[Federal Register Volume 61, Number 215 (Tuesday, November 5, 1996)]
[Rules and Regulations]
[Pages 57278-57280]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-28411]
[[Page 57277]]
_______________________________________________________________________
Part VIII
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
21 CFR Parts 50, 312, and 812
Protection of Human Subjects; Informed Consent Verification; Final Rule
Federal Register / Vol. 61, No. 215 / Tuesday, November 5, 1996 /
Rules and Regulations
[[Page 57278]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 50, 312, and 812
[Docket No. 95N-0359]
Protection of Human Subjects; Informed Consent Verification
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is amending its current
informed consent regulations to require that the consent form signed by
the subject or the subject's legally authorized representative, be
dated by the subject or the subject's legally authorized representative
at the time consent is given. FDA is also amending its regulation on
case histories to clarify what adequate case histories include and to
clarify that the case histories must document that informed consent was
obtained prior to participation in a study. FDA is taking this action
in response to problems the agency has had on occasion verifying that
informed consent was obtained from a research subject prior to
participation in a study because the consent document was not dated and
other verification was not contained in the individual's case history
documentation. The agency believes that by explicitly requiring that
the consent form be dated at the time it is signed and requiring the
case history to document that consent was obtained prior to
participation in a study, the agency will be able to help ensure that
informed consent was, in fact, obtained prior to entry into the study
as required by FDA regulations.
DATES: The regulation is effective December 5, 1996.
FOR FURTHER INFORMATION CONTACT: Gary L. Chadwick, Office of Health
Affairs (HFY-20), Food and Drug Administration, 5600 Fishers Lane,
Rockville, MD 20857, 301-827-1685.
SUPPLEMENTARY INFORMATION:
I. Background
In the Federal Register of December 22, 1995 (60 FR 66530), FDA
proposed to amend FDA's current informed consent regulations to require
that the written consent form signed by the subject or the subject's
legally authorized representative, be dated by the subject or the
subject's legally authorized representative at the time consent is
given. FDA also proposed to amend its regulation on case histories to
clarify what adequate case histories include.
Interested persons were given until March 21, 1996, to comment on
the proposed rule. The agency received a total of eight comments: One
from a patient advocacy group, three from pharmaceutical companies, one
from a medical device company, and three from private individuals. All
of these comments supported the proposal to amend the agency's informed
consent regulations to require that consent forms be dated by the
subject or subject's legally authorized representative at the time
consent is given. One comment expressed support for the agency's
proposal to clarify the meaning of adequate case histories; the
remaining comments were silent on this issue. Several of these comments
recommended additional changes to the informed consent regulations.
These comments and FDA's responses are discussed below.
II. Comments
1. One comment suggested that the agency should require not only
the date, but also the time, that the consent form was signed in order
to be able to verify that consent was obtained prior to a subject's
entry into a study. This comment expressed concern by the potential 24-
hour window created by requiring the date and not the time for research
subjects who sign the consent form on the day that they begin their
participation in the study. The comment suggested that this 24-hour
window should be closed to ensure that investigators fulfill their
responsibilities and to enable the agency to verify that consent is
obtained prior to entry into the study. The comment provided the
following three additional reasons for requiring the time of day that
the consent form is signed: (1) The role of informed consent in
clinical investigations is to help ensure voluntary decisionmaking
about enrollment in a study, (2) documentation of the timing of the
signature helps to provide evidence of when consent was obtained in
relation to when the investigational intervention commenced, and (3)
the interest of historians and scholars in knowing whether the research
was conducted in accordance with societal standards related to the
conduct of research.
The agency has considered this comment and whether the regulation
should be modified to permit verification that consent was obtained
prior to a subject's entry into a study when both consent is obtained
and participation in a study occur on the same day. The agency agrees
that when, for example, the consent form is signed on the same day that
the subject begins participation in the study, it may not be able to
verify from a dated consent form that consent was obtained prior to an
individual's participation in the research; therefore, other
documentation may be needed. However, the agency does not think that it
is appropriate to require the time of signature to be included on every
consent form in order to permit this verification.
