[Federal Register Volume 71, Number 167 (Tuesday, August 29, 2006)]
[Proposed Rules]
[Pages 51143-51146]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E6-14264]
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Proposed Rules
Federal Register
________________________________________________________________________
This section of the FEDERAL REGISTER contains notices to the public of
the proposed issuance of rules and regulations. The purpose of these
notices is to give interested persons an opportunity to participate in
the rule making prior to the adoption of the final rules.
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Federal Register / Vol. 71, No. 167 / Tuesday, August 29, 2006 /
Proposed Rules
[[Page 51143]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 50
[Docket No. 2006D-0331]
Conduct of Emergency Clinical Research; Public Hearing
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice of public hearing; request for comments.
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SUMMARY: The Food and Drug Administration (FDA) is announcing a public
hearing on emergency research conducted without informed consent under
FDA's emergency research rule. The public hearing announced in this
document is part of FDA's Human Subject Protection and Bioresearch
Monitoring Initiative. We are particularly interested in hearing the
views of individuals and groups who have encountered challenges in the
conduct of emergency research in the absence of informed consent,
including patient advocacy groups, individuals who have participated in
clinical studies, institutional review board members (IRBs), sponsors,
clinical investigators, medical societies, ethicists, and other
interested parties. We are seeking input on a number of specific
questions regarding aspects of emergency research and additional human
subject protections. Elsewhere in this issue of the Federal Register,
we are also issuing a draft guidance entitled ``Guidance for
Institutional Review Boards, Clinical Investigators, and Sponsors;
Exception from Informed Consent Requirements for Emergency Research.''
We will consider comments received on this draft guidance together with
comments and suggestions received at the hearing to determine whether
the current framework is adequate for the ethical conduct of emergency
research, or whether modifications would be appropriate.
DATES: The public hearing will be held on October 11, 2006, from 8 a.m.
to 6 p.m. However, depending upon the level of public participation,
the meeting may end early. Submit written or electronic comments by
November 27, 2006. The administrative record of the hearing will remain
open for 45 days following the hearing.
ADDRESSES: The public hearing will be held at the University System of
Maryland Shady Grove Center, 9630 Gudelsky Dr., Rockville, MD 20850.
Submit written comments to the Division of Dockets Management (HFA-
305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852. Submit electronic comments to http://www.accessdata.fda.gov/scripts/oc/dockets/commentdocket.cfm.
See section I. of the SUPPLEMENTARY INFORMATION section for
information on how to participate in the meeting.
FOR FURTHER INFORMATION CONTACT: Terrie L. Crescenzi, Office of the
Commissioner (HF-18), Food and Drug Administration, 5600 Fishers Lane,
rm. 14B-45, Rockville, MD 20857, 301-827-7864, FAX: 301-443-9718,
[email protected].
SUPPLEMENTARY INFORMATION:
I. How to Participate in the Meeting
All individuals wishing to make a presentation at the hearing must
indicate their intent, the question to be addressed, and also provide
an abstract of the presentation by September 20, 2006. Submit written
or electronic comments by November 27, 2006, at the Division of Dockets
Management (see ADDRESSES).
The procedures governing the hearing are found in part 15 (21 CFR
part 15). If you wish to make an oral presentation during the hearing,
you must state your intention on your submission to the docket (see
ADDRESSES). To present, submit your name, title, business affiliation,
address, telephone number, fax number, and e-mail address. FDA has
identified questions and subject matter of special interest in section
V of this document. You should also identify by number each question
you wish to address in your presentation, although presentations do not
have to be limited to those questions. FDA will do its best to
accommodate requests to speak. Individuals and organizations with
common interests are urged to consolidate or coordinate their
presentations, and to request time for a joint presentation. FDA may
require joint presentations by persons with common interests. FDA will
determine the amount of time allotted to each presenter and the
approximate time that each oral presentation is scheduled to begin. FDA
will prepare the hearing schedule indicating which persons will be
making oral presentations and the time allotted to each person, which
will be filed with the Division of Dockets Management (see ADDRESSES)
and mailed or telephoned before the hearing to each participant.
