[Federal Register Volume 62, Number 194 (Tuesday, October 7, 1997)]
[Rules and Regulations]
[Pages 52237-52253]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-26255]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 20, 310, 312, 314, and 600
[Docket No. 93N-0181]
RIN 0910-AA97
Expedited Safety Reporting Requirements for Human Drug and
Biological Products
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is amending its
expedited safety reporting regulations for human drug and biological
products to provide consistency with the elements of FDA Form 3500A for
use in pre- and postmarketing safety reporting;
[[Page 52238]]
implement definitions, reporting periods, formats, and standards as
recommended by the International Conference on Harmonisation of
Technical Requirements for Registration of Pharmaceuticals for Human
Use (ICH) and by the World Health Organization's Council for
International Organizations of Medical Sciences (CIOMS); require
applicants, manufacturers, packers, and distributors, as well as
licensed manufacturers and other manufacturers of biological products,
to develop written procedures for postmarketing safety monitoring and
reporting; state that FDA Form 3500A reports that FDA forwards to any
person subject to the postmarketing safety reporting requirements are
not required to be resubmitted to the agency; and make other revisions
to the regulations to provide uniformity with definitions and
procedures used in expedited pre- and postmarketing safety reporting
for human drug and biological products. These changes simplify and
facilitate expedited safety reporting and enhance agencywide
consistency in the collection of postmarketing safety data.
DATES: This regulation is effective April 6, 1998. Submit written
comments on the information collection provisions of this final rule by
December 8, 1997.
ADDRESSES: Submit written comments on the information collection
provisions of this final rule to the Dockets Management Branch (HFA-
305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23,
Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT:
For information concerning human drug products: Audrey A. Thomas,
Center for Drug Evaluation and Research (HFD-7), Food and Drug
Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-594-5625.
For information concerning human biological products: Valerie A.
Butler, Center for Biologics Evaluation and Research (HFM-17), Food and
Drug Administration, 1401 Rockville Pike, suite 200N, Rockville, MD
20852-1448, 301-594-3074.
SUPPLEMENTARY INFORMATION:
I. Introduction
In the Federal Register of October 27, 1994 (59 FR 54046), FDA
published a proposed rule to amend the regulations for expedited and
periodic pre- and postmarketing safety reporting for human drug and
biological products (hereinafter referred to as the October 1994
proposal). FDA also proposed to amend the requirements for clinical
study design and conduct and annual sponsor reporting in the
investigational new drug application (IND) regulations.
As explained in the October 1994 proposal, the amendments to the
safety reporting regulations are intended to provide consistency with
certain standardized definitions, procedures, and formats developed by
ICH and CIOMS (59 FR 54046 at 54047). In the Federal Register of July
9, 1993 (58 FR 37408), FDA published an ICH draft guideline entitled
``Clinical Safety Data Management: Definitions and Standards for
Expedited Reporting'' (hereinafter referred to as the draft ICH E2A
guideline). The public was given an opportunity to comment on the draft
ICH E2A guideline. After consideration of the comments received and
revisions to the draft guideline, ICH finalized the guideline. In the
Federal Register of March 1, 1995 (60 FR 11284), FDA published the ICH
final guideline (hereinafter referred to as the final ICH E2A
guideline). Although the final ICH E2A guideline pertains to expedited
safety reporting during the preapproval phase of drug development, for
consistency and simplicity many of the definitions, reporting periods,
formats, and standards also could apply to FDA's expedited
postmarketing safety reporting requirements.
In this final rule, FDA is amending its regulations for expedited
safety reporting to implement certain definitions, reporting periods,
and formats recommended in the final ICH E2A guideline. FDA is
considering other recommendations in the final ICH E2A guideline that
were not included in the October 1994 proposal and plans to propose
additional amendments to its expedited safety reporting regulations
shortly (e.g., pre- and postmarketing reporting of adverse drug
reactions rather than adverse drug experiences, submission of expedited
safety reports to FDA from clinical investigations based on the opinion
of either the sponsor or investigator).
FDA is delaying finalization of the proposed amendments to the
periodic postmarketing safety reporting regulations (59 FR 54046). The
proposed amendments were based, for the most part, on recommendations
developed by the CIOMS Working Group II (Ref. 1). ICH also developed
recommendations, based on the CIOMS Working Group II proposals, for
periodic postmarketing safety reporting. In the Federal Register of May
19, 1997 (62 FR 27470), FDA published an ICH final guideline entitled
``Clinical Safety Data Management: Periodic Safety Update Reports for
Marketed Drugs'' (hereinafter referred to as the ICH E2C guideline).
FDA will finalize the proposed amendments to the periodic postmarketing
safety reporting regulations after consideration of the provisions of
the ICH E2C guideline.
In light of the comments the agency received, FDA has reconsidered
the proposed amendments to the requirements for clinical study design
and conduct and annual sponsor reporting under the IND (59 FR 54046).
In general, the comments opposed the proposed amendments because the
current IND regulations protect the safety of the public in all but the
most unusual cases. Based on these general comments and others specific
to each of the proposed amendments, the agency has decided to withdraw
the proposed amendments to the IND requirements for clinical study
design and conduct and annual sponsor reporting. The agency will,
instead, develop a guidance document providing recommendations on study
design and monitoring of investigational drugs used to treat serious
and potentially fatal illnesses, with particular attention to detection
of adverse events that are similar to those caused by the underlying
disease. In developing the draft guidance document, FDA will consider
comments submitted in response to the proposed amendments and will
provide opportunity for public input on the document prior to its
implementation. Thus, in this final rule, FDA is withdrawing the
proposed amendments to the IND regulations (part 312 (21 CFR part 312))
at Secs. 312.23, the second sentence of 312.32(c)(1)(i), 312.33,
312.37, 312.42, 312.44, 312.56, and 312.64 (59 FR 54046 at 54057 to
54059).
In the Federal Register of June 25, 1997 (62 FR 34166), FDA
published a final rule to amend its regulations on expedited reporting
of postmarketing adverse experiences to revoke the requirement for
increased frequency reports as expedited reports for human drug and
licensed biological products. Thus, in this final rule, FDA is
withdrawing the proposed amendments to the increased frequency
reporting requirements published in the October 1994 proposal.
II. Background
In the Federal Register of June 3, 1993 (58 FR 31596), FDA
announced the availability of a new form for reporting single cases of
adverse events and product problems with medications, devices, and
other FDA-regulated medical products (hereinafter referred to as the
June 1993 notice). This form is available in two versions: FDA Form
3500 is for use by health care professionals and consumers for
[[Page 52239]]
voluntary reporting; FDA Form 3500A is for use by any person subject to
FDA's mandatory safety reporting regulations. Adverse events associated
with vaccines continue to be reported to FDA and the Centers for
Disease Control and Prevention using the Vaccine Adverse Event
Reporting System (VAERS) form.
Under the existing regulations, manufacturers, packers, and
distributors; applicants of approved new and abbreviated marketing
applications for drugs and antibiotics; and licensed manufacturers and
other manufacturers of biological products must submit expedited
reports of postmarketing adverse drug experiences under 21 CFR 310.305,
314.80, 314.98, and 600.80. Sponsors of IND's must also submit
expedited reports, under Sec. 312.32, for adverse experiences
associated with the use of an investigational human drug or biological
product. Currently, there is no standard form for these IND expedited
safety reports.
FDA Forms 3500 and 3500A are part of FDA's Medical Products
Reporting Program (MedWatch) and are designed to facilitate safety
reporting for most FDA-regulated human medical products by the entire
health care community, including manufacturers, distributors, user
facilities, and health care professionals. FDA issued the new forms to
simplify and consolidate safety reporting for human drug products,
biologics, and medical devices, as well as other FDA-regulated medical
products. The new forms eliminate redundant or nonessential elements
from past reporting forms and clarify those areas that have caused
confusion.
In developing FDA Forms 3500 and 3500A, and in developing the
revisions to the expedited safety reporting regulations that are the
subject of this final rule, the agency considered several ICH and CIOMS
recommendations. These organizations were formed to facilitate
international consideration of issues, particularly safety issues,
concerning the use of both foreign and domestic data in the development
and use of drugs and biological products. ICH has worked to promote the
harmonization of technical requirements for the registration of
pharmaceutical products among three regions: The European Union, Japan,
and the United States. In addition, several CIOMS working groups have
served to coordinate and standardize the international reporting of
suspected postmarketing adverse drug reactions by pharmaceutical
manufacturers to regulatory authorities. FDA believes the changes
recommended by CIOMS and ICH will result in more effective and
efficient safety reporting to regulatory authorities worldwide.
III. Description of the Final Rule
This final rule amends parts 20, 310, 312, 314, and 600 (21 CFR
parts 20, 310, 312, 314, and 600) to revise definitions, requirements,
and procedures for expedited pre- and postmarketing safety reporting.
This rulemaking finalizes many of the expedited safety reporting
provisions as proposed in the October 1994 proposal. In addition, this
final rule reflects amendments to the October 1994 proposal that were
made in response to comments (discussed in section IV of this
document), including comments recommending greater consistency with the
ICH E2A guideline and uniformity between pre- and postmarketing safety
reporting definitions. This final rule also incorporates minor
revisions for clarity and further consistency. The major provisions of
the final rule are summarized as follows:
1. FDA Forms 3500/3500A. As proposed, the final rule permits
sponsors to submit IND safety reports, under Sec. 312.32(c)(1)(i), on
FDA Form 3500A rather than in a narrative format, and replaces, at
Secs. 310.305 and 314.80, Form FDA-1639 with FDA Form 3500A for use in
postmarketing safety reporting for human drug products. The final rule
also replaces, at Sec. 20.112, Form FDA-1639 with FDA Form 3500 for
voluntary drug experience reporting by physicians and hospitals. The
final rule, like the proposed rule, instructs applicants,
manufacturers, packers, and distributors to obtain approval from FDA's
MedWatch office before using an alternative reporting format for
postmarketing safety reporting under Secs. 310.305(d)(3)(ii) and
314.80(f)(3)(ii). Pre- and postmarketing safety reporting of foreign
events may continue to be reported to FDA on the CIOMS I form (Ref. 2).
After consideration of the comments, the final rule, unlike the
proposed rule, permits use of the CIOMS I form for this purpose without
prior FDA approval.
2. Definitions. In response to comments, the proposed definition of
``serious'' at Secs. 310.305(b), 312.32(a), 314.80(a), and 600.80(a)
has been revised to make it consistent with the definition of
``serious'' in the final ICH E2A guideline and with the definition of
``serious'' used in FDA Form 3500A. To provide uniformity between the
pre- and postmarketing definitions of ``serious,'' the following
information has been removed from the current definition of ``serious
adverse experience'' at Sec. 312.32(a) and added as a reporting
requirement to the IND safety reporting regulations at
Sec. 312.32(c)(1)(i):
With respect to results obtained from tests in laboratory
animals, a serious adverse drug experience includes any experience
suggesting a significant risk for human subjects, including any
finding of mutagenicity, teratogenicity, or carcinogenicity.
This revision represents an organizational change that does not impose
a new burden because sponsors are already required to report such
information to FDA.