FDA notes that adding the time of day to the consent form may not
provide the additional assurance suggested by the comment. The
investigational new drug application and investigational device
exemption regulations (parts 312 and 812 (21 CFR parts 312 and 812)) do
not require the time of day to be recorded in the individual's case
history for each research intervention. In practice, the time of day is
generally not recorded in case histories, except when time-sensitive
procedures are carried out. Therefore, recording the time of day on the
consent form may not establish that the form was signed before
participation in the study. Rather than requiring the time of day to
accomplish the agency's verification goal, the agency has modified Secs.
312.62(b) and 812.140(a)(3)(i) to allow flexibility in approaches to
providing verification. These sections now state ``The case history for
each individual shall document that informed consent was obtained prior
to participation in the study.'' This case history documentation may be
contained in the case report form; in the individual's medical record,
e.g., in progress notes of the physician, on the individual's hospital
chart, in the nurse's notes; on the consent form; in a combination of
these documents; or elsewhere in the individual's case history. The
documentation may consist of, e.g., a chronological record of the
sequence of events that establishes that informed consent was obtained
prior to a procedure required by the clinical investigation, or the
time that consent was obtained and the time of the first study-related
procedure performed on the individual.
The agency notes that 21 CFR 56.109(c) provides for an exception
from the requirement for written documentation of informed consent and
that part 50 (21 CFR part 50) provides for certain limited exceptions
to the requirement for obtaining informed consent. This rule does not
change those regulatory provisions.
2. Another comment recommended that the agency conduct a
comprehensive review of the informed consent process, noting that a
``flaw in the system has been the failure of IRBs
[[Page 57279]]
to insist that the consent form be drafted in lay language'' and that
such a review would disclose other problems. This comment went on to
note that during FDA inspections, the comment was unaware of FDA
challenging the content of consent forms.
This comment does not request a change in the regulations. The
agency already requires consent documents to describe, in language that
is understandable to subjects, all relevant information about the
study.
Under the agency's Bioresearch Monitoring Program, FDA conducts
onsite inspections of institutional review boards (IRB's) and clinical
investigators. During the IRB inspections, IRB members and/or
administrators are interviewed regarding procedures and then IRB
records are inspected to verify compliance with parts 50 and 56. During
these inspections, copies of informed consent forms approved by the IRB
are collected and reviewed by agency components. Under FDA's clinical
investigator compliance program, FDA conducts study-specific
inspections and audits of investigators conducting clinical trials of
FDA-regulated products. These inspections also include an evaluation of
whether the informed consent document conforms to FDA regulations (part
50). Through these inspections, the agency is able to assess whether
there are common problems with these documents such as their failure to
include all the required elements of informed consent specified in
Sec. 50.25 and their failure to explain technical/scientific language.
FDA provides information to IRB's and investigators to address these
issues. (See the ``FDA Information Sheets for Institutional Review
Boards and Clinical Investigators'' reprinted March 1996, pages 52-53.
Copies are available from Gary L. Chadwick, Office of Health Affairs
(address above) or on the World Wide Web (http://www.fda.gov/oc/oha/
informed.html).)
To improve the quality of consent forms, following an inspection
where deficiencies are found, FDA explains its regulatory requirements
as well as deficiencies found in consent forms to clinical
investigators and IRB's in post-inspection letters. FDA also carries
out a wide variety of educational efforts in the area of human subject
protection; a part of these educational efforts is focused on issues
associated with informed consent. By making clinical investigators and
IRB's aware of FDA regulatory requirements and problems related to
informed consent and human subject protection, FDA thinks that the
consent process and the protections provided to research subjects will
be improved.
3. One comment recommended that the requirement that the consent
form be dated at the time the form is signed not be retrospectively
applied to research subjects entered into a study prior to the
effective date of the final rule.
The agency agrees with this comment and does not intend to
retrospectively apply this rule to research subjects entered into a
study prior to its effective date. Thus, this final rule applies to
research subjects entered into studies on or after the effective date
of this regulation.
4. Another comment recommended that Sec. 50.27(b)(2) be amended to
require that ``short forms and summaries'' be dated at the time that
they are signed.
