``adverse events'' 
beyond those that constitute ``unanticipated problems.'' Those 
reporting requirements often utilize variable definitions of what 
constitutes such an event and require these reports on different 
timeframes and on various templates utilizing inconsistent vocabularies 
describing the severity and nature of these events.
    The adverse event data collected by each agency are stored and 
maintained in separate datasets. The lack of connectivity and 
interoperability inhibits the conduct of integrated analyses and 
comparative studies about the frequency and severity of adverse events. 
Similarly, current policy requirements and current data collection 
practices do not foster the collection of data about the numbers of 
participants in various areas of research--information that is needed 
for characterizing the magnitude and severity of any risks.
    We are considering a number of changes to improve the current 
system for the real-time prompt collection of such data. These changes 
are intended to simplify and consolidate the reporting of information 
that is already required to be promptly reported by an investigator, 
and not to expand the information that has to be reported. These 
changes involve (1) Using a standardized, streamlined set of data 
elements that nonetheless are flexible enough to enable customized 
safety reporting and compliance with most Federal agency reporting 
requirements; (2) implementing a prototype of a Web-based, Federal-wide 
portal (already developed by NIH, FDA, and 4 other Federal agencies) 
that would build on these data elements and allow investigators to 
submit electronically certain pre- and post-market safety data and 
automatically have it delivered to appropriate agencies and oversight 
bodies; and (3) harmonizing safety reporting guidance across all 
Federal agencies, including harmonizing terminology and clarifying the 
scope and timing of such reports. In addition to these changes, the 
Federal government is also considering creating a central Web-based 
repository to house a great deal of the information collected through 
the portal.
    These innovations create the possibility of eliminating much of the 
existing multiplicity of different and confusing reporting mechanisms, 
and could foster greater uniformity and comparability among the safety 
information that gets reported. Consolidation of data reported using 
consistent vocabularies and terms would allow for more powerful and 
meaningful analyses of safety information across types of research 
studies than are possible at present.
    Comments and recommendations are requested on any of the above 
proposals

[[Page 44528]]

under consideration and on the following specific questions:
    Question 67: Is the scope of events that must be reported under 
current policies, including the reporting of certain ``unanticipated 
problems'' as required under the Common Rule, generally adequate?
    Question 68: With regard to data reported to the Federal 
government:
    a. Should the number of research participants in Federally funded 
human subjects research be reported (either to funding agencies or to a 
central authority)? If so, how?
    b. What additional data, not currently being collected, about 
participants in human subjects research should be systematically 
collected in order to provide an empirically-based assessment of the 
risks of particular areas of research or of human subjects research 
more globally?
    c. To what types of research should such a requirement apply (e.g., 
interventional studies only; all types of human subjects research, 
including behavioral and social science research)? In addition, are 
there other strategies and methods that should be implemented for 
gathering information on the effectiveness of the human subjects 
protection system?
    Question 69: There are a variety of possible ways to support an 
empiric approach to optimizing human subjects protections. Toward that 
end, is it desirable to have all data on adverse events and 
unanticipated problems collected in a central database accessible by 
all pertinent Federal agencies?
    Question 70: Clinical trials assessing the safety and efficacy of 
FDA-regulated medical products (i.e., phase II through IV studies) are 
generally required to register and, following study completion, report 
summary results, including adverse events, in the publicly accessible 
database ClinicalTrials.gov. Is the access to information on individual 
studies provided by this resource sufficiently comprehensive and timely 
for the purposes of informing the public about the overall safety of 
all research with human participants?

VII. Extension of Federal Regulations

    Currently, an institution engaged in non-exempt human subjects 
research conducted or supported by any Federal department or agency 
that has adopted the Common Rule is required to hold an OHRP-approved 
Federalwide Assurance (FWA) or another assurance of compliance approved 
by the department or agency conducting or supporting the research. The 
FWA mandates the application of the Common Rule only to certain 
Federally funded research projects. Most institutions voluntarily 
extend the applicability of their FWAs to all the research conducted at 
their institutions, even research not conducted or supported by one of 
the Federal departments or agencies that have adopted the Common Rule. 
However, such extension is not required.
    The IOM and NBAC, among many others, have called for legislation 
that would extend the Common Rule protections to all research with 
human subjects conducted in the U.S., regardless of funding source.
    We are considering an alternative regulatory proposal to partially 
fulfill this goal: requiring domestic institutions that receive some 
Federal funding from a Common Rule agency for research with human 
subjects to extend the Common Rule protections to all research studies 
conducted at their institution.
    Comments and recommendations are requested on the following:
    Question 71: Should the applicability of the Common Rule be 
extended to all research that is not Federally funded that is being 
conducted at a domestic institution that receives some Federal funding 
for research with human subjects from a Common Rule agency?