In response to comments, the final rule also amends the proposed
definitions of ``disability'' and ``life-threatening'' at
Secs. 310.305(b), 314.80(a), and 600.80(a) for consistency with the
final ICH E2A guideline and for clarity. In addition, the definition of
``disability'' has been added to the ``definitions'' section of the
premarketing safety reporting regulations at Sec. 312.32(a), and the
definition of ``life-threatening'' has been removed from the
``telephone safety report'' section of the premarketing safety
reporting regulations at Sec. 312.32(c)(2) and added to the
``definitions'' section of these regulations at Sec. 312.32(a). For
further clarity and consistency in reporting adverse drug experiences
that are life-threatening, FDA has decided to replace, at
Secs. 310.305(b), 312.32(a), 314.80(a), and 600.80(a), the word
``serious'' with ``severe'' so that the first sentence of the
definition of ``life-threatening'' includes the following: ``* * *,
i.e., [Life-threatening] does not include a reaction that, had it
occurred in a more severe form, might have caused death.'' As explained
in the final ICH E2A guideline, ``severe'' refers to the intensity
(severity) of a specific event (e.g., mild, moderate, or severe
myocardial infarction); the event itself may be of relatively minor
medical significance such as a severe headache. The term ``serious,''
however, is based on patient/event outcome or action criteria usually
associated with events that pose a threat to a patient's life or
functioning (e.g., an event that results in death or that is life-
threatening or requires inpatient hospitalization) (60 FR 11284 at
11285). FDA has also decided to remove the following sentence from this
definition: ``For example, drug-induced hepatitis that resolved without
evidence of hepatic failure would not be considered life-threatening
even though drug-induced hepatitis can be fatal.'' Use of hepatitis as
an example for life-threatening may be confusing because viral
transmission of certain types of hepatitis through blood products could
be life-
[[Page 52240]]
threatening. To harmonize pre- and postmarketing safety reporting
definitions, FDA has decided to withdraw the examples listed in the
proposed postmarketing definition of ``life-threatening'' at
Secs. 310.305(b), 314.80(a), and 600.80(a). The agency has decided,
instead, to revise the guidances associated with this final rule to
include examples of life-threatening adverse drug experiences (CDER's
``Guideline for Postmarketing Reporting of Adverse Drug Experiences,''
March 1992 and CBER's ``Guideline for Adverse Experience Reporting for
Licensed Biological Products,'' October 1993).
In this final rule, FDA is incorporating minor changes to the
definition of ``unexpected'' adverse drug experience at
Secs. 310.305(b), 312.32(a), 314.80(a), and 600.80(a) to provide
uniformity between pre- and postmarketing safety reporting definitions
and consistency with the ICH E2A guideline.
The definition of ``unexpected'' adverse drug experience at
Secs. 310.305(b), 314.80(a), and 600.80(a) currently states:
* * * an adverse drug experience that is not listed in the
current labeling for the drug product and includes an event that may
be symptomatically and pathophysiologically related to an event
listed in the labeling, but differs from the event because of
greater severity or specificity. For example, under this definition,
hepatic necrosis would be unexpected (by virtue of greater severity)
if the labeling only referred to elevated hepatic enzymes or
hepatitis. Similarly, cerebral thromboembolism and cerebral
vasculitis would be unexpected (by virtue of greater specificity) if
the labeling only listed cerebral vascular accidents.
To clarify what must be reported to the agency as an ``unexpected
adverse drug experience,'' FDA is amending this definition by adding
the following sentence:
``Unexpected,'' as used in this definition, refers to an adverse
drug experience that has not been previously observed (i.e.,
included in the labeling) rather than from the perspective of such
experience not being anticipated from the pharmacological properties
of the pharmaceutical product.
This amendment is consistent with the discussion of ``expectedness of
an adverse drug reaction'' in the final ICH E2A guideline:
The purpose of expedited reporting is to make regulators,
investigators, and other appropriate people aware of new, important
information on serious reactions. Therefore, such reporting will
generally involve events previously unobserved or undocumented, and
a guideline is needed on how to define an event as ``unexpected'' or
``expected'' (expected/ unexpected from the perspective of
previously observed, not on the basis of what might be anticipated
from the pharmacological properties of a medicinal product).
The definition of ``unexpected adverse experience'' at
Sec. 312.32(a) currently states:
* * * any adverse experience that is not identified in nature,
severity, or frequency in the current investigator brochure; or, if
an investigator brochure is not required, that is not identified in
nature, severity, or freuquency [sic] in the risk information
described in the general investigational plan or elsewhere in the
current application, as amended.
For clarity and consistency, FDA is amending this definition to conform
with the definition of ``unexpected'' at Secs. 310.305(b), 314.80(a),
and 600.80(a) by removing the references to frequency, replacing the
word ``nature'' with the word ``specificity,'' adding examples of
unexpected adverse drug experiences, and making other minor revisions.
The revised definition at Sec. 312.32(a) states:
Unexpected adverse drug experience: Any adverse drug experience,
the specificity or severity of which is not consistent with the
current investigator brochure; or if an investigator brochure is not
required or available, the specificity or severity of which is not
consistent with the risk information described in the general
investigational plan or elsewhere in the current application, as
amended. For example, under this definition, hepatic necrosis would
be unexpected (by virtue of greater severity) if the investigator
brochure only referred to elevated hepatic enzymes or hepatitis.
Similarly, cerebral thromboembolism and cerebral vasculitis would be
unexpected (by virtue of greater specificity) if the investigator
brochure only listed cerebral vascular accidents. ``Unexpected,'' as
used in this definition, refers to an adverse drug experience that
has not been previously observed (e.g., included in the investigator
brochure) rather than from the perspective of such experience not
being anticipated from the pharmacological properties of the
pharmaceutical product.
3. IND Safety Reports. As proposed, the final rule revises the time
period for submitting written IND safety reports, under
Sec. 312.32(c)(1) and (d)(3), from 10 working days to 15 calendar days,
and revises the time period for submitting telephone IND safety
reports, under Sec. 312.32(c)(2), from 3 working days to 7 calendar
days. The final rule also permits telephone safety reports to be made
by facsimile transmission under Sec. 312.32(c)(2). The final rule, as
proposed with minor revisions for clarity, also states, at
Sec. 312.32(c)(1)(i), that FDA may require sponsors to submit
additional data.
In response to comments, FDA is making minor revisions to its IND
safety reporting regulations to provide greater consistency with the
final ICH E2A guideline. Currently, the requirement at Sec. 312.32(b)
states:
The sponsor shall promptly review all information relevant to
the safety of the drug obtained or otherwise received by the sponsor
from any source, foreign or domestic, including information derived
from clinical investigations, animal investigations, commercial
marketing experience, reports in the scientific literature, and
unpublished scientific papers.
To clarify the phrase ``any source,'' FDA is adding ``epidemiological
investigations'' and ``foreign regulatory authorities that have not
already been previously reported to the agency by the sponsor'' to the
list of examples in Sec. 312.32(b). This revision does not impose a new
burden because sponsors are already required to review all information
relevant to the safety of the drug obtained or otherwise received by
the sponsor from any source, foreign or domestic. The amendment
clarifies for sponsors the type of safety information that must be
examined for determination of whether information should be submitted
to the agency in IND safety reports. This revision is consistent with
the final ICH E2A guideline (60 FR 11284 at 11285 and 11286):
[Expedited reporting] applies to reports from spontaneous
sources and from any type of clinical or epidemiological
investigation, independent of design or purpose.
The agency does not expect sponsors to search adverse drug experience
data bases generated by regulatory authorities for safety information
or to submit to FDA adverse drug experience reports submitted to them
by FDA.
FDA is also amending its IND safety reporting regulations at
Sec. 312.32(c)(1)(i), as noted above, by adding, with minor revisions,
language that is being moved from the current definition of ``serious
adverse experience'' at Sec. 312.32(a):
any finding from tests in laboratory animals that suggests a
significant risk for human subjects including reports of
mutagenicity, teratogenicity, or carcinogenicity.
This revision represents an organizational change that does not impose
any new burden because sponsors are currently required to report such
information to FDA. For clarity and consistency, FDA is amending
Sec. 312.32(c)(1)(i) to state that reports from animal studies and
epidemiological studies must be submitted in a narrative format rather
than on FDA Form 3500A because FDA Form 3500A has been designed for
reporting of adverse experience information from an individual patient.
4. Postmarketing 15-day Alert and Followup Reports. As proposed,
the final rule revises, at Secs. 310.305(c), 314.80(c), and 600.80(c),
the time period for submitting postmarketing Alert reports from 15
working days to 15 calendar days. For clarity, the final rule is being
amended, at Sec. 310.305(c)(1)(i),
[[Page 52241]]
to state that the 15 calendar day timeframe for reporting adverse drug
experiences on marketed prescription drugs for human use without
approved new drug applications (NDA's) begins upon initial receipt of
the information by the person whose name appears on the label. In
addition, the final rule at Secs. 310.305(c)(2), 314.80(c)(1)(ii), and
600.80(c)(1)(ii), as proposed, advises any person subject to the
reporting requirements under Secs. 310.305(c), 314.80(c), and
600.80(c), who has been unable to obtain additional information for
adverse drug experiences that are the subject of postmarketing 15-day
Alert reports, to maintain records of their unsuccessful attempts to
seek additional information. For clarity, the final rule is being
amended, at Sec. 310.305(c)(2), to state that 15-day Alert reports and
followups to them must be submitted under separate cover.
The final rule specifies, like the proposed rule, at
Secs. 310.305(c)(6), 314.80(b), and 600.80(b), that no one subject to
this rule is required to resubmit to the agency reports of adverse drug
experiences that the agency has forwarded to them. For clarity, the
final rule is being amended, at Secs. 310.305(c)(6), 314.80(b), and
600.80(b), to emphasize that followup reports must be submitted for
reports received from the agency. The final rule also requires, at
Secs. 310.305(a), 314.80(b), and 600.80(b), any person subject to the
reporting requirements under Secs. 310.305(c), 314.80(c), and 600.80(c)
to develop written procedures for the postmarketing surveillance,
receipt, evaluation, and reporting of adverse drug experiences to FDA.
In response to comments, the final rule permits persons subject to the
reporting requirements under Secs. 310.305(c), 314.80(c), and 600.80(c)
to submit reports of serious adverse drug experiences to a
manufacturer, applicant, or licensed manufacturer of a final biological
product instead of FDA in 5 calendar days, instead of 3 calendar days
as proposed.
In this final rule, FDA is also amending the postmarketing
expedited reporting regulations, at Secs. 314.80(c)(1)(i) and
600.80(c)(1)(i), by replacing, in the first sentence, the phrase
``regardless of source'' with the phrase ``whether foreign or
domestic.'' This amendment is consistent with Secs. 314.80(b) and
600.80(b) which describe adverse drug experience information that must
be reviewed by applicants and licensed manufacturers:
Each applicant (Any person having a product license) * * * shall
promptly review all adverse drug experience information (pertaining
to its product) obtained or otherwise received by the applicant
(licensed manufacturer) from any source, foreign or domestic,
including * * *.
FDA is making this revision to clarify that 15-day Alert reports are to
be submitted for appropriate foreign as well as domestic adverse drug
experiences.
5. Implementation Schedule. The effective date for this final rule
has been extended to 180 days after its publication in the Federal
Register to allow sufficient time for the agency to comply with the
provisions of the Paperwork Reduction Act of 1995. Any person subject
to FDA's mandatory safety reporting requirements may comply with the
provisions of this final rule prior to its effective date.
6. Guidances. In the Federal Register of February 27, 1997 (62 FR
8961), FDA published a notice of a guidance document entitled ``Good
Guidance Practices (GGP's),'' in which FDA announced that notices of
draft and final guidances will be provided both in the Federal Register
and on the FDA World Wide Web (WWW) home page (http://www.fda.gov) (62
FR 8961 at 8965). In this final rule, FDA is amending its postmarketing
safety reporting regulations at Secs. 314.80(j) and 600.80(j) to remove
reference to guidelines prepared by the agency for submission of
reports of adverse drug experiences and suggested followup
investigation of these reports. FDA is also withdrawing its proposed
amendments of October 27, 1994, regarding the availability of adverse
experience reporting guidelines under Secs. 310.305(g), 314.80(j), and
600.80(j). FDA is making these amendments because the guidance document
of February 27, 1997, describes processes for timely notification of
availability of draft and final guidance documents and it is no longer
necessary for the agency to include reference to these documents in its
postmarketing safety reporting regulations.