The agency does not think that Sec. 50.27(b)(2) needs to be
revised. The provision set forth in Sec. 50.27(a) requiring that a
written consent form be dated at the time of consent applies both to a
written consent document that embodies the elements of informed consent
(Sec. 50.27(b)(1)) as well as to a ``short form'' written consent
document (stating that the elements of informed consent required by
Sec. 50.25 have been presented orally to the subject or the subject's
legally authorized representative (Sec. 50.27(b)(2))). Thus, the agency
is not revising Sec. 50.27(b)(2).
5. One comment was received on the clarifying amendment of what
constitutes adequate case history records. The comment supported the
amendment; however, the agency believes that the respondent
misunderstood the agency's intention. The comment suggested that the
proposed change to Sec. 312.62(b) would allow case report forms to be
collected earlier by the sponsor because investigators would not need
to transcribe information onto a case report form if that information
were contained in the subject's medical records.
This comment misinterpreted the clarifying amendment to
Sec. 312.62(b). The revisions to this section were to clarify that
adequate case history records include the case report forms and
supporting data, including, e.g., signed and dated consent forms and
medical records. The purpose of the case report form is to provide
sufficient information for the sponsor to evaluate the use of the
product in an individual subject; thus, the case report form may need
to duplicate information contained in the subject's medical record. If
the case report form is made a permanent part of the subject's medical
record, then the medical record may not need to contain information
that is contained in that case report form. In most instances, the
agency thinks that information is typically entered into the subject's
medical record first; then, it is entered onto the case report form for
transmittal to the research sponsor.
6. On the agency's own initiative, it has made technical changes to
the conforming amendments at Secs. 312.53, 312.62, and 812.140(a)(3).
In Sec. 312.53(c)(1)(vi)(d), ``patients'' has been changed to
``potential subjects'' to clarify that an individual who participates
in a research study may be either a healthy individual or a patient. In
addition, the agency has deleted the phrase ``or any persons used as
controls'' because ``subject'' is defined as a recipient of an
investigational new drug or as a control. (See Sec. 312.3(b).) In
Sec. 312.62(b), ``treated with the investigational drug'' has been
changed to ``administered the investigational drug'' to clarify that
the administration of an investigational drug may not constitute
treatment. In Sec. 312.62(b), examples have been added to describe the
variety of documents that are considered to be part of an individual's
medical record. These documents include, for example, progress notes of
the physician, the individual's hospital chart(s), and the nurses'
notes. Section 812.140(a)(3) has been amended to clarify what
constitutes adequate case history records and to provide examples of
the variety of documents that are considered to be part of an
individual's medical record; this clarification is consistent with the
language contained in Sec. 312.62(b).
III. Environmental Impact
The agency has determined under 21 CFR 25.24(a)(8) that this action
is of a type that does not individually or cumulatively have a
significant effect on the human environment. Therefore, neither an
environmental assessment nor an environmental impact statement is
required.
IV. Analysis of Impacts
FDA has examined the impacts of the final rule under Executive
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612).
Executive Order 12866 directs agencies to assess all costs and benefits
of available regulatory alternatives and, when regulation is necessary,
to select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). The agency believes that
this final rule is consistent with the regulatory philosophy and
[[Page 57280]]
principles identified in the Executive Order. In addition, the final
rule is not a significant regulatory action as defined by the Executive
Order and so is not subject to review under the Executive Order.
If a rule has a significant economic impact on a substantial number
of small entities, the Regulatory Flexibility Act requires agencies to
analyze regulatory options that would minimize any significant impact
of a rule on small entities. This rule simply adds a requirement that
consent forms be dated at the time that they are signed and that the
individual's case history documents that consent was obtained prior to
participation in a study in order to permit the agency to verify that
informed consent is obtained prior to an individual's entry into a
research study. Because the majority of consent forms are currently
dated at the time that they are signed and the majority of case
histories currently contain this verifying information, the
Commissioner of Food and Drugs certifies that the final rule will not
have a significant economic impact on a substantial number of small
entities. Therefore, under the Regulatory Flexibility Act, no further
analysis is required.