VIII. Clarifying and Harmonizing Regulatory Requirements and Agency 
Guidance

    From the outset of the development of the Common Rule, the 
importance of consistency across the Federal government has been 
recognized. In May 1982, the Chairman of the Federal Coordinating 
Council for Science, Engineering, and Technology appointed an Ad Hoc 
Committee for the Protection of Human Research Subjects. In 
consultation with OSTP and the Office of Management and Budget, the Ad 
Hoc Committee agreed that uniformity is desirable among departments and 
agencies to eliminate unnecessary regulation and to promote increased 
understanding and ease of compliance by institutions that conduct 
Federally supported or regulated research involving human subjects. By 
1991, 15 Federal departments and agencies had adopted the Common Rule.
    However, each of the departments and agencies that have adopted the 
Common Rule may issue its own guidance regarding the protection of 
human subjects. Consequently, there are variations in the guidances 
issued.
    In addition, other Federal laws and regulations have been enacted 
that relate to the protection of human subjects, most prominently, the 
research provisions of the HIPAA Privacy Rule. However, since the HIPAA 
regulations were developed mainly for the clinical context,\88\ the 
rules are inconsistent with the Common Rule in certain areas. As noted 
above, one such inconsistency is the definition of identifiable data 
and another is the manner in which the two rules treat consent for 
future research.
    Currently, there are multiple efforts to address such variation in 
guidance across the Federal government. The Common Rule departments and 
agencies have procedures for sharing proposed guidance before it is 
adopted. FDA and OHRP have been working closely on enhancing 
harmonization of guidance.
    As the label of the Common Rule suggests, there seems to be a 
compelling case for consistency across Federal departments and agencies 
regarding guidance on the protections of human subjects. Nevertheless, 
there are arguments in favor of some departments or agencies imposing 
specific requirements, apart from the Common Rule, that are tailored to 
certain types of research. The various agencies that oversee the 
protection of human subjects range from regulatory agencies, to those 
agencies and departments that conduct research, to those that support 
and sponsor research. In addition, in some cases, statutory differences 
among the agencies have resulted in different regulatory requirements 
and agency guidances. Not only do the agencies have different 
relationships to the research, they oversee very different types and 
phases of research and thus there may be reasonable justifications for 
differences in guidance. Moreover, achieving consensus across the 
entire Federal government may be arduous, preventing timely issuance of 
guidance.
    Comments and recommendations are requested on the following:
    Question 72: To what extent do the differences in guidance on 
research protections from different agencies either strengthen or 
weaken protections for human subjects?
    Question 73: To what extent do the existing differences in guidance 
on research protections from different agencies either facilitate or 
inhibit the conduct of research domestically and internationally? What 
are the most important such differences influencing the conduct of 
research?
    Question 74: If all Common Rule agencies issued one set of 
guidance, would research be facilitated both domestically and 
internationally? Would a single set of guidance be able to adequately 
address human subjects protections in diverse populations and

[[Page 44529]]

contexts, and across the broad range of research contexts (including 
biomedical, national security, education and other types of social and 
behavioral research)?

IX. Agency Request for Information

    When submitting responses to the specific questions asked in this 
notice, please cite the specific question by number.
    In addition to the specific solicitation of comments throughout 
this ANPRM, general comment is invited on the current system of 
protections for human research subjects as implemented through the 
Common Rule, the HIPAA Privacy and Security Rules, and any other rules, 
regulations or guidance documents. In particular, comments are sought 
not only on ways to improve the efficiency of the current system, but 
about circumstances in which the protections provided by the current 
system might be inadequate and in need of supplementation or change in 
order to make sure that subjects are receiving appropriate protections.

    Dated: July 20, 2011.
John Holdren,
Director, Office of Science Technology and Policy.
Kathleen Sebelius,
Secretary, HHS.