Persons making oral presentations should arrive early to be sure that
they are present to make their presentation in case the schedule
advances. Individuals who are not present when called upon will likely
lose their ability to make their oral presentation. However, the
administrative record of the hearing will remain open for 45 days
following the hearing and individuals may submit written comments to
the docket as described in section VII of this document. Presenters
should submit two copies of each presentation given. All participants
are encouraged to attend the entire hearing.
If you need special accommodations due to a disability, please
contact Terrie L. Crescenzi (see FOR FURTHER INFORMATION CONTACT).
II. Background
On October 2, 1996, FDA issued a final rule providing a narrow
exception from the requirement of obtaining and documenting informed
consent from each human subject prior to initiation of a clinical
investigation. The intent of the regulation was to facilitate certain
emergency research while ensuring adequate protection of human subjects
(61 FR 51498, October 2, 1996). In the decade following issuance of the
regulation, we have received approximately 60 requests to conduct a
clinical investigation under Sec. 50.24 (21 CFR 50.24) with an
exception from the informed consent requirements. Now that we have
received a sizeable number of requests, we have reviewed our experience
with emergency clinical research under the 1996 regulatory framework.
We have heard informally from some individuals that the additional
safeguards in Sec. 50.24 are either insufficient or too poorly defined
to protect subjects; others have said that
[[Page 51144]]
the safeguards in the regulation are too onerous and interfere with
important research; still others have said that the regulation contains
the appropriate safeguards, but that further guidance is needed. In
addition, some have asserted that important emergency research is not
being carried out for a variety of reasons. These reasons include the
difficulties inherent in emergency research trial designs, and the
challenges and cost of applying specific aspects of Sec. 50.24.
III. Purpose and Scope of the Hearing
The purpose of this hearing is to provide patient advocacy groups,
individuals who have participated in clinical studies, IRBs, sponsors,
clinical investigators, medical societies, ethicists, and other
interested parties with an opportunity to discuss their experiences and
concerns in the conduct of emergency research without informed consent
under Sec. 50.24, and to determine whether the current framework is
adequate for the ethical conduct of emergency research or needs
modification. The hearing will give us the opportunity to hear these
parties' concerns related to the challenges of conducting
scientifically rigorous emergency research while maintaining human
subject protections and their suggestions for improving the process. We
hope to obtain information that will help in developing strategies to
address the identified challenges.
IV. Summary of Regulatory Requirements for Emergency Research
The regulation at Sec. 50.24(a) describes the following criteria
that must be met for a clinical investigation to be eligible for an
exception from the informed consent requirements. The responsible IRB
must find and document the following:
(1) The human subjects are in a life-threatening situation,
available treatments are unproven or unsatisfactory, and the collection
of valid scientific evidence, which may include evidence obtained
through randomized placebo-controlled investigations, is necessary to
determine the safety and effectiveness of particular interventions.
(2) Obtaining informed consent is not feasible because:
(a) The subjects will not be able to give their informed consent
as a result of their medical condition;
(b) The intervention under investigation must be administered
before consent from the subjects' legally authorized representatives is
feasible; and
(c) There is no reasonable way to identify prospectively the
individuals likely to become eligible for participation in the clinical
investigation.
(3) Participation in the research holds out the prospect of direct
benefit to the subjects because:
(a) Subjects are facing a life-threatening situation that
necessitates intervention;
(b) Appropriate animal and other preclinical studies have been
conducted, and the information derived from those studies and related
evidence support the potential for the intervention to provide a direct
benefit to the individual subjects; and
(c) Risks associated with the investigation are reasonable in
relation to what is known about the medical condition of the potential
class of subjects, the risks and benefits of standard therapy, if any,
and what is known about the risks and benefits of the proposed
intervention or activity.
(4) The clinical investigation could not practicably be carried out
without the exception from informed consent.
(5) The proposed investigational plan defines the length of the
potential therapeutic window based on scientific evidence, and the
investigator has committed to attempting to contact a legally
authorized representative for each subject within that window of time
and, if feasible, to asking the legally authorized representative
contacted for consent within that window rather than proceeding without
consent. The investigator will summarize efforts made to contact
legally authorized representatives and make this information available
to the IRB at the time of continuing review.