V. Paperwork Reduction Act of 1995
This final rule contains no additional information collection
requirements which are subject to review by the Office of Management
and Budget under the Paperwork Reduction Act of 1995 (Pub. L. 104-13).
List of Subjects
21 CFR Part 50
Human research subjects, Informed consent, Prisoners, Reporting and
recordkeeping requirements, Safety.
21 CFR Part 312
Drugs, Exports, Imports, Investigations, Labeling, Medical
research, Reporting and recordkeeping requirements, Safety.
21 CFR Part 812
Health records, Medical devices, Medical research, Reporting and
recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR part
50 is amended as follows:
PART 50--PROTECTION OF HUMAN SUBJECTS
1. The authority citation for 21 CFR part 50 continues to read as
follows:
Authority: Secs. 201, 406, 408, 409, 502, 503, 505, 506, 507,
510, 513-516, 518-520, 701, 721, 801 of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. 321, 346, 346a, 348, 352, 353, 355, 356,
357, 360, 360c-360f, 360h-360j, 371, 379e, 381); secs. 215, 301,
351, 354-360F of the Public Health Service Act (42 U.S.C. 216, 241,
262, 263b-263n).
2. Section 50.27 is amended by revising paragraph (a) to read as
follows:
Sec. 50.27 Documentation of informed consent.
(a) Except as provided in Sec. 56.109(c), informed consent shall be
documented by the use of a written consent form approved by the IRB and
signed and dated by the subject or the subject's legally authorized
representative at the time of consent. A copy shall be given to the
person signing the form.
* * * * *
PART 312--INVESTIGATIONAL NEW DRUG APPLICATION
3. The authority citation for 21 CFR part 312 continues to read as
follows:
Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701 of
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351,
352, 353, 355, 356, 357, 371); sec. 351 of the Public Health Service
Act (42 U.S.C. 262).
4. Section 312.53 is amended by revising paragraph (c)(1)(vi)(d) to
read as follows:
Sec. 312.53 Selecting investigators and monitors.
* * * * *
(c) * * *
(1) * * *
(vi) * * *
(d) Will inform any potential subjects that the drugs are being
used for investigational purposes and will ensure that the requirements
relating to obtaining informed consent (21 CFR part 50) and
institutional review board review and approval (21 CFR part 56) are
met;
* * * * *
5. Section 312.62 is amended by revising paragraph (b) to read as
follows:
Sec. 312.62 Investigator recordkeeping and record retention.
* * * * *
(b) Case histories. An investigator is required to prepare and
maintain adequate and accurate case histories that record all
observations and other data pertinent to the investigation on each
individual administered the investigational drug or employed as a
control in the investigation. Case histories include the case report
forms and supporting data including, for example, signed and dated
consent forms and medical records including, for example, progress
notes of the physician, the individual's hospital chart(s), and the
nurses' notes. The case history for each individual shall document that
informed consent was obtained prior to participation in the study.
* * * * *
PART 812--INVESTIGATIONAL DEVICE EXEMPTIONS
6. The authority citation for 21 CFR part 812 continues to read as
follows:
Authority: Secs. 301, 501, 502, 503, 505, 506, 507, 510, 513-
516, 518-520, 701, 702, 704, 721, 801 of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. 331, 351, 352, 353, 355, 356, 357, 360,
360c-360f, 360h-360j, 371, 372, 374, 379e, 381); secs. 215, 301,
351, 354-360F of the Public Health Service Act (42 U.S.C. 216, 241,
262, 263b-263n).
7. Section 812.140 is amended by revising the introductory text of
paragraph (a)(3) and adding a new sentence to the end of paragraph
(a)(3)(i) to read as follows:
Sec. 812.140 Records.
(a) * * *
(3) Records of each subject's case history and exposure to the
device. Case histories include the case report forms and supporting
data including, for example, signed and dated consent forms and medical
records including, for example, progress notes of the physician, the
individual's hospital chart(s), and the nurses' notes. Such records
shall include:
(i) * * * The case history for each individual shall document that
informed consent was obtained prior to participation in the study.
* * * * *
Dated: October 28, 1996.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-28411 Filed 11-4-96; 8:45 am]
BILLING CODE 4160-01-F