    \1\ The Federal Policy for the Protection of Human Subjects or 
the ``Common Rule'' was published in 1991 and codified in separate 
regulations by 15 Federal departments and agencies, as listed below 
(each agency includes in its chapter of the Code of Federal 
Regulations [CFR] section numbers and language that are identical to 
those of 45 CFR part 46, subpart A).
    These agencies included the Department of Agriculture (7 CFR 
part 1c), Department of Commerce (15 CFR part 27), Department of 
Defense (32 CFR part 219), Department of Education (34 CFR part 97), 
Department of Energy (10 CFR part 745), Department of Health and 
Human Services (45 CFR part 46 subpart A), Department of Housing and 
Urban Development (24 CFR part 60), Department of Justice (28 CFR 
part 46), Department of Veterans Affairs (38 CFR part 16), 
Department of Transportation (49 CFR part 11), Consumer Product 
Safety Commission (16 CFR part 1028), Environmental Protection 
Agency (40 CFR part 26), Agency for International Development (22 
CFR part 225), National Aeronautics and Space Administration (14 CFR 
part 1230), National Science Foundation (45 CFR part 690).
    In addition, the Central Intelligence Agency must comply with 
all subparts of 45 CFR part 46 under Executive Order 12333, and in 
accordance with the Intelligence Reform and Terrorism Protection Act 
of 2004 (Pub. L. 108-458, Section 8306), the Department of Homeland 
Security adopted policies implementing the protections for human 
research subjects under 45 CFR part 46 for research it conducts or 
supports.
    For all participating departments and agencies the Common Rule 
outlines the basic provisions for IRBs, informed consent, and 
Assurances of Compliance. HHS has developed additional regulations 
for the human subjects research it conducts or supports that apply 
to particular special populations: 45 CFR part 46 subparts B-D apply 
to research involving pregnant women, human fetuses, and neonates 
(subpart B), prisoners (subpart C), and children (subpart D).
    \2\ Congressional Budget Office. Research and Development in the 
Pharmaceutical Industry. October 2006.
    \3\ Federman DD, Hanna KE, Rodriguez LL, eds. Responsible 
Research: A Systems Approach to Protecting Research Participants. 
Washington, DC: National Academies Press; 2002.
    \4\ Nass SJ, Levit LA, Gostin LO, eds. Beyond the HIPAA Privacy 
Rule: Enhancing Privacy, Improving Health Through Research. 
Washington, DC: National Academies Press; 2009.
    \5\ Human Subjects Research: HHS Takes Steps to Strengthen 
Protections, But Concerns Remain. GAO-01-775T, May 23, 2001.
    \6\ Scientific Research: Continued Vigilance Critical to 
Protecting Human Subjects. T-HEHS-96-102, Mar 12, 1996
    \7\ Scientific Research: Continued Vigilance Critical to 
Protecting Human Subjects. HEHS-96-72, Mar 8, 1996.
    \8\ Kim S, Ubel P, De Vries R. Pruning the regulatory tree: For 
human-subjects research, maximum regulation does not mean maximum 
protection. Nature 2009;457:534-535.
    \9\ Emanuel EJ, Wood A, Fleischman A, et al. Oversight of human 
participants research: Identifying problems to evaluate reform 
proposals. Ann Int Med 2004;141(4):282-291.
    \10\ Lynn J, Baily MA, Bottrell M, et al. The ethics of using 
quality improvement methods in health care. Ann Int Med 
2007;146(9):666-673.
    \11\ National Bioethics Advisory Commission, Ethical and Policy 
Issues in Research Involving Human Participants. Bethesda, MD; 2001.
    \12\ Executive Order, Improving Regulation and Regulatory 
Review. January 18, 2011.
    \13\ Wendler D, Varma S. Minimal risk in pediatric research. J 
Peds 2006;149:855-861.