(6) The IRB has reviewed and approved informed consent procedures
and an informed consent document consistent with Sec. 50.25. These
procedures and the informed consent document are to be used with
subjects or their legally authorized representatives in situations
where use of such procedures and documents is feasible. The IRB has
reviewed and approved procedures and information to be used when
providing an opportunity for a family member to object to a subject's
participation in the clinical investigation consistent with Sec.
50.25(a)(7)(v).
(7) Additional protections of the rights and welfare of the
subjects will be provided, including, at least:
(a) Consultation (including, where appropriate, consultation
carried out by the IRB) with representatives of the communities in
which the clinical investigation will be conducted and from which the
subjects will be drawn;
(b) Public disclosure to the communities in which the clinical
investigation will be conducted and from which the subjects will be
drawn, prior to initiation of the clinical investigation, of plans for
the investigation and its risks and expected benefits:
(c) Public disclosure of sufficient information following
completion of the clinical investigation to apprise the community and
researchers of the study, including the demographic characteristics of
the research population, and its results;
(d) Establishment of an independent data monitoring committee to
exercise oversight of the clinical investigation; and
(e) If obtaining informed consent is not feasible and a legally
authorized representative is not reasonably available, the investigator
has committed, if feasible, to attempting to contact within the
therapeutic window the subject's family member who is not a legally
authorized representative, and asking whether he or she objects to the
subject's participation in the clinical investigation. The investigator
will summarize efforts made to contact family members and make this
information available to the IRB at the time of continuing review.
V. Issues for Discussion
At this part 15 hearing, we will be specifically inviting comments
on the questions discussed in sections V.A and V.B of this document.
A. Scientific Aspects of Emergency Research and Human Subject
Protection
In studies conducted under Investigational New Drug (IND) or
Investigational Device Exemption (IDE) applications without an
exception from the informed consent requirements, the products tested
need not show particular promise of being superior to existing
treatments in order for a clinical investigation to proceed. This is
acceptable because the subject has the opportunity to make an informed
decision and choose whether to participate in the clinical
investigation. In the special case where a clinical investigation is
permitted to proceed with an exception from the informed consent
requirements, however, the regulation demands that participation hold
out the prospect of direct benefit
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for participants, as suggested by animal data, other preclinical
studies, and related evidence. We recognize that it can be difficult to
determine whether a new treatment holds out enough of a prospect of
direct benefit to allow a clinical investigation to go forward and to
determine whether available treatment is ``unproven or
unsatisfactory''.
Therefore, FDA would like interested parties to address the
following questions:
(1) Are the criteria for allowing studies conducted under Sec.
50.24 adequate to protect human subjects and to promote scientifically
rigorous research? Are any additional criteria warranted?
(2) Are the following criteria easily understood and, if not, how
can they be clarified?
(a) ``Available treatments are unsatisfactory or unproven'' (Sec.
50.24(a)(1))
(b) ``Prospect of direct benefit'' (Sec. 50.24(a)(3))
(c) ``Practicably'' (Sec. 50.24(a)(4))
(3) Are there other criteria in the regulation, besides those
identified in criteria (2)(a) through (c), that need to be clarified?
(4) Are there challenges that have not been explicitly addressed in
the regulation in designing scientifically rigorous and ethically sound
emergency research protocols (e.g., pediatric protocols)? If there are
such challenges, should they be addressed and how?
B. Additional Human Subject Protections
Recognizing that emergency research presents unique human subject
protection and ethical challenges, Sec. 50.24 requires that additional
human subject protections be provided. In particular, in order to
ensure that emergency research is conducted with respect for the human
subjects as discussed in the Belmont Report,\1\ FDA recognizes that it
is important to inform and consult with the communities involved (which
include the communities where the clinical investigation will be
conducted and from which the subjects will be drawn). Therefore, Sec.