At the present time, FDA is in the process of revising guidances
pertaining to this final rule (CDER's ``Guideline for Postmarketing
Reporting of Adverse Drug Experiences,'' March 1992 and CBER's
``Guideline for Adverse Experience Reporting for Licensed Biological
Products,'' October 1993) to provide persons with the agency's current
thinking on reporting of postmarketing adverse drug experiences. The
agency will provide notice of availability of any draft or final
guidance document pertaining to these regulations in the Federal
Register and on the FDA WWW home page.
IV. Comments on the Proposed Rule
FDA received 57 comments on the proposed rule from representatives
of pharmaceutical companies, health care professional and
pharmaceutical associations, academic and government institutions, and
individuals. The comments addressed all aspects of the October 1994
proposal, including those areas that are not being finalized in this
final rule. In general, the comments endorsed FDA's efforts in the
proposal to support global harmonization through the adoption of
certain ICH and CIOMS recommendations. However, many comments described
areas where the proposed regulations did not conform to the
international guidelines, and recommended that the proposal be revised
to be more consistent. The agency also received comments recommending
uniformity between its pre- and postmarketing safety reporting
definitions. In response to these comments, FDA, as described in
section III of this document, is amending its regulations to implement
additional provisions recommended in the final ICH E2A guideline and to
provide uniformity in its safety reporting definitions.
A discussion of the comments pertaining to this final rule and the
agency's responses follows.
A. Definition of Disability
FDA proposed to define ``disability,'' in Secs. 310.305(b),
314.80(a), and 600.80(a), as ``a substantial disruption of a person's
ability to carry out normal life functions.''
1. Eight comments requested clarification of this definition. One
comment asked whether it included missing work because of an adverse
experience, quitting a job, an inability to get out of bed, or a
decrease in earning capacity. Another comment asked if it included
nausea, vomiting, and diarrhea that would keep a person home from work.
One questioned whether the proposed definition included events such as
migraine headaches, severe influenza, or accidental trauma (e.g.,
sprained ankle). Another comment contended that if the proposed
definition is intended to mean the substantial disruption of normal
life functions, then such a condition would require hospitalization or
the in-house use of life-support equipment.
FDA proposed to include the definition of ``disability'' in the
regulations to enable reporters to determine when a ``serious'' adverse
drug experience occurs. The extent of a disability required for a
serious adverse drug experience is described in the
[[Page 52242]]
definition of ``serious'' by the phrase ``* * * results in persistent
or significant disability/incapacity * * *.'' Thus, only a persistent
or significant or incapacitating disability is intended. The type of
disability that would constitute a serious adverse drug experience is
also described in the final ICH E2A guideline, which states that a
serious adverse drug experience is based on events that pose a threat
to a patient's life or functioning and not on events of relatively
minor medical significance (60 FR 11284 at 11285). Thus, disability is
not intended to include experiences of relatively minor medical
significance such as headache, nausea, vomiting, diarrhea, influenza,
and accidental trauma (e.g., sprained ankle).
For clarity, FDA has revised the proposed definition of
``disability'' by substituting the words ``to conduct'' for the words
``to carry out.''
To assure a consistent interpretation of serious adverse drug
experience in premarketing and postmarketing safety reporting, FDA has
decided to revise the ``definitions'' section of the IND safety reports
regulation, at Sec. 312.32(a), by adding the definition of
``disability'' that is used in the postmarketing safety reporting
regulations at Secs. 310.305(b), 314.80(a), and 600.80(a).
B. Definition of Life-Threatening
FDA proposed to define ``life-threatening,'' in Secs. 310.305(b),
314.80(a), and 600.80(a), as follows:
[T]hat the patient was, in the view of the initial reporter, at
immediate risk of death from the adverse experience as it occurred.
It does not include an adverse experience that, had it occurred in a
more serious form, might have caused death. For example, product-
induced hepatitis that resolved without evidence of hepatic failure
would not be considered life-threatening even though hepatitis of a
more severe nature can be fatal. Similarly, an allergic reaction
resulting in angioedema of the face would not be life-threatening,
even though angioedema of the larynx, allergic bronchospasm, or
anaphylaxis can be fatal.
2. Five comments opposed the use of the phrase ``in the view of the
initial reporter.'' The comments stated that the initial reporter could
be a lay person whose judgment of what constitutes an ``immediate risk
of death'' may be contrary to an evaluation by a medically
knowledgeable source. Several comments suggested alternative language
for the definition to minimize inaccurate reporting of events. One
comment requested deletion of the word ``initial.'' Another suggested
changing the phrase ``initial reporter'' to ``a health care
professional directly associated with the care of the patient,'' while
a third recommended changing the word ``reporter'' to ``health care
provider who reports the adverse experience.''
FDA declines to amend the proposed definition of ``life-
threatening'' by deleting or revising the phrase ``in the view of the
initial reporter.'' As explained in the June 1993 notice (58 FR 31596
and 31604), FDA encourages health care professionals and consumers to
report adverse drug experiences to manufacturers. FDA Form 3500A
includes a section for identifying the ``initial reporter'' and for
indicating the reporter's occupation and whether the person is a health
care professional. Thus, the manufacturer and FDA will know whether the
adverse drug experience report came from a lay person or a health care
professional and can take that information into account when evaluating
the report.
Current IND safety reporting regulations for telephone reports
define a ``life-threatening'' experience at Sec. 312.32(c)(2), as:
* * * that the patient was, in the view of the investigator, at
immediate (emphasis added) risk of death from the reaction as it
occurred, i.e., it does not include a reaction that, had it occurred
in a more serious form, might have caused death. For example, drug-
induced hepatitis that resolved without evidence of hepatic failure
would not be considered life-threatening even though drug-induced
hepatitis can be fatal.
FDA has decided, on its own initiative, to remove the definition of
``life-threatening'' from the telephone safety reports section, at
Sec. 312.32(c)(2), and add it to the general ``definitions'' section of
Sec. 312.32, at Sec. 312.32(a). This action will clarify that reporting
of life-threatening events apply to both written and telephone IND
safety reports. FDA has also replaced ``serious'' with ``severe'' in
the definition of ``life-threatening'' to make it consistent with the
final ICH E2A guideline. FDA has also decided, on its own initiative,
to add the words ``or subject'' after ``patient'' in this definition to
clarify that IND safety reports apply to healthy subjects as well as
patients. FDA has also removed the last sentence in the definition of
``life-threatening'' under Sec. 312.32 (and the last two sentences in
the proposed postmarketing definition of ``life-threatening'' under
Secs. 310.305(b), 314.80(a), and 600.80(a)), as noted in section III of
this document, to minimize confusion. The revised definition of ``life-
threatening adverse drug experience'' in the IND safety reporting
regulations at Sec. 312.32(a) reads as follows:
Any adverse drug experience that places the patient or subject,
in the view of the investigator, at immediate risk of death from the
reaction as it occurred, i.e., it does not include a reaction that,
had it occurred in a more severe form, might have caused death.
C. Definition of Serious
FDA proposed to revise the definition of ``serious,'' in
Secs. 310.305(b), 312.32(a), 314.80(a), and 600.80(a), to read as
follows:
Serious means an adverse drug experience occurring at any dose
that is fatal or life-threatening, results in persistent or
significant disability/incapacity, requires or prolongs inpatient
hospitalization, necessitates medical or surgical intervention to
preclude permanent impairment of a body function or permanent damage
to a body structure, or is a congenital anomaly.
3. Twenty-five comments opposed all or parts of the phrase
``necessitates medical or surgical intervention to preclude permanent
impairment of a body function or permanent damage to a body
structure.'' Nine comments stated that this phrase makes the U.S.
definition of ``serious'' inconsistent with harmonized safety reporting
standards such as the ICH E2A and E6 guidelines and with the CIOMS II
report. One comment said that although the phrase was included to
provide a consistent definition of what constitutes a serious adverse
event for all FDA-regulated products, it causes inconsistency between
United States and international reporting requirements. Another comment
said that the difference in definitions between the United States and
the international community will cause confusion and additional expense
for manufacturers who are complying with the reporting requirements of
several countries. One comment stated that if the definition is
finalized as proposed, preparation and submission of a single
postmarketing periodic report worldwide will not be possible. Another
comment said that a definition as important as ``serious'' should be
internationally consistent in order to be easy to learn, quote, and
recognize in global clinical development and medical safety. One
comment noted that it would be especially difficult to implement the
proposed criterion of ``medical/surgical intervention'' during the
course of an ongoing clinical study.
Ten comments recommended deletion of the phrase. Eleven comments
requested clarification of the phrase because it is too vague and
misinterpretation would result in overreporting or underreporting of
adverse events. Another comment suggested that the phrase be reworded
as an ``unusual and potentially serious experience that necessitates
any medical or surgical intervention.'' One comment recommended
adopting the approach in the final ICH E2A guideline of including
``medical and surgical intervention''
[[Page 52243]]
within the area of ``other important medical events.'' The comment
indicated that the guideline leaves the determination of whether or not
such an event is serious to medical and scientific judgment.
As explained in the June 1993 notice (58 FR 31596), FDA Forms 3500
and 3500A are designed to encourage and facilitate the reporting of
adverse events and product problems for most FDA-regulated human
medical products by the entire health care community, including
manufacturers, distributors, user facilities, and health care
professionals. This includes reporting of adverse events and product
problems with human drug products, biologics, and medical devices, as
well as other FDA-regulated medical products.
FDA adopted several recommendations from ICH and CIOMS in
developing the definitions used in the forms and in the proposed
amendments to the safety reporting regulations for human drug and
biological products. The agency believes that certain standardized
definitions, procedures, and formats proposed by ICH and CIOMS will
result in more effective and efficient safety reporting to regulatory
authorities worldwide. The agency proposed to amend the definition of
``serious'' to have a consistent definition of what constitutes a
serious adverse drug experience for all FDA-regulated products and to
avoid confusion about what events should be reported to regulatory
authorities worldwide.
FDA agrees with the comments that the differences between the
definition of serious, as proposed, and the definition recommended in
the final ICH E2A guideline and in the CIOMS II report may create
confusion about what events to report as serious. Therefore, the agency
has revised the definition of ``serious'' to be consistent with the
final ICH E2A guideline (60 FR 11284 at 11285) and FDA Forms 3500 and
3500A. The revised definition states:
Any adverse drug experience occurring at any dose that results
in any of the following outcomes: Death, a life-threatening adverse
drug experience, inpatient hospitalization or prolongation of
existing hospitalization, a persistent or significant disability/
incapacity, or a congenital anomaly/birth defect. Important medical
events that may not result in death, be life-threatening, or require
hospitalization may be considered a serious adverse drug experience
when, based upon appropriate medical judgment, they may jeopardize
the patient or subject and may require medical or surgical
intervention to prevent one of the outcomes listed in this
definition. Examples of such medical events include allergic
bronchospasm requiring intensive treatment in an emergency room or
at home, blood dyscrasias or convulsions that do not result in
inpatient hospitalization, or the development of drug dependency or
drug abuse.
The term ``serious'' is defined similarly in the final ICH E2A
guideline (60 FR 11284 at 11285) as:
A serious adverse event (experience) or reaction is any untoward
medical occurrence that at any dose:
Results in death,
Is life-threatening,
* * *
Requires inpatient hospitalization or prolongation of
existing hospitalization,
Results in persistent or significant disability/
incapacity, or
Is a congenital anomaly/birth defect.
Medical and scientific judgment should be exercised in deciding
whether expedited reporting is appropriate in other situations, such
as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize
the patient or may require intervention to prevent one of the other
outcomes listed in the definition above. These should also usually
be considered serious.
