Conduct of Emergency Clinical Research; Public Hearing, 51143-51146 [E6-14264]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 71, Number 167 (Tuesday, August 29, 2006)]
[Proposed Rules]
[Pages 51143-51146]
From the Federal Register Online via the Government Printing 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we are also issuing a draft guidance entitled ``Guidance for 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We will consider comments received on this draft guidance together with 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 https://
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, 
terrie.crescenzi@fda.hhs.gov.

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 https://
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