    \14\ Kim S, Ubel P, De Vries R. Pruning the regulatory tree: For 
human-subjects research, maximum regulation does not mean maximum 
protection. Nature 2009;457:534-535.
    \15\ Center for Advanced Study. The Illinois White Paper: 
Improving the System for Protecting Human Subjects: Counteracting 
IRB ``Mission Creep.'' 2005.
    \16\ American Association of University Professors. Academic 
Freedom and the Institutional Review Board. 2006.
    \17\ Kim S, Ubel P, De Vries R. Pruning the regulatory tree: For 
human-subjects research, maximum regulation does not mean maximum 
protection. Nature 2009;457:534-535.
    \18\ National Research Council, Protecting Participants and 
Facilitating Social and Behavioral Sciences Research. Washington, 
DC: National Academies Press; 2003.
    \19\ Center for Advanced Study. The Illinois White Paper: 
Improving the System for Protecting Human Subjects: Counteracting 
IRB ``Mission Creep.'' 2005.
    \20\ Schrag Z. Ethical Imperialism. Baltimore, MD: Johns Hopkins 
University Press; 2010.
    \21\ Schrag ZM. How talking became human subjects research: The 
federal regulation of the social sciences. J Policy History 
2009;21(01):3.
    \22\ Bledsoe CH, Sherin B, Galinsky AG, et al. Regulating 
creativity: Research and survival in the IRB iron cage. Northwestern 
U L Rev 2007;101:593-641.
    \23\ Emanuel EJ, Wood A, Fleischman A, et al. Oversight of human 
participants research: Identifying problems to evaluate reform 
proposals. Ann Int Med 2004;141(4):282-291.
    \24\ Albala I, Doyle M, Appelbaum PS. The evolution of consent 
forms for research: A quarter century of changes. IRB: Ethics & 
Human Research 2010;32(3):7-11.
    \25\ Paasche-Orlow MK, Taylor HA, Brancati F. Readability 
standards for informed-consent forms as compared with actual 
readability. N Engl J Med 2003;348:721-726.
    \26\ Sharp MS. Consent documents for oncology trials: Does 
anybody read these things? Am J Clin Onc 2004;27:570-575.
    \27\ Levine RJ. Informed consent: Some challenges to the 
universal validity of the western model. J Law Med Ethics 1991;19(3-
4):207-213.
    \28\ Cribb R. Ethical regulation and humanities research in 
Australia: Problems and consequences. Monash Bioethics Rev 
2004;23(3):39-57.
    \29\ Wertz DC. Public Perceptions: Surveys of Attitudes Toward 
Biotechnology. In: Murray TH, Mehlman MJ, eds. Encyclopedia of 
Ethical, Legal and Policy Issues in Biotechnology. John Wiley & 
Sons; 2002.
    \30\ 45 CFR part 160 and 45 CFR part 164, subparts A and E.
    \31\ http://www.justice.gov/opcl/privstat.htm; and http://www.justice.gov/opcl/1974privacyact-overview.htm.
    \32\ Coleman CH, Bou[euml]sseau MC. How do we know that research 
ethics committees are really working? The neglected role of outcomes 
assessment in research ethics review. BMC Med Ethics 2008;9:6.
    \33\ Steinbrook R. Improving protection for research subjects. N 
Engl J Med 2002;346:1425-1430.
    \34\ Nass SJ, Levit LA, Gostin LO, eds. Beyond the HIPAA Privacy 
Rule: Enhancing Privacy, Improving Health Through Research. 
Washington, DC: National Academies Press; 2009.
    \35\ Pritts JL. The Importance and Value of Protecting the 
Privacy of Health Information: The Roles of the HIPAA Privacy Rule 
and the Common Rule in Health Research. 2008. http://www.iom.edu/~/
media/Files/Activity%20Files/Research/HIPAAandResearch/
PrittsPrivacyFinalDraftweb.ashx.
    \36\ Any references in this notice to the ``Common Rule,'' 
unless otherwise specified, should be understood as including the 
relevant portions of the FDA regulations.
    \37\ 76 FR 11482, March 2, 2011.
    \38\ 45 CFR 46.110.
    \39\ 45 CFR 46.101(b).