Examples of such events are intensive treatment in an emergency
room or at home for allergic bronchospasm; blood dyscrasias or
convulsions that do not result in hospitalization; or development of
drug dependency or drug abuse.
The revised definition of ``serious'' is also consistent with
section B.2 of FDA Forms 3500 and 3500A, which directs persons
completing the forms to indicate which of the following outcomes is
attributed to the adverse event: ``death, life-threatening,
hospitalization--initial or prolonged, disability, congenital anomaly,
required intervention to prevent permanent impairment/damage, or
other.''
In order to make the definition of ``serious'' in the premarketing
safety reporting regulations at Sec. 312.32(a) uniform with the revised
definition of ``serious'' in the postmarketing safety reporting
regulations at Secs. 310.305(b), 314.80(a), and 600.80(a), FDA is
removing the following sentence from the current definition of
``serious'' at Sec. 312.32(a), and adding it, with minor revisions, to
the IND written safety reporting requirements under
Sec. 312.32(c)(1)(i):
With respect to results obtained from tests in laboratory
animals, a serious adverse drug experience includes any experience
suggesting a significant risk for human subjects, including any
finding of mutagenicity, teratogenicity, or carcinogenicity.
4. One comment requested adding the phrase ``including overdose and
underdose'' after the phrase ``occurring at any dose'' in the
definition of ``serious'' in order to eliminate confusion. Otherwise,
the comment claimed, adverse outcomes associated with underdoses may be
interpreted as a lack of therapeutic effect rather than an adverse drug
experience.
FDA declines to amend the definition of ``serious'' to include the
phrase ``including overdose or underdose.'' Use of the phrase
``occurring at any dose'' in the revised definition of ``serious'' will
ensure that serious adverse drug experiences occurring at any dose,
including an overdose or an underdose, must be reported.
5. Five comments asked for examples of what is considered serious.
One comment asked whether intravenous (IV) treatment for dehydration
without hospital admission or the use of IV antibiotics, blood
products, or dialysis would be considered serious.
FDA advises that use of IV fluids, antibiotics, or blood products,
or dialysis may or may not be serious, depending on why they are being
used. A decision using medical judgment should be made based on the
circumstances surrounding each case. As stated in the revised
definition of ``serious'', other examples include allergic bronchospasm
requiring intensive treatment in an emergency room or at home, blood
dyscrasias or convulsions that do not result in inpatient
hospitalization, and the development of drug dependency or drug abuse.
6. Five comments requested clarification of the following sentence
in the preamble to the proposed rule under the discussion of the
definition of ``serious'': ``FDA notes that a serious adverse
experience would not include the discontinuation of therapy, changes in
dosage, or routine treatment with a prescription medication'' (59 FR
54046 at 54048). One comment stated that the sentence should also be
included in the codified definition of ``serious'' because the
qualifiers are extremely important in limiting the range of events not
considered serious. Three comments asked for clarification of the
phrase ``routine treatment with a prescription medication.'' One of
these comments noted that treatment with any new medication could
potentially be considered a medical intervention and therefore could be
classified as serious. Another comment requested clarification of the
phrase ``would not include discontinuation of therapy'' because it
implies that discontinuation of therapy in response to a clinically
significant rise in serum aminotransferases or serum creatinine would
not be considered intervention and therefore would not be serious.
FDA declines to revise the definition of ``serious'' to include
examples of events not considered serious. FDA
[[Page 52244]]
clarifies that discontinuation of therapy, changes in dosage, and
routine treatment with a prescription medication are not in themselves
serious events but may occur as the result of a serious event.
7. Several comments discussed the use of the words ``persistent''
and ``permanent'' in the definition of ``serious''. One comment
requested rewording the phrase ``persistent or significant disability''
to read ``permanent or persistent disability.'' Another comment
suggested that the term ``permanent disability'' in the current
definition of ``serious'' should be retained because replacing
``permanent'' with ``persistent'' does not further define disability.
The comment noted that a condition like influenza might be
significantly incapacitating but may not qualify as a serious event.
Three comments recommended changing the word ``permanent'' to
``persistent'' in the phrase ``preclude permanent impairment of a body
function or permanent damage to a body system.'' One comment requested
that the phrase ``persistent or significant disability'' be used
instead of ``permanent or significant disability'' in the definition of
``serious'' in proposed Sec. 312.32(a) in order to be consistent with
proposed Secs. 310.305(b), 314.80(a), and 600.80(a).
As explained in the preamble to the October 1994 proposal (59 FR
54046 at 54047), FDA is revising the phrase ``is permanently
disabling'' to ``results in a persistent or significant disability/
incapacity'' in order to clarify that a disability need not be
permanent to be considered a serious adverse drug experience. Thus, FDA
declines to substitute the phrase ``permanent or persistent
disability'' for ``persistent or significant disability'' or retain
``permanent disability.'' In addition, FDA has corrected the
typographical error in proposed Sec. 312.32(a) by revising ``permanent
or significant disability'' to read ``persistent or significant
disability.''
8. One comment requested the addition of the word ``immediately''
before ``life-threatening'' in the definition of ``serious''. The
comment stated that although ``immediate'' is stated in the definition
of ``life-threatening'', it is not indicated on FDA Form 3500 or 3500A.
As a result, reporters may interpret ``life-threatening'' to mean
``potentially'' life-threatening rather than ``immediately'' life-
threatening.
FDA declines to revise the definition of ``serious'' to add the
word ``immediately'' before ``life-threatening'' because the phrase
``at immediate risk of death'' is part of the definition of ``life-
threatening adverse drug experience.'' Although the word
``immediately'' does not appear before the word ``life-threatening'' on
FDA Forms 3500 and 3500A, the MedWatch ``FDA Desk Guide for Adverse
Event and Product Problem Reporting'' explains that a life-threatening
adverse event would be immediate.
D. IND Safety Reports--Written
FDA proposed to revise the requirements for submitting written IND
safety reports, under Sec. 312.32(c)(1) and (d)(3), by altering the
time period for submitting such reports from 10 working days to 15
calendar days. In addition, FDA proposed to permit sponsors to submit
written IND safety reports to the agency by using FDA Form 3500A or in
a narrative format. If a sponsor chose to use FDA Form 3500A,
additional narrative data might be required if the agency determined
that insufficient data were submitted on the form.
9. Three comments expressed support for the 15 calendar days
timeframe. One comment commended FDA for requiring the same timeframe
for both pre- and postmarketing expedited reporting. Two other comments
requested that the timeframe be increased to 20 calendar days, while
another comment recommended any period longer than 15 calendar days.
The comments stated that 15 calendar days would not provide enough time
for the submission of reports or for contacting non-U.S. physicians.
One comment noted that a longer timeframe would permit better review
and reporting of serious adverse experiences.
As explained in the October 1994 proposal (59 FR 54046 at 54051),
FDA believes that the extended timeframe is sufficient for sponsors to
gather appropriate data to help initially interpret the reports before
submitting them to FDA. This timeframe is also consistent with the 15
calendar day period in the final ICH E2A guideline (60 FR 11284 at
11286).
10. Although one comment expressed support for use of FDA Form
3500A for written IND safety reports because it would provide
consistency with the form for postmarketing reports, another comment
requested that the form not be required for these reports because of
limited space for describing narrative information.
FDA notes that it is not ``requiring'' use of FDA Form 3500A for
written IND safety reports. Reporters may use the form or,
alternatively, may submit these reports in a narrative format. In
addition, as explained in the June 1993 notice announcing the
availability of the form, reporters may use additional blank sheets of
paper, referenced to the section of the form being described, to
complete any narrative sections of the form.
In the June 1993 notice (58 FR 31596 at 31598), FDA also stated
that companies may use the CIOMS I form for reporting foreign events
after obtaining FDA approval. FDA has decided, based on comments to its
postmarketing safety reporting regulations (see section IV.F of this
document), to amend Sec. 312.32(c)(1) to permit use of the CIOMS I form
for reporting foreign events without prior approval. FDA has decided to
take this action to expedite reporting of foreign events and harmonize
its pre- and postmarketing safety reporting regulations.
11. One comment requested clarification about what sponsors must
include in a written IND safety report. The comment also requested
guidance on how often a report should be submitted and whether one is
required every time a new case is reported.
Under Sec. 312.32(b), as amended in this final rule, FDA requires
that the sponsor must promptly review all information relevant to the
safety of the drug obtained or otherwise received by the sponsor from
any source, foreign or domestic, including information derived from any
clinical or epidemiological investigations, animal investigations,
commercial marketing experience, reports in the scientific literature,
and unpublished scientific papers, as well as reports from foreign
regulatory authorities that have not already been previously reported
to the agency by the sponsor. This requirement qualifies for sponsors
the type of safety information that must be examined for determination
of whether the information should be included in IND safety reports.
As noted earlier, FDA is amending its IND safety reports
regulations, at Sec. 312.32, by moving, for organizational purposes,
certain information from the current definition of ``serious adverse
experience,'' at Sec. 312.32(a), to the written IND safety reports
section, at Sec. 312.32(c)(1)(i). Under Sec. 312.32(c)(1)(i), as
revised in this final rule, sponsors must submit written IND safety
reports to FDA and all participating investigators within 15 calendar
days after the sponsor's receipt of information on any adverse
experience associated with the use of the drug that is both serious and
unexpected; or any finding from tests in laboratory animals that
suggests a significant risk for human subjects including reports of
[[Page 52245]]
mutagenicity, teratogenicity, or carcinogenicity.
FDA advises sponsors, as described in greater detail in the final
ICH E2A guideline (60 FR 11284 at 11285 and 11286), to submit in
written IND safety reports as much information as possible on a case.
In some instances, information for final description and evaluation of
a case report may not be available within 15 calendar days.
Nevertheless, initial reports should be submitted within this timeframe
when the following minimum criteria are met: An identifiable patient; a
suspected medicinal product; an identifiable reporter; and an adverse
event or outcome that can be identified as serious and unexpected, and
for which, in clinical investigation cases, there is a reasonable
suspected causal relationship between the investigational product and
the adverse event (i.e., the causal relationship cannot be ruled out).
For reportable events that occur during a ``blinded'' clinical
investigation, sponsors should only break the blind for the subject in
question. Sponsors should consult with the FDA review division
responsible for their IND in situations in which the sponsor believes
that breaking the blind would compromise their study (e.g., when a
fatal or other serious outcome is the primary efficacy endpoint in a
clinical investigation). Reportable events attributed to a specific
dosage form, formulation, or route of administration should be cross-
referenced to other IND's for the drug. Reportable events associated
with a particular population or for a specific indication should also
be cross-referenced to other IND's for the drug.
FDA expects sponsors to submit written IND safety reports every
time the sponsor receives or otherwise obtains information about a
serious and unexpected adverse experience associated with the use of
the drug until the current investigator brochure or, if the
investigator brochure is not required, until the risk information
described in the general investigational plan or elsewhere in the
current application is amended. This is consistent with the final ICH
E2A guideline (60 FR 11284 at 11285): ``Until source documents are
amended, expedited reporting is required for additional occurrences of
the reaction.''
12. One comment asked when a written safety report would be due if
the 15th day occurs on a weekend or holiday.
FDA advises that if the 15th calendar day occurs on a weekend or
U.S. Federal holiday, the written safety report would be due the 1st
working day after the weekend or U.S. Federal holiday.
E. IND Safety Reports--Telephone
FDA proposed to revise the requirements for submitting IND safety
reports by telephone, under Sec. 312.32(c)(2), by altering the time
period for submitting such reports from 3 working days to 7 calendar
days. FDA also proposed to allow telephone safety reports to be made by
facsimile transmission.