50.24 contains a number of additional human subject protections,
several of which are specifically designed to provide relevant
information to the involved communities. Such additional protections
include: (1) Community consultation, (2) public disclosure prior to
initiation of the clinical investigation of plans for the investigation
and its risks and expected benefits, and (3) public disclosure
following completion of the clinical investigation of information to
apprise the community and researchers of the study, including the
demographic characteristics of the research population, and its
results.
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\1\ The Belmont Report--Ethical Principles and Guidelines for
the Protection of Human Subjects of Research, The National
Commission for the Protection of Human Subjects of Biomedical and
Behavioral Research (44 FR 23192, April 18, 1979).
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Community Consultation
The regulation (Sec. 50.24 (a)(7)(i)) requires consultation with
representatives of the communities described previously, but provides
few details about how to do this or what would constitute adequate
consultation. We are aware that community consultation poses challenges
and therefore invite comments on the following questions.
(5) What are the costs, benefits, and feasibility of community
consultation as currently required under Sec. 50.24?
(6) What aspects of community consultation as currently practiced
are effective mechanisms for human subject protection? Are there
additional practices that could enhance human subject protection?
(7) Are there elements of community consultation, both procedural
and substantive, that should, at a minimum, be required (e.g., types of
information presented, number and types of meetings or interactions,
number of people reached)?
(8) Would opt-out mechanisms (e.g., advanced directives, jewelry
similar to medical alert bracelet/necklace, and driver's license
indicators) to identify individuals who do not wish to be included as
subjects in particular emergency research studies provide a necessary
protection for human subjects? If so, are they feasible?
(9) Who should use the information obtained from the community
consultation process and how should they use it? Should the regulation
be more specific on this point, and if so, what should it provide?
(10) Are there others besides the IRB (e.g., sponsors, clinical
investigators, community leaders, advisory committees, ethicists) who
should play a role in determining the adequacy of the plan for
community consultation and the material to be publicly disclosed?
(11) The community consultation process typically includes meetings
and discussions about the study with the community.
(a) Should the regulation require documentation of meeting
activities and discussions in sufficient detail to show the information
that was disclosed and the community reaction to the clinical
investigation? If so, who should be responsible for such documentation
(e.g., clinical investigator, sponsor)?
(b) The regulations (see 21 CFR 312.54(a) and 812.47(a)) currently
require the sponsor to submit the information publicly disclosed prior
to study initiation and after completion to FDA Docket Number 1995S-
0158 (formerly 95S-0158). Should the regulation also require that
documentation of community consultation activities be submitted to FDA,
for example by being placed in the public docket? If so, who should be
responsible for doing this?
(c) Should this information also be available elsewhere such as on
clinicaltrials.gov?\2\
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\2\ (FDA has verified the Web site address, but FDA is not
responsible for any subsequent changes to the Web site after this
document publishes in the Federal Register.)
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Public Disclosure Prior to Initiation
The regulation requires public disclosure, before the study begins,
of plans for the investigation and its risks and expected benefits
(Sec. 50.24(a)(7)(ii)) as an important protection for human subjects.
We ask for comments on the following questions regarding such public
disclosure.
(12) Are there certain types of information (e.g., adverse event
reports, study protocol, informed consent document) that should, at a
minimum, be publicly disclosed to the communities in which the clinical
investigation will be conducted and from which the subjects will be
drawn?
(13) Should the full protocol, or other information such as the
investigator's brochure, for emergency research be available (e.g.,
through FDA's public docket, clinicaltrials.gov) to the general public
before initiation of the clinical investigation? If so, should
protocols or other information be available for all emergency research
or only for certain emergency research?
Public Disclosure Following Completion
The regulation requires public disclosure of sufficient information
following completion of the clinical investigation to apprise the
community and researchers of the study, including demographic
characteristics of the research population and the study results (Sec.
50.24(a)(7)(iii)).
(14) Is there information regarding study results that, at a
minimum, should always be disclosed after the clinical investigation is
completed? If so, what is that information?
(15) How can this disclosure best be accomplished? Who should be
responsible for this disclosure?
