[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]



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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

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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