13. Two comments expressed support for the 7 calendar day
timeframe. Other comments requested longer timeframes because 7 days
does not provide a significant difference from the current time period,
and because additional time is needed for contacting non-U.S.
physicians. One comment asked for a timeframe of 10 calendar days, and
another requested any period longer than 7 calendar days.
FDA declines to lengthen the timeframe for IND safety reports by
telephone or facsimile transmission. FDA believes it is important that
unexpected fatal or life-threatening experiences associated with the
use of the drug be reported to the agency as expeditiously as possible.
A 7 calendar day timeframe is reasonable for these types of reports.
This timeframe is also consistent with recommendations in the final ICH
E2A guideline (60 FR 11284 at 11286).
14. Three comments supported FDA's proposal to accept telephone
safety reports by ``facsimile transmission.'' The comments also
requested that FDA permit transmission of these reports by other
electronic mechanisms such as Internet or electronic mail systems.
In the Federal Register of March 20, 1997 (62 FR 13430), FDA
published a final rule that permits the agency to accept electronic
records, electronic signatures, and handwritten signatures executed to
electronic records as generally equivalent to paper records and
handwritten signatures executed on paper. FDA stated in this final rule
that it will announce in the Federal Register when it is prepared to
accept certain submissions in electronic format only. At the present
time, FDA is not prepared to accept electronic submission of IND safety
reports, but is developing a system to accept such submissions in the
future.
15. One comment requested that FDA restore the phrase ``in the
clinical studies conducted under the IND'' to the language in
Sec. 312.32(c)(2) for telephone safety reports of any unexpected fatal
or life-threatening experience associated with the use of the drug. The
phrase did not appear in the October 27, 1994, proposed revisions to
this section.
It is FDA's intention not to restrict telephone safety reports of
any unexpected fatal or life-threatening experience associated with the
use of the drug to clinical studies conducted under the IND. As stated
under Sec. 312.32(b), as revised in this final rule, the sponsor shall
promptly review all information relevant to the safety of the drug
obtained or otherwise received by the sponsor from any source, foreign
or domestic, including information derived from any clinical or
epidemiological investigations, animal investigations, commercial
marketing experience, reports in the scientific literature, and
unpublished scientific papers, as well as reports from foreign
regulatory authorities that have not already been previously reported
to the agency by the sponsor. Thus, the sponsor is responsible for
notifying FDA by telephone or facsimile transmission, as soon as
possible, but in no event later than 7 calendar days, of any unexpected
fatal or life-threatening experience associated with the use of the
drug from any source. This requirement is consistent with the final ICH
E2A guideline (60 FR 11284 at 11286):
Information obtained by a sponsor or manufacturer on serious,
unexpected reports from any source should be submitted on an
expedited basis to appropriate regulatory authorities if the minimum
criteria for expedited reporting can be met.
F. Postmarketing Alert and Followup Reports
FDA proposed to amend Secs. 310.305(c), 314.80(c), and 600.80(c) by
reorganizing, renumbering, and retitling the paragraphs in these
sections to distinguish between postmarketing 15-day Alert reports and
followups to these reports. FDA also proposed to distinguish between
the reporting intervals for postmarketing 15-day Alert reports and the
intervals proposed for postmarketing periodic reports. In addition, FDA
proposed to amend Secs. 310.305(c)(1) through (c)(4), 314.80(c)(1)(i)
through (c)(1)(iv), and 600.80(c)(1)(i) through (c)(1)(iv), to alter
the time period for submitting postmarketing 15-day Alert reports and
followup reports from 15 working days to 15 calendar days.
16. Twelve comments stated that the 15 calendar day timeframe is
overly burdensome. One comment noted that the change from 15 working
days to 15 calendar days would result in approximately one-third (6
days) less time for preparation of reports for submission to FDA.
Another comment indicated that, although the proposed
[[Page 52246]]
timeframe is in accord with the final ICH E2A guideline, it would cause
significant disruption in reporting schedules and would probably result
in incomplete reports. Another comment stated that the revised
timeframe would not provide international companies with sufficient
time to receive and translate foreign reports. One comment said that
the proposed timeframe incorrectly assumes that reporters are
universally accessible anywhere in the world. Six comments offered
suggestions for alternative timeframes. Three comments recommended 20
calendar days, one recommended 21 calendar days, and another
recommended 22 calendar days. Two of the comments encouraged retention
of the 15 working day timeframe currently required by FDA.
FDA declines to revise its proposed 15 calendar day timeframe for
postmarketing Alert reports. The agency proposed to revise the
reporting period from 15 working days to 15 calendar days to provide
consistency in pre- and postmarketing safety reporting timeframes for
products and to decrease misunderstandings with reporting requirements
by stating all timeframes in terms of calendar days. This timeframe is
consistent with the 15 calendar day reporting timeframe in the final
ICH E2A guideline (60 FR 11284 at 11286) and consistent with the change
in timeframe set forth in this final rule at Sec. 312.32(c)(1) and
(d)(3) for IND safety reporting of serious and unexpected experiences.
This timeframe is sufficient for persons subject to the postmarketing
safety reporting requirements to gather appropriate data and initially
interpret reports before submitting them to the agency.
In this final rule, FDA is amending its postmarketing expedited
safety reporting regulations, at Sec. 310.305(c)(1)(i), by adding the
following phrase to the end of the first sentence: ``by the person
whose name appears on the label.'' FDA is making this revision to
clarify when the 15 calendar day timeframe begins for marketed
prescription drugs for human use without approved new drug
applications. This change is consistent with current language under
Secs. 314.80(c)(1)(i) and 600.80(c)(1)(i) for marketed prescription
drugs for human use with approved NDA's and for licensed biological
products. Under Sec. 314.80(c)(1)(i), 15-day Alert reports must be
submitted no later than 15 calendar days of initial receipt of
information by the applicant. Under Sec. 600.80(c)(1)(i), such reports
must be submitted within the same timeframe based on initial receipt of
information by the licensed manufacturer.
17. Two comments requested that they be permitted to use the CIOMS
I form for reporting foreign events as an alternative to FDA Form 3500A
without obtaining prior FDA approval. In addition, the comments
preferred using the CIOMS I form instead of FDA Form 3500A for all
adverse drug experience reporting worldwide.
In the June 1993 notice, the agency stated that reporters may use
the CIOMS I form for reporting foreign events with prior FDA approval.
FDA has considered the comments and has decided to revise
Secs. 310.305, 314.80, and 600.80 to permit the use of the CIOMS I form
for reports of foreign events without first obtaining prior FDA
approval. FDA is taking this action to expedite the reporting of
foreign events.
FDA will continue to require use of FDA Form 3500A for reports of
domestic events. FDA Form 3500A is more comprehensive than the CIOMS I
form and includes elements recommended by the final ICH E2A guideline
that are not part of the CIOMS I form (60 FR 11284 at 11287). For
example, the following items are included in FDA Form 3500A and
requested in the ICH E2A guideline but are not included in the CIOMS I
form: Body weight, the terms ``congenital anomaly'' and ``other''
(identifiers of adverse event outcomes), the lot number and dosage
strength of suspected medicinal product(s), details on the event
reporter, and the regulatory code number (e.g., IND/NDA number).
18. One comment requested that FDA accept postmarketing 15-day
Alert and followup reports through electronic transmission.
As explained above, FDA has published a final rule to permit the
agency to accept electronic records, electronic signatures, and
handwritten signatures executed to electronic records as generally
equivalent to paper records and handwritten signatures executed on
paper (62 FR 13430). At the present time, FDA is not prepared to accept
electronic submission of 15-day Alert reports, but is developing a
system to accept such submissions in the future.
G. Written Procedures for Monitoring Adverse Drug Experiences
FDA proposed to amend Secs. 310.305(a), 314.80(b), and 600.80(b) to
require that any person subject to the reporting requirements under
Secs. 310.305(c), 314.80(c), and 600.80(c) develop written procedures
for the surveillance, receipt, evaluation, and reporting of adverse
drug experiences to FDA.
19. One comment opposed this amendment. The comment stated that
these written procedures are customary and usual in the industry and,
if made part of a regulation, could be potentially burdensome to
manufacturers and would permit FDA to dictate internal procedures.
FDA declines to withdraw this proposed amendment. As explained in
the preamble to the October 1994 proposal (59 FR 54046 at 54053), this
requirement would improve postmarketing surveillance by applicants and
manufacturers and would enhance an applicant's and a manufacturer's
ability to evaluate and report adverse drug experiences to the agency.
In addition, because such written procedures are usual and customary,
FDA believes that this provision would not impose a new burden on
applicants and manufacturers.
20. One comment stated that it is inappropriate to require packers
and distributors to develop written procedures for the surveillance,
receipt, evaluation, and reporting of adverse drug experiences to FDA
if they elect to submit these reports to the manufacturer.
Under Secs. 310.305(c)(1)(i), 314.80(c)(1)(iv), and
600.80(c)(1)(iv), packers and distributors are subject to the reporting
requirements if their name appears on the label of a marketed
prescription drug product or licensed biological product. A packer or
distributor who elects to submit adverse drug experience reports to an
applicant, manufacturer, or licensed manufacturer of a final biological
product under Secs. 310.305(c)(4), 314.80(c)(1)(iv), and
600.80(c)(1)(iv) must include information about making such an election
in their written procedures, as well as procedures for recordkeeping
required to be maintained under these regulations. For the reasons
explained in the October 1994 proposal (59 FR 54046 at 54053), it is
appropriate to require that these packers and distributors develop
written procedures to ensure that they comply with these regulations.
21. One comment requested that FDA specify the minimum requirements
for a company's written procedures for reporting adverse drug
experiences.
FDA declines to specify minimum requirements for written reporting
procedures. As explained in the October 1994 proposal (59 FR 54046 at
54053), written procedures for handling adverse drug experiences are
customary and usual in the pharmaceutical industry. In
[[Page 52247]]
addition, such procedures have been required for many years by FDA's
current good manufacturing practice (CGMP) regulations for finished
pharmaceuticals (21 CFR 211.198).
H. Submission of Postmarketing 15-day Alert Reports by Persons Other
Than Applicants, Manufacturers, and Licensed Manufacturers of a Final
Biological Product
Current postmarketing safety reporting regulations, at
Sec. 310.305(c)(5), permit packers and distributors to submit reports
of serious adverse drug experiences to the manufacturer instead of FDA.
Under Sec. 314.80(c)(1)(iii), manufacturers, packers, and distributors
may submit these reports to the applicant. Under
Sec. 600.80(c)(1)(iii), packers, distributors, and manufacturers other
than licensed manufacturers of the final biological product may submit
these reports to the licensed manufacturer of the final product.
Currently, these reports must be submitted within 3 working days of
their receipt. FDA proposed to revise this timeframe to 3 calendar
days. The manufacturer, applicant, and licensed manufacturer of the
final biological product would then comply with the requirements
described in this section by submitting the report to FDA as soon as
possible, but in no case later than 15 calendar days of initial receipt
of the information.
22. Five comments opposed changing 3 working days to 3 calendar
days because the new timeframe is overly burdensome, especially if the
period includes holidays or weekends. One comment said that
manufacturers, packers, distributors, and shared and joint
manufacturers would probably submit these reports directly to FDA in
order to utilize the longer timeframe. This would result in duplicative
reporting to the agency. The comments suggested alternative timeframes.
Three comments recommended 5 calendar days, one recommended 7 calendar
days, and another recommended that the current requirement of 3 working
days be maintained.
FDA agrees with the comments and has revised the final rule at
Secs. 310.305(c)(4), 314.80(c)(1)(iv), and 600.80(c)(1)(iv) to permit
manufacturers, packers, and distributors, as well as manufacturers,
packers, distributors, shared manufacturers, joint manufacturers, and
any other participant involved in divided manufacturing of a biological
product, to submit reports of serious adverse drug experiences to the
manufacturer, applicant, or licensed manufacturer of the final
biological product in 5 calendar days.