[[Page 44530]]

    \40\ http://answers.hhs.gov/ohrp/categories/1564.
    \41\ Cann CI, Rothman KJ. IRBs and epidemiological research: How 
inappropriate restrictions hamper studies. IRB 1984;6(4):5-7.
    \42\ Silverman H, Hull SC, Sugarman J. Variability among 
institutional review boards' decisions within the context of a 
multicenter trial. Crit Care Med.2001;29:235-241.
    \43\ Dziak K, Anderson R, Sevick MA, Weisman CS, Levine DW, 
Scholle SH. Variations among institutional review board reviews in a 
multisite health services research study. Health Services Res 
2005;40:279-290.
    \44\ Hirshon JM, Krugman SD, Witting MD et al. Variability in 
institutional review board assessment of minimal-risk research. Acad 
Emerg Med 2002;9:1417-1420.
    \45\ Federman DD, Hanna KE, Rodriguez LL, eds. Responsible 
Research: A Systems Approach to Protecting Research Participants. 
Washington, DC: National Academies Press; 2002.
    \46\ Nass SJ, Levit LA, Gostin LO, eds. Beyond the HIPAA Privacy 
Rule: Enhancing Privacy, Improving Health Through Research. 
Washington, DC: National Academies Press; 2009.
    \47\ Green LA, Lowery JC, Kowalski CP, Wyszewianski L. Impact of 
institutional review board practice variation on observational 
health services research. Health Serv Res 2006;41:214-230.
    \48\ 45 CFR 46.102(i).
    \49\ Hirshon JM, Krugman SD, Witting MD et al. Variability in 
institutional review board assessment of minimal-risk research. Acad 
Emerg Med 2002;9:1417-1420.
    \50\ Gawande A. A Lifesaving Checklist. New York Times, December 
30, 2007.
    \51\ Lynn J, Baily MA, Bottrell M, et al. The ethics of using 
quality improvement methods in health care. Ann Int Med 
2007;146(9):666-673.
    \52\ Kimmelman J. Valuing risk: The ethical review of clinical 
trial safety. Kennedy Inst Ethics J 2004;14:369-93.
    \53\ Schrag Z. Ethical Imperialism. Baltimore, MD: Johns Hopkins 
University Press; 2010:45-46, 70-71.
    \54\ Dziak K, Anderson R, Sevick MA, Weisman CS, Levine DW, 
Scholle SH. Variations among institutional review board reviews in a 
multisite health services research study. Health Services Res 
2005;40:279-290.
    \55\ Emanuel EJ, Wood A, Fleischman A, et al. Oversight of human 
participants research: Identifying problems to evaluate reform 
proposals. Ann Int Med 2004;141(4):282-291.
    \56\ Jansen LA. Local IRBs, multicenter trials, and the ethics 
of internal amendments. IRB,2005;27(4):7-11.
    \57\ https://www.aamc.org/initiatives/clinicalresearch/irbreview/.
    \58\ Infectious Disease Society of America. Grinding to a halt: 
The effects of the increasing regulatory burden on research and 
quality improvement efforts. Clin Infect Dis 2009;49:328-35.
    \59\ http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM127013.pdf.
    \60\ For general requirements for informed consent see 45 CFR 
46.116 and 21 CFR 50.25. There are provisions under 45 CFR part 46, 
subpart A, that allow for the waiver of some or all of the elements 
of informed consent. (See Sec. Sec.  46.116(c) and 46.116.(d)). 
FDA's statute limits the circumstances under which informed consent 
can be waived. Thus, FDA regulations contain only two exceptions 
from informed consent under 21 CFR 50.23 and 50.24.
    \61\ Menikoff J, Richards E. What the Doctor Didn't Say: The 
Hidden Truth about Medical Research. New York, NY: Oxford University 
Press; 2006:113-123.
    \62\ Menikoff J, Richards E. What the Doctor Didn't Say: The 
Hidden Truth about Medical Research. New York, NY: Oxford University 
Press; 2006:113-123.
    \63\ Albala I, Doyle M, Appelbaum PS. The evolution of consent 
forms for research: A quarter century of changes. IRB 2010;32(3):7-
11.
    \64\ Schneider CE. The Hydra. Hastings Center Rep 2010;40(4):9-
11.
    \65\ Paasche-Orlow MK, Taylor HA, Brancati F. Readability 
standards for informed-consent forms as compared with actual 
readability. N Engl J Med 2003;348:721-726.
    \66\ Goldstein AO, Frasier P, Curtis P, Reid A, Kreher NE. 
Consent form readability in university-sponsored research. J Fam 
Pract 1996;42:606-611.
    \67\ Philipson SJ, Doyle MA, Gabram SG, Nightingale C, Philipson 
EH. Informed consent for research: a study to evaluate readability 
and processability to effect change. J Investig Med 1995;43:459-467.
    \68\ Green LA, Lowery JC, Kowalski CP, Wyszewianski L. Impact of 
institutional review board practice variation on observational 
health services research. Health Serv Res 2006;41:214-230.
    \69\ Under 45 CFR 46.116(c), an IRB may approve a consent 
procedure which does not include, or which alters, some or all of 
the elements of informed consent otherwise required under 45 CFR 