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(16) When should a clinical investigation be considered
``completed?'' How soon after a clinical investigation is completed
should the results be disclosed?
(17) How can we assure timely disclosure of study results after
completion of a study?
Public Discussion of Emergency Research
Currently, all emergency research protocols are subject to IRB
review and community consultation. FDA has received some suggestions
that it may be important, at least in some cases, to have additional
public discussion, such as during an open meeting of an advisory
committee or other expert panel. We invite comment on the following
questions. Is there a need for such additional review and public
discussion? If so, what criteria would be used to determine which
protocols should be subject to this additional review and discussion?
(18) What type of venue would be best for this additional review
and public discussion?
(19) What information should be included in this review?
Additional Challenges
(20) Are there any additional challenges to the conduct of
emergency research that have not been identified in the preceding
questions?
(21) If so, what are they and how should they be addressed?
VI. Notice of Hearing Under 21 CFR Part 15
The Acting Commissioner of Food and Drugs (the Acting Commissioner)
is announcing that the public hearing will be held in accordance with
part 15. The hearing will be conducted by a presiding officer, who will
be accompanied by FDA senior management from the Office of the
Commissioner, the Center for Biologics Evaluation and Research, the
Center for Drug Evaluation and Research, the Center for Devices and
Radiological Health, the Office of Policy, and the Office of Human
Research Protection.
Persons who wish to participate in the part 15 hearing must file a
written or electronic submission with the Division of Dockets
Management (see ADDRESSES and DATES). To ensure timely handling, any
outer envelope should be clearly marked with the docket number found in
brackets in the heading of this document, along with the statement
``Emergency Research.'' Requests to make a presentation should contain
the potential presenter's name; address; telephone number; affiliation,
if any; the sponsor of the presentation (e.g., the organization paying
travel expenses or fees), if any; a brief summary of the presentation
(including the discussion questions identified by number that will be
addressed).
Under Sec. 15.30(f), the hearing is informal, and the rules of
evidence do not apply. No participant may interrupt the presentation of
another participant. Only the presiding officer and panel members may
question any person during or at the conclusion of each presentation.
Public hearings under part 15 are subject to FDA's policy and
procedures for electronic media coverage of FDA's public administrative
proceedings (part 10 (21 CFR part 10, subpart C)). Under Sec. 10.205,
representatives of the electronic media may be permitted, subject to
certain limitations, to videotape, film, or otherwise record FDA's
public administrative proceedings, including presentations by
participants.
To the extent that the conditions for the hearing, as described in
this document, conflict with any provisions set out in part 15, this
document acts as a waiver of those provisions as specified in Sec.
15.30(h).
VII. Request for Comments
Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) written or electronic notices of participation and
comments for consideration at the hearing. To permit time for all
interested persons to submit data, information, or views on this
subject, the administrative record of the hearing will remain open for
45 days following the hearing. Persons who wish to provide additional
materials for consideration should file these materials with the
Division of Dockets Management (see ADDRESSES). You should annotate and
organize your comments to identify the specific questions identified by
number to which they refer (see section V of this document). Two paper
copies of any mailed comments are to be submitted, except that
individuals may submit one paper copy. Comments are to be identified
with the docket number at the heading of this document. Received
comments may be seen in Division of Dockets Management (see ADDRESSES)
between 9 a.m. and 4 p.m., Monday through Friday.
VIII. Transcripts
The hearing will be transcribed as stipulated in Sec. 15.30(b).
Transcripts of the hearing will be available for review at the Division
of Dockets Management (see ADDRESSES) and on the Internet at http://www.fda.gov/ohrms/dockets approximately 21 days after the hearing. You
may place orders for copies of the transcript at the meeting or through
the Freedom of Information Office (HFI-35), Food and Drug
Administration, 5600 Fishers Lane, rm. 6-30, Rockville, MD 20857, at a
cost of 10 cents per page.
Dated: August 18, 2006.
Jeffrey Shuren,
Associate Commissioner for Policy.
[FR Doc. E6-14264 Filed 8-25-06; 8:45 am]
BILLING CODE 4160-01-S