23. One comment requested that the regulations state that
manufacturers should not submit to FDA reports it receives from a
reporter, if the reporter has submitted the report to FDA.
FDA declines to revise its regulations to exempt manufacturers from
submitting safety reports to FDA that it receives from a voluntary
reporter who has submitted the report to FDA, regardless of whether the
reporter is a physician, pharmacist, or other health care professional,
or a consumer. The agency requires manufacturers to submit such reports
to FDA to ensure that the agency receives all safety reports. However,
as now stated at Secs. 310.305(c)(6), 314.80(b), and 600.80(b), no one
subject to the postmarketing safety reporting regulations at
Secs. 310.305(c), 314.80(c), and 600.80(c) is required to resubmit to
the agency FDA Form 3500A reports that the agency has forwarded to
them.
I. General Comments
24. One comment asked whether the Federal Register notices
announcing the availability of FDA Forms 3500 and 3500A had been
withdrawn, revised, or replaced by the October 1994 proposal. The
comment indicated that the effective date for FDA Form 3500A was put on
hold pending revision of the regulations for safety reporting.
The June 1993 notice (58 FR 31596), announced the availability of
FDA Forms 3500 and 3500A. The use of FDA Form 3500 was effective
immediately, while the use of FDA Form 3500A was scheduled to be
effective on November 30, 1993. Manufacturers, medical device
distributors, and user facilities were encouraged to begin using the
form immediately. In the Federal Register of December 3, 1993 (58 FR
64001), FDA extended the effective date for use of FDA Form 3500A until
FDA issues a final rule amending the regulations to require the use of
the form. This final rule makes the requirement for use of FDA Form
3500A effective on April 6, 1998.
25. Four comments requested that FDA publish guidelines to explain
the proposed regulations. Two of the comments asked whether a draft
guideline could be published with an opportunity for public comment
before publication of the final rule.
In the Federal Register of March 1, 1995 (60 FR 11284), FDA
published the final ICH E2A guideline ``Clinical Safety Data
Management: Definitions and Standards for Expedited Reporting.''
Concerning the opportunity for comment on guidances, on July 9, 1993
(58 FR 37408), FDA published the draft ICH E2A guideline for public
comment.
As described under section III of this document, FDA is in the
process of revising guidances pertaining to this final rule and will
provide opportunity for public comment and notice of availability of
any draft or final guidance documents in the Federal Register and on
FDA's WWW home page, under the GGP's (62 FR 8961).
26. One comment asked whether information on the United Kingdom
Medicines Control Agency's Medical Dictionary for Drug Regulatory
Affairs would be incorporated into the final rule.
This terminology was not discussed in the proposed rule and will
not be incorporated into this final rule. At the September 1994 CIOMS
meeting, it was agreed that this terminology would be the basis for the
development of a new international medical terminology to support
classification of terms relating to all aspects of drug regulation. In
July 1997, ICH developed a final consensus guideline on this topic (ICH
M1). At this time, FDA is considering the ICH M1 document.
V. Environmental Impact
The agency has determined under 21 CFR 25.30(h) 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.
VI. Analysis of Impacts
The agency has considered the potential economic impact of this
final rule under Executive Order 12866, the Regulatory Flexibility Act
(5 U.S.C. 601-612), as amended by Subtitle D of the Small Business
Regulatory Fairness Act of 1996 (Pub. L. 104-721), and the Unfunded
Mandates Reform Act of 1995 (Pub. L. 104-4). 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
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.
[[Page 52248]]
The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. The agency certifies that the final rule will not
have a significant economic impact on a substantial number of small
entities. According to the Small Business Administration, manufacturers
of medicinals and botanicals or pharmaceutical preparations with 750 or
less employees, and manufacturers of diagnostic substances or
biological products with 500 or less employees are considered a small
business. As discussed in section VII of this document, modifications
and additions to the recordkeeping requirements will not result in a
change in industry's current recordkeeping burden hours. Therefore,
under the Regulatory Flexibility Act, no further analysis is needed.
The final rule will also not impose annual expenditures of $100
million or more on either State, local, and tribal governments in
aggregate, or on the private sector. Therefore, a written statement and
economic analysis is not required as prescribed under section 202(a) of
the Unfunded Mandates Reform Act of 1995.
VII. Paperwork Reduction Act of 1995
This final rule contains information collection provisions that are
subject to review by the Office of Management and Budget (OMB) under
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). The title,
description, and respondent description of the information collection
provisions are shown below.
Title: Expedited Safety Reporting Requirements for Human Drug and
Biological Products; Final Rule.
Description: FDA is amending its current expedited safety reporting
requirements to replace current Form FDA-1639 with new FDA Form 3500A;
to revise certain definitions, reporting periods and formats; to
require applicants, manufacturers, packers, and distributors, as well
as licensed manufacturers and other manufacturers of biological
products to develop written procedures for postmarketing safety
monitoring and reporting of adverse drug experiences to FDA; and to
make other revisions to provide uniformity to the expedited pre- and
postmarketing safety reporting regulations. These changes will simplify
and facilitate expedited safety reporting and enhance agencywide
consistency in the collection of postmarketing safety data.
Respondent Description: Businesses and other for-profit
organizations, State or local governments, Federal agencies, and
nonprofit institutions.
FDA believes that this final rule will not result in any increase
in paperwork burden as compared to current expedited safety reporting
requirements. The new requirement under Secs. 310.305(a), 314.80(b),
and 600.80(b), that persons subject to the postmarketing safety
reporting requirements develop written procedures for the surveillance,
receipt, evaluation, and reporting to FDA of adverse drug experiences,
does not impose a new burden because it codifies a practice that is
already customary and usual in the pharmaceutical industry for handling
adverse drug experiences.
The new recordkeeping requirements under Secs. 310.305(c)(2),
314.80(c)(1)(ii), and 600.80(c)(1)(ii), that persons subject to the
postmarketing safety reporting requirements maintain records of
unsuccessful attempts to obtain additional followup information on 15-
day Alert reports, do not result in a change in the burden. Current
regulations provide for submission of a followup report describing
steps taken to seek additional information and the reasons why it could
not be obtained; FDA estimates that the effort needed to file this
existing information will be, at worst, no more than the effort that
would have been required to submit it to FDA.
The new language in Sec. 312.32(b) explicitly requiring that
sponsors review: (1) Information derived from any epidemiological
investigations, or (2) reports from foreign regulatory authorities that
have not already been previously reported to the agency by the sponsor
does not impose a new burden because this amendment is only a
clarification. Sponsors are already required to review all information
relevant to the safety of the drug obtained or otherwise received by
the sponsor from any source, foreign or domestic.
Although the October 1994 proposal provided a 90-day comment period
under the Paperwork Reduction Act of 1980, FDA is providing an
additional opportunity for public comment under the Paperwork Reduction
Act of 1995, which was enacted after the expiration of the comment
period and applies to this final rule. Therefore, FDA now invites
comments on: (1) Whether the proposed collection of information is
necessary for the proper performance of FDA's functions, including
whether the information will have practical utility; (2) the accuracy
of FDA's estimate of the burden of the proposed collection of
information, including the validity of the methodology and assumptions
used; (3) ways to enhance the quality, utility, and clarity of the
information to be collected; and (4) ways to minimize the burden of the
collection of information on respondents, including through the use of
automated collection techniques, when appropriate, and other forms of
information technology. Individuals and organizations may submit
comments on the information collection provisions of this final rule by
December 8, 1997. Comments should be directed to the Dockets Management
Branch (address above).
At the close of the 60-day comment period, FDA will review the
comments received, revise the information collection provisions as
necessary, and submit these provisions to OMB for review and approval.
FDA will publish a notice in the Federal Register when the information
collection provisions are submitted to OMB, and an opportunity for
public comment to OMB will be provided at that time. Prior to the
effective date of this final rule, FDA will publish a notice in the
Federal Register of OMB's decision to approve, modify, or disapprove
the information collection provisions. An agency may not conduct or
sponsor, and a person is not required to respond to, a collection of
information unless it displays a currently valid OMB control number.
VIII. References
The following references have been placed on display at the Dockets
Management Branch (address above) and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday.
1. International Reporting of Periodic Drug-Safety Update
Summaries, Final Report of CIOMS Working Group II, 1992.
2. International Reporting of Adverse Drug Reactions, Final
Report of CIOMS Working Group I, 1990.
List of Subjects
21 CFR Part 20
Confidential business information, Courts, Freedom of information,
Government employees.
21 CFR Part 310
Administrative practice and procedure, Drugs, Labeling, Medical
devices, Reporting and recordkeeping requirements.
21 CFR Part 312
Drugs, Exports, Imports, Investigations, Labeling, Medical
research, Reporting and recordkeeping requirements, Safety.
[[Page 52249]]
21 CFR Part 314
Administrative practice and procedure, Confidential business
information, Drugs, Reporting and recordkeeping requirements.
21 CFR Part 600
Biologics, Reporting and recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act, the
Public Health Service Act, and under authority delegated to the
Commissioner of Food and Drugs, 21 CFR parts 20, 310, 312, 314, and 600
are amended as follows:
PART 20--PUBLIC INFORMATION
1. The authority citation for 21 CFR part 20 continues to read as
follows:
Authority: Secs. 201-903 of the Federal Food, Drug, and Cosmetic
Act (21 U.S.C. 321-393); secs. 301, 302, 303, 307, 310, 311, 351,
352, 354-360F, 361, 362, 1701-1706, 2101 of the Public Health
Service Act (42 U.S.C. 241, 242, 242a, 242l, 242n, 243, 262, 263,
263b-263n, 264, 265, 300u-300u-5, 300aa-1); 5 U.S.C. 552; 18 U.S.C.
1905; 19 U.S.C. 2531-2582; 21 U.S.C. 1401-1403.
Sec. 20.112 [Amended]
2. Section 20.112 Voluntary drug experience reports submitted by
physicians and hospitals is amended in paragraph (a) by removing the
words ``Form FDA-1639'' and adding in their place ``FDA Form 3500''.
PART 310--NEW DRUGS
3. The authority citation for 21 CFR part 310 continues to read as
follows:
Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 512-
516, 520, 601(a), 701, 704, 705, 721 of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357,
360b-360f, 360j, 361(a), 371, 374, 375, 379e); secs. 215, 301,
302(a), 351, 354-360F of the Public Health Service Act (42 U.S.C.
216, 241, 242(a), 262, 263b-263n).
4. Section 310.305 is amended by adding a new sentence at the end
of paragraph (a); by revising paragraphs (b), (c), (d)(1), (d)(3)(ii),
and (d)(4); by removing in paragraph (d)(2), the introductory text of
paragraph (d)(3), and paragraph (d)(3)(i) the words ``Form FDA-1639''
or ``FDA-1639'' and adding in their place ``FDA Form 3500A'' to read as
follows:
Sec. 310.305 Records and reports concerning adverse drug experiences
on marketed prescription drugs for human use without approved new drug
applications.
(a) * * * Any person subject to the reporting requirements of
paragraph (c) of this section shall also develop written procedures for
the surveillance, receipt, evaluation, and reporting of postmarketing
adverse drug experiences to FDA.
(b) Definitions. The following definitions of terms apply to this
section:
Adverse drug experience. Any adverse event associated with the use
of a drug in humans, whether or not considered drug related, including
the following: An adverse event occurring in the course of the use of a
drug product in professional practice; an adverse event occurring from
drug overdose whether accidental or intentional; an adverse event
occurring from drug abuse; an adverse event occurring from drug
withdrawal; and any failure of expected pharmacological action.