part 46, or waive the requirement to obtain informed consent 
provided the IRB finds and documents that: (1) The research or 
demonstration project is to be conducted by or subject to the 
approval of state or local government officials and is designed to 
study, evaluate, or otherwise examine: (i) public benefit or service 
programs; (ii) procedures for obtaining benefits or services under 
those programs; (iii) possible changes in or alternatives to those 
programs or procedures; or (iv) possible changes in methods or 
levels of payment for benefits or services under those programs; and 
(2) The research could not practicably be carried out without the 
waiver or alteration.
    Under 45 CFR 46.116(d), an IRB may approve a consent procedure 
which does not include, or which alters, some or all of the elements 
of informed consent otherwise required under 45 CFR part 46, or 
waive the requirements to obtain informed consent provided the IRB 
finds and documents that: (1) The research involves no more than 
minimal risk to the subjects; (2) The waiver or alteration will not 
adversely affect the rights and welfare of the subjects; (3) The 
research could not practicably be carried out without the waiver or 
alteration; and (4) Whenever appropriate, the subjects will be 
provided with additional pertinent information after participation.
    \70\ Green LA, Lowery JC, Kowalski CP, Wyszewianski L. Impact of 
institutional review board practice variation on observational 
health services research. Health Serv Res 2006;41:214-230.
    \71\ Sanders AB, Hiller K, Duldner J. Researchers' understanding 
of the federal guidelines for waiver of and exception from informed 
consent. Acad Emerg Med 2005;12:1045-1049.
    \72\ http://www.dhhs.gov/ohrp/sachrp/sachrpletter013108.html.
    \73\ Nass SJ, Levit LA, Gostin LO, eds. Beyond the HIPAA Privacy 
Rule: Enhancing Privacy, Improving Health Through Research. 
Washington, DC: National Academies Press; 2009.
    \74\ Skloot R. The Immortal Life of Henrietta Lacks. New York: 
Crown Publishers; 2010.
    \75\ Furness PN. One-time general consent for research on 
biological samples: Good idea, but will it happen? BMJ 
2006;332(7542):665.
    \76\ Anderlik M. Commercial biobanks and genetic research: 
ethical and legal issues. Am J Pharmacogenomics. 2003;3:203-215.
    \77\ Hansson MG, Dillner J, Bartram CR, Carlson JA, Helgesson 
G.Should donors be allowed to give broad consent to future biobank 
research?. Lancet Oncol 2006;7:266-269.
    \78\ Wendler D. One-time general consent for research on 
biological samples: is it compatible with the health insurance 
portability and accountability act? Arch Intern Med.2006;166:1449-
1452.
    \79\ Murphy J, Scott J, Kaufman D, Geller G, LeRoy L, Hudson K. 
Public perspectives on informed consent for biobanking. Am J Public 
Health 2009;99:2128-2134.
    \80\ Kaufman DJ, Murphy-Bollinger J, Scott J, Hudson KL. Public 
opinion about the importance of privacy in biobank research, Am J 
Human Genet 2009;85:643-654.
    \81\ Secretary's Advisory Committee on Human Research 
Protections. SACHRP letter to HHS Secretary. January 31, 2008. 
http://www.dhhs.gov/ohrp/sachrp/sachrpletter013108.html.
    \82\ Privacy Act of 1974, as amended. http://www.justice.gov/opcl/privstat.htm; and Department of Justice, Office of Privacy and 
Civil Liberties. Overview of the Privacy Act of 1974. http://www.justice.gov/opcl/1974privacyact-overview.htm.
    \83\ Pub. L. 107-347. http://www.whitehouse.gov/sites/default/files/omb/assets/omb/inforeg/cipsea/cipsea_statute.pdf and Office 
of Management and Budget. Implementation Guidance for Title V of the 
E-Government Act, Confidential Information Protection and 
Statistical Efficiency Act of 2002. http://www.whitehouse.gov/sites/default/files/omb/assets/omb/fedreg/2007/061507_cipsea_guidance.pdf.
    \84\ 45 CFR 46.102(f).
    \85\ Nass SJ, Levit LA, Gostin LO, eds. Beyond the HIPAA Privacy 
Rule: Enhancing Privacy, Improving Health Through Research. 
Washington, DC: National Academies Press; 2009.
    \86\ 45 CFR part 160 and 45 CFR part 164, subparts A and C.

[[Page 44531]]

    \87\ 45 CFR part 160 and 45 CFR part 164, subparts A and D.
    \88\ The Common Rule evolved from a long series of measures 
designed to protect individual research subjects from physical and 
mental harm. In contrast, the HIPAA Privacy Rule evolved from data 
protection standards such as the Fair Information Practices. See 
Pritts JL (2008). The Importance and Value of Protecting the Privacy 
of Health Information: The Roles of the HIPAA Privacy Rule and the 
Common Rule in Health Research.

[FR Doc. 2011-18792 Filed 7-22-11; 11:15 am]
BILLING CODE 4150-28-P