Disability. A substantial disruption of a person's ability to
conduct normal life functions.
Life-threatening adverse drug experience. Any adverse drug
experience that places the patient, in the view of the initial
reporter, at immediate risk of death from the adverse drug experience
as it occurred, i.e., it does not include an adverse drug experience
that, had it occurred in a more severe form, might have caused death.
Serious adverse drug experience. Any adverse drug experience
occurring at any dose that results in any of the following outcomes:
Death, a life-threatening adverse drug experience, inpatient
hospitalization or prolongation of existing hospitalization, a
persistent or significant disability/ incapacity, or a congenital
anomaly/birth defect. Important medical events that may not result in
death, be life-threatening, or require hospitalization may be
considered a serious adverse drug experience when, based upon
appropriate medical judgment, they may jeopardize the patient or
subject and may require medical or surgical intervention to prevent one
of the outcomes listed in this definition. Examples of such medical
events include allergic bronchospasm requiring intensive treatment in
an emergency room or at home, blood dyscrasias or convulsions that do
not result in inpatient hospitalization, or the development of drug
dependency or drug abuse.
Unexpected adverse drug experience. Any adverse drug experience
that is not listed in the current labeling for the drug product. This
includes events that may be symptomatically and pathophysiologically
related to an event listed in the labeling, but differ from the event
because of greater severity or specificity. For example, under this
definition, hepatic necrosis would be unexpected (by virtue of greater
severity) if the labeling only referred to elevated hepatic enzymes or
hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis
would be unexpected (by virtue of greater specificity) if the labeling
only listed cerebral vascular accidents. ``Unexpected,'' as used in
this definition, refers to an adverse drug experience that has not been
previously observed (i.e., included in the labeling) rather than from
the perspective of such experience not being anticipated from the
pharmacological properties of the pharmaceutical product.
(c) Reporting requirements. Each person identified in paragraph
(c)(1)(i) of this section shall report to FDA adverse drug experience
information as described in this section and shall submit one copy of
each report to the Division of Pharmacovigilance and Epidemiology (HFD-
730), Center for Drug Evaluation and Research, Food and Drug
Administration, 5600 Fishers Lane, Rockville, MD 20857.
(1) Postmarketing 15-day ``Alert reports''. (i) Any person whose
name appears on the label of a marketed prescription drug product as
its manufacturer, packer, or distributor shall report to FDA each
adverse drug experience received or otherwise obtained that is both
serious and unexpected as soon as possible, but in no case later than
15 calendar days of initial receipt of the information by the person
whose name appears on the label. Each report shall be accompanied by a
copy of the current labeling for the drug product.
(ii) A person identified in paragraph (c)(1)(i) of this section is
not required to submit a 15-day ``Alert report'' for an adverse drug
experience obtained from a postmarketing study (whether or not
conducted under an investigational new drug application) unless the
applicant concludes that there is a reasonable possibility that the
drug caused the adverse experience.
(2) Postmarketing 15-day ``Alert reports''--followup. Each person
identified in paragraph (c)(1)(i) of this section shall promptly
investigate all serious, unexpected adverse drug experiences that are
the subject of these postmarketing 15-day Alert reports and shall
submit followup reports within 15 calendar days of receipt of new
information or as requested by FDA. If additional information is not
obtainable, records should be maintained of the unsuccessful steps
taken to seek additional information. Postmarketing 15-day Alert
reports and followups to them shall be submitted under separate cover.
[[Page 52250]]
(3) Submission of reports. To avoid unnecessary duplication in the
submission of, and followup to, reports required in this section, a
packer's or distributor's obligations may be met by submission of all
reports of serious adverse drug experiences to the manufacturer of the
drug product. If a packer or distributor elects to submit these adverse
drug experience reports to the manufacturer rather than to FDA, it
shall submit each report to the manufacturer within 5 calendar days of
its receipt by the packer or distributor, and the manufacturer shall
then comply with the requirements of this section even if its name does
not appear on the label of the drug product. Under this circumstance,
the packer or distributor shall maintain a record of this action which
shall include:
(i) A copy of each adverse drug experience report;
(ii) The date the report was received by the packer or distributor;
(iii) The date the report was submitted to the manufacturer; and
(iv) The name and address of the manufacturer.
(4) Each report submitted to FDA under this section shall bear
prominent identification as to its contents, i.e., ``15-day Alert
report,'' or ``15-day Alert report-followup.''
(5) A person identified in paragraph (c)(1)(i) of this section is
not required to resubmit to FDA adverse drug experience reports
forwarded to that person by FDA; however, the person must submit all
followup information on such reports to FDA.
(d) * * * (1) Except as provided in paragraph (d)(3) of this
section, each person identified in paragraph (c)(1)(i) of this section
shall submit each report of a serious and unexpected adverse drug
experience on an FDA Form 3500A (foreign events may be submitted either
on an FDA Form 3500A or, if preferred, on a CIOMS I form).
* * * * *
(3) * * *
(ii) The format is agreed to in advance by MedWatch: The FDA
Medical Products Reporting Program.
(4) Ten copies or fewer of FDA Form 3500A and/or a copy of the
instructions for completing the form may be obtained from the Division
of Pharmacovigilance and Epidemiology (HFD-730), Center for Drug
Evaluation and Research, Food and Drug Administration, 5600 Fishers
Lane, Rockville, MD 20857. More than 10 copies of the form may be
obtained by writing to the Consolidated Forms and Publications
Distribution Center, Washington Commerce Center, 3222 Hubbard Rd.,
Landover, MD 20785.
* * * * *
PART 312--INVESTIGATIONAL NEW DRUG APPLICATION
5. 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).
6. Section 312.32 is amended by revising paragraphs (a), (b),
(c)(1)(i), (c)(2), and (d)(3); by adding in the second sentence of
paragraph (c)(3) the words ``new drug review'' before the phrase
``division in the Center for Drug Evaluation and Research'' and the
words ``the director of the product review division in'' before the
phrase ``the Center for Biologics Evaluation and Research''; and by
removing in paragraph (e) the word ``section'' and replacing it with
the word ``part'', to read as follows:
Sec. 312.32 IND safety reports.
(a) Definitions. The following definitions of terms apply to this
section:
Associated with the use of the drug. There is a reasonable
possibility that the experience may have been caused by the drug.
Disability. A substantial disruption of a person's ability to
conduct normal life functions.
Life-threatening adverse drug experience. Any adverse drug
experience that places the patient or subject, in the view of the
investigator, at immediate risk of death from the reaction as it
occurred, i.e., it does not include a reaction that, had it occurred in
a more severe form, might have caused death.
Serious adverse drug experience: Any adverse drug experience
occurring at any dose that results in any of the following outcomes:
Death, a life-threatening adverse drug experience, inpatient
hospitalization or prolongation of existing hospitalization, a
persistent or significant disability/ incapacity, or a congenital
anomaly/birth defect. Important medical events that may not result in
death, be life-threatening, or require hospitalization may be
considered a serious adverse drug experience when, based upon
appropriate medical judgment, they may jeopardize the patient or
subject and may require medical or surgical intervention to prevent one
of the outcomes listed in this definition. Examples of such medical
events include allergic bronchospasm requiring intensive treatment in
an emergency room or at home, blood dyscrasias or convulsions that do
not result in inpatient hospitalization, or the development of drug
dependency or drug abuse.
Unexpected adverse drug experience: Any adverse drug experience,
the specificity or severity of which is not consistent with the current
investigator brochure; or, if an investigator brochure is not required
or available, the specificity or severity of which is not consistent
with the risk information described in the general investigational plan
or elsewhere in the current application, as amended. For example, under
this definition, hepatic necrosis would be unexpected (by virtue of
greater severity) if the investigator brochure only referred to
elevated hepatic enzymes or hepatitis. Similarly, cerebral
thromboembolism and cerebral vasculitis would be unexpected (by virtue
of greater specificity) if the investigator brochure only listed
cerebral vascular accidents. ``Unexpected,'' as used in this
definition, refers to an adverse drug experience that has not been
previously observed (e.g., included in the investigator brochure)
rather than from the perspective of such experience not being
anticipated from the pharmacological properties of the pharmaceutical
product.
(b) Review of safety information. The sponsor shall promptly review
all information relevant to the safety of the drug obtained or
otherwise received by the sponsor from any source, foreign or domestic,
including information derived from any clinical or epidemiological
investigations, animal investigations, commercial marketing experience,
reports in the scientific literature, and unpublished scientific
papers, as well as reports from foreign regulatory authorities that
have not already been previously reported to the agency by the sponsor.
(c) IND safety reports. (1) Written reports--(i) The sponsor shall
notify FDA and all participating investigators in a written IND safety
report of:
(A) Any adverse experience associated with the use of the drug that
is both serious and unexpected; or
(B) Any finding from tests in laboratory animals that suggests a
significant risk for human subjects including reports of mutagenicity,
teratogenicity, or carcinogenicity. Each notification shall be made as
soon as possible and in no event later than 15 calendar days after the
sponsor's initial receipt of the information. Each written notification
may be submitted on FDA
[[Page 52251]]
Form 3500A or in a narrative format (foreign events may be submitted
either on an FDA Form 3500A or, if preferred, on a CIOMS I form;
reports from animal or epidemiological studies shall be submitted in a
narrative format) and shall bear prominent identification of its
contents, i.e., ``IND Safety Report.'' Each written notification to FDA
shall be transmitted to the FDA new drug review division in the Center
for Drug Evaluation and Research or the product review division in the
Center for Biologics Evaluation and Research that has responsibility
for review of the IND. If FDA determines that additional data are
needed, the agency may require further data to be submitted.
* * * * *
(2) Telephone and facsimile transmission safety reports. The
sponsor shall also notify FDA by telephone or by facsimile transmission
of any unexpected fatal or life-threatening experience associated with
the use of the drug as soon as possible but in no event later than 7
calendar days after the sponsor's initial receipt of the information.
Each telephone call or facsimile transmission to FDA shall be
transmitted to the FDA new drug review division in the Center for Drug
Evaluation and Research or the product review division in the Center
for Biologics Evaluation and Research that has responsibility for
review of the IND.
* * * * *
(d) * * *
(3) If the results of a sponsor's investigation show that an
adverse drug experience not initially determined to be reportable under
paragraph (c) of this section is so reportable, the sponsor shall
report such experience in a written safety report as soon as possible,
but in no event later than 15 calendar days after the determination is
made.
* * * * *
PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG OR AN
ANTIBIOTIC DRUG
7. The authority citation for 21 CFR part 314 continues to read as
follows:
Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701,
704, 721 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321,
331, 351, 352, 353, 355, 356, 357, 371, 374, 379e).
8. Section 314.80 is amended by revising paragraphs (a), (c)(1),
(f)(1), (f)(3)(ii), and (f)(4) and the introductory text of paragraph
(c); by adding two new sentences at the end of paragraph (b); by
removing in paragraph (d)(2) the words ``Epidemiology and
Surveillance'' and adding in their place the words ``Pharmacovigilance
and Epidemiology''; by removing in paragraphs (c)(2)(ii)(b), (d)(2),
(f)(2), and (f)(3) and in the heading for paragraph (f) the words
``Form FDA-1639'' or ``FDA-1639'' and adding in their place the words
``FDA Form 3500A''; and by removing paragraph (j) and redesignating
paragraphs (k) and (l) as paragraphs (j) and (k), respectively, to read
as follows:
Sec. 314.80 Postmarketing reporting of adverse drug experiences.
(a) Definitions. The following definitions of terms apply to this
section:
Adverse drug experience. Any adverse event associated with the use
of a drug in humans, whether or not considered drug related, including
the following: An adverse event occurring in the course of the use of a
drug product in professional practice; an adverse event occurring from
drug overdose whether accidental or intentional; an adverse event
occurring from drug abuse; an adverse event occurring from drug
withdrawal; and any failure of expected pharmacological action.
Disability. A substantial disruption of a person's ability to
conduct normal life functions.
Life-threatening adverse drug experience. Any adverse drug
experience that places the patient, in the view of the initial
reporter, at immediate risk of death from the adverse drug experience
as it occurred, i.e., it does not include an adverse drug experience
that, had it occurred in a more severe form, might have caused death.
Serious adverse drug experience. Any adverse drug experience
occurring at any dose that results in any of the following outcomes:
Death, a life-threatening adverse drug experience, inpatient
hospitalization or prolongation of existing hospitalization, a
persistent or significant disability/ incapacity, or a congenital
anomaly/birth defect. Important medical events that may not result in
death, be life-threatening, or require hospitalization may be
considered a serious adverse drug experience when, based upon
appropriate medical judgment, they may jeopardize the patient or
subject and may require medical or surgical intervention to prevent one
of the outcomes listed in this definition. Examples of such medical
events include allergic bronchospasm requiring intensive treatment in
an emergency room or at home, blood dyscrasias or convulsions that do
not result in inpatient hospitalization, or the development of drug
dependency or drug abuse.
Unexpected adverse drug experience. Any adverse drug experience
that is not listed in the current labeling for the drug product. This
includes events that may be symptomatically and pathophysiologically
related to an event listed in the labeling, but differ from the event
because of greater severity or specificity. For example, under this
definition, hepatic necrosis would be unexpected (by virtue of greater
severity) if the labeling only referred to elevated hepatic enzymes or
hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis
would be unexpected (by virtue of greater specificity) if the labeling
only listed cerebral vascular accidents. ``Unexpected,'' as used in
this definition, refers to an adverse drug experience that has not been
previously observed (i.e., included in the labeling) rather than from
the perspective of such experience not being anticipated from the
pharmacological properties of the pharmaceutical product.
(b) * * * Applicants are not required to resubmit to FDA adverse
drug experience reports forwarded to the applicant by FDA; however,
applicants must submit all followup information on such reports to FDA.
Any person subject to the reporting requirements under paragraph (c) of
this section shall also develop written procedures for the
surveillance, receipt, evaluation, and reporting of postmarketing
adverse drug experiences to FDA.
(c) Reporting requirements. The applicant shall report to FDA
adverse drug experience information, as described in this section. The
applicant shall submit two copies of each report described in this
section to the Central Document Room, 12229 Wilkins Ave., Rockville, MD
20852. FDA may waive the requirement for the second copy in appropriate
instances.
(1)(i) Postmarketing 15-day ``Alert reports''. The applicant shall
report each adverse drug experience that is both serious and
unexpected, whether foreign or domestic, as soon as possible but in no
case later than 15 calendar days of initial receipt of the information
by the applicant.
(ii) Postmarketing 15-day ``Alert reports''--followup. The
applicant shall promptly investigate all adverse drug experiences that
are the subject of these postmarketing 15-day Alert reports and shall
submit followup reports within 15 calendar days of receipt of new
information or as requested by FDA. If additional information is not
obtainable, records should be maintained of the unsuccessful steps
taken to seek additional information. Postmarketing 15-day Alert
reports and followups to
[[Page 52252]]
them shall be submitted under separate cover.
(iii) Submission of reports. The requirements of paragraphs
(c)(1)(i) and (c)(1)(ii) of this section, concerning the submission of
postmarketing 15-day Alert reports, shall also apply to any person
other than the applicant (nonapplicant) whose name appears on the label
of an approved drug product as a manufacturer, packer, or distributor.
To avoid unnecessary duplication in the submission to FDA of reports
required by paragraphs (c)(1)(i) and (c)(1)(ii) of this section,
obligations of a nonapplicant may be met by submission of all reports
of serious adverse drug experiences to the applicant. If a nonapplicant
elects to submit adverse drug experience reports to the applicant
rather than to FDA, the nonapplicant shall submit each report to the
applicant within 5 calendar days of receipt of the report by the
nonapplicant, and the applicant shall then comply with the requirements
of this section. Under this circumstance, the nonapplicant shall
maintain a record of this action which shall include:
(A) A copy of each adverse drug experience report;
(B) The date the report was received by the nonapplicant;
(C) The date the report was submitted to the applicant; and
(D) The name and address of the applicant.
(iv) Report identification. Each report submitted under this
paragraph shall bear prominent identification as to its contents, i.e.,
``15-day Alert report,'' or ``15-day Alert report-followup.''
* * * * *
(f) * * * (1) Except as provided in paragraph (f)(3) of this
section, the applicant shall complete FDA Form 3500A for each report of
an adverse drug experience (foreign events may be submitted either on
an FDA Form 3500A or, if preferred, on a CIOMS I form).
* * * * *
(3) * * * (ii) the format is agreed to in advance by MedWatch: The
FDA Medical Products Reporting Program.
(4) Ten copies or fewer of FDA Form 3500A and/or a copy of the
instructions for completing the form may be obtained from the Division
of Pharmacovigilance and Epidemiology (HFD-730), Center for Drug
Evaluation and Research, Food and Drug Administration, 5600 Fishers
Lane, Rockville, MD 20857. More than 10 copies of the form may be
obtained by writing to the Consolidated Forms and Publications
Distribution Center, Washington Commerce Center, 3222 Hubbard Rd.,
Landover, MD 20785.
* * * * *
PART 600--BIOLOGICAL PRODUCTS: GENERAL
9. The authority citation for 21 CFR part 600 continues to read as
follows:
Authority: Secs. 201, 501, 502, 503, 505, 510, 519, 701, 704 of
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352,
353, 355, 360, 360i, 371, 374); secs. 215, 351, 352, 353, 361, 2125
of the Public Health Service Act (42 U.S.C. 216, 262, 263, 263a,
264, 300aa-25).
10. Section 600.80 is amended by revising paragraphs (a), (c)(1),
(f)(1), and the first sentence of paragraph (g); by adding two new
sentences at the end of paragraph (b); and by removing paragraph (j)
and redesignating paragraphs (k), (l), and (m) as paragraphs (j), (k),
and (l), respectively, to read as follows:
Sec. 600.80 Postmarketing reporting of adverse experiences.
(a) Definitions. The following definitions of terms apply to this
section:
Adverse experience. Any adverse event associated with the use of a
biological product in humans, whether or not considered product
related, including the following: An adverse event occurring in the
course of the use of a biological product in professional practice; an
adverse event occurring from overdose of the product whether accidental
or intentional; an adverse event occurring from abuse of the product;
an adverse event occurring from withdrawal of the product; and any
failure of expected pharmacological action.
Blood Component. As defined in Sec. 606.3(c) of this chapter.
Disability. A substantial disruption of a person's ability to
conduct normal life functions.
Life-threatening adverse experience. Any adverse experience that
places the patient, in the view of the initial reporter, at immediate
risk of death from the adverse experience as it occurred, i.e., it does
not include an adverse experience that, had it occurred in a more
severe form, might have caused death.
Serious adverse experience. Any adverse experience occurring at any
dose that results in any of the following outcomes: Death, a life-
threatening adverse experience, inpatient hospitalization or
prolongation of existing hospitalization, a persistent or significant
disability/incapacity, or a congenital anomaly/birth defect. Important
medical events that may not result in death, be life-threatening, or
require hospitalization may be considered a serious adverse experience
when, based upon appropriate medical judgment, they may jeopardize the
patient or subject and may require medical or surgical intervention to
prevent one of the outcomes listed in this definition. Examples of such
medical events include allergic bronchospasm requiring intensive
treatment in an emergency room or at home, blood dyscrasias or
convulsions that do not result in inpatient hospitalization, or the
development of drug dependency or drug abuse.
Unexpected adverse experience: Any adverse experience that is not
listed in the current labeling for the biological product. This
includes events that may be symptomatically and pathophysiologically
related to an event listed in the labeling, but differ from the event
because of greater severity or specificity. For example, under this
definition, hepatic necrosis would be unexpected (by virtue of greater
severity) if the labeling only referred to elevated hepatic enzymes or
hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis
would be unexpected (by virtue of greater specificity) if the labeling
only listed cerebral vascular accidents. ``Unexpected,'' as used in
this definition, refers to an adverse experience that has not been
previously observed (i.e., included in the labeling) rather than from
the perspective of such experience not being anticipated from the
pharmacological properties of the pharmaceutical product.
(b) * * * Licensed manufacturers are not required to resubmit to
FDA adverse product experience reports forwarded to the licensed
manufacturer by FDA; licensed manufacturers, however, must submit all
followup information on such reports to FDA. Any person subject to the
reporting requirements under paragraph (c) of this section shall also
develop written procedures for the surveillance, receipt, evaluation,
and reporting of postmarketing adverse experiences to FDA.
(c) * * *
(1)(i) Postmarketing 15-day ``Alert reports''. The licensed
manufacturer shall report each adverse experience that is both serious
and unexpected, whether foreign or domestic, as soon as possible but in
no case later than 15 calendar days of initial receipt of the
information by the licensed manufacturer.
(ii) Postmarketing 15-day ``Alert reports''--followup. The licensed
manufacturer shall promptly investigate
[[Page 52253]]
all adverse experiences that are the subject of these postmarketing 15-
day Alert reports and shall submit followup reports within 15 calendar
days of receipt of new information or as requested by FDA. If
additional information is not obtainable, records should be maintained
of the unsuccessful steps taken to seek additional information.
Postmarketing 15-day Alert reports and followups to them shall be
submitted under separate cover.
(iii) Submission of reports. The requirements of paragraphs
(c)(1)(i) and (c)(1)(ii) of this section, concerning the submission of
postmarketing 15-day Alert reports, shall also apply to any person
whose name appears on the label of a licensed biological product as a
manufacturer, packer, distributor, shared manufacturer, joint
manufacturer, or any other participant involved in divided
manufacturing. To avoid unnecessary duplication in the submission to
FDA of reports required by paragraphs (c)(1)(i) and (c)(1)(ii) of this
section, obligations of persons other than the licensed manufacturer of
the final biological product may be met by submission of all reports of
serious adverse experiences to the licensed manufacturer of the final
product. If a person elects to submit adverse experience reports to the
licensed manufacturer of the final product rather than to FDA, the
person shall submit each report to the licensed manufacturer of the
final product within 5 calendar days of receipt of the report by the
person, and the licensed manufacturer of the final product shall then
comply with the requirements of this section. Under this circumstance,
a person who elects to submit reports to the licensed manufacturer of
the final product shall maintain a record of this action which shall
include:
(A) A copy of all adverse biological product experience reports
submitted to the licensed manufacturer of the final product;
(B) The date the report was received by the person;
(C) The date the report was submitted to the licensed manufacturer
of the final product; and
(D) The name and address of the licensed manufacturer of the final
product.
(iv) Report identification. Each report submitted under this
paragraph shall bear prominent identification as to its contents, i.e.,
``15-day Alert report,'' or ``15-day Alert report-followup.''
* * * * *
(f) Reporting forms. (1) Except as provided in paragraph (f)(3) of
this section, the licensed manufacturer shall complete the reporting
form designated by FDA for each report of an adverse experience (FDA
Form 3500A, or, for vaccines, a VAERS form; foreign events including
those associated with the use of vaccines, may be submitted either on
an FDA Form 3500A or, if preferred, on a CIOMS I form).
* * * * *
(g) Multiple reports. A licensed manufacturer should not include in
reports under this section any adverse experience that occurred in
clinical trials if they were previously submitted as part of the
license application. * * *
* * * * *
Dated: September 25, 1997.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 97-26255 Filed 10-6-97; 8:45 am]
BILLING CODE 4160-01-F
