[Federal Register: March 14, 2003 (Volume 68, Number 50)]
[Proposed Rules]
[Page 12405-12497]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr14mr03-18]
[[Page 12405]]
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Part II
Department of Health and Human Services
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Food and Drug Administration
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21 CFR Parts 310, 312, et al.
Safety Reporting Requirements for Human Drug and Biological Products;
Proposed Rule
[[Page 12406]]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 310, 312, 314, 320, 600, 601, and 606
[Docket No. 00N-1484]
RIN 0910-AA97
Safety Reporting Requirements for Human Drug and Biological
Products
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
its pre- and postmarketing safety reporting regulations for human drug
and biological products to implement definitions and reporting formats
and standards 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 (WHO's) Council for International Organizations of
Medical Sciences (CIOMS); codify the agency's expectations for timely
acquisition, evaluation, and submission of relevant safety information
for marketed drugs and licensed biological products; require that
certain information, such as domestic reports of medication errors, be
submitted to the agency in an expedited manner; clarify certain
requirements; and make other minor revisions. FDA is also proposing to
amend its postmarketing annual reporting regulations for human drug and
licensed biological products by revising the content for these reports.
FDA is taking this action to strengthen its ability to monitor the
safety of human drugs and biological products. The intended effect of
these changes is to further worldwide consistency in the collection of
safety information and submission of safety reports, increase the
quality of safety reports, expedite FDA's review of critical safety
information, and enable the agency to protect and promote public
health. These proposed changes would be an important step toward global
harmonization of safety reporting requirements and additional efforts
are underway within the Department of Health and Human Services to
harmonize the reporting requirements of U.S. Federal agencies (e.g.,
FDA and the National Institutes of Health (NIH) are continuing to work
together to address the best ways to streamline information sharing and
harmonize, to the extent possible, the safety reporting requirements of
the two agencies).
DATES: Submit written comments by July 14, 2003. Submit written
comments on the collection of information by April 14, 2003.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852, e-mail: FDADockets@oc.fda.gov or to the Internet
at http://www.accessdata.fda.gov/scripts/oc/dockets/comments/
commentdocket.cfm.
FAX written comments on the information collection
provisions to the Office of Information and Regulatory Affairs, Office
of Management and Budget (OMB), New Executive Office Bldg., 725 17th
St. NW., rm. 10235, Washington, DC 20503, Attn: Stuart Shapiro, Desk
Officer for FDA, 202-395-6974.
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, 301-594-5626.
For information concerning human biological products: Miles Braun,
Center for Biologics Evaluation and Research (HFM-220), Food and Drug
Administration, 1401 Rockville Pike, Rockville, MD 20852-1448, 301-827-
6079.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Previous Safety Reporting Rulemaking and Current Guidances
II. Introduction
A. Persons Subject to the Safety Reporting Regulations
1. Premarketing Expedited Safety Reporting Regulations
2. Postmarketing Safety Reporting Regulations
3. Terms Used in This Document
B. Rationale for This Proposal
1. International Standards
2. Quality of Postmarketing Safety Reports
3. New Postmarketing Expedited Safety Reports
a. Medication errors
b. Unexpected SADRs with unknown outcome
c. Always expedited reports
d. Blood and blood component safety reports
4. Bioavailability and Bioequivalence Studies Not Subject to an
Investigational New Drug Application (IND)
C. New Safety Reporting Abbreviations
D. Highlights of Proposed Changes to FDA's Safety Reporting
Regulations
III. Description of the Proposed Rule
A. Definitions
1. Suspected Adverse Drug Reaction (SADR)
2. A Life-Threatening SADR
3. Serious SADR, Nonserious SADR, and SADR With Unknown Outcome
4. Contractor
5. Minimum Data Set and Full Data Set for an Individual Case
Safety Report
6. Active Query
7. Spontaneous Report
8. Medication Error
9. Company Core Data Sheet, Company Core Safety Information
(CCSI), Listed SADR, Unlisted SADR, and Unexpected SADR
10. Data Lock Point and International Birth Date
B. IND Safety Reports
1. Review of Safety Information
2. Written IND Safety Reports
a. Minimum data set
b. Serious and unexpected SADRs
c. Information sufficient to consider product administration
changes
d. Reporting format
3. Telephone Safety Reports
4. IND Safety Reporting for Drugs Marketed in the United States
5. Investigator Reporting
C. Postmarketing Safety Reporting
1. Prescription Drugs Marketed for Human Use Without an Approved
Application
2. Review of Safety Information
3. Reporting Requirements
4. Request for Alternative Reporting Frequency
5. Determination of Outcome, Minimum Data Set, and Full Data Set
6. Spontaneous Reports and Reports From Clinical Trials
7. Lack of Efficacy Reports
D. Postmarketing Expedited Reports
1. Serious and Unexpected SADRs
2. Information Sufficient to Consider Product Administration
Changes
3. Unexpected SADRs With Unknown Outcome
4. Always Expedited Reports
5. Medication Errors
6. Followup Reports
7. Supporting Documentation
8. Scientific Literature
9. Contractors and Shared Manufacturers
10. Prescription Drugs Marketed for Human Use Without an
Approved Application
11. Class Action Lawsuits
12. Blood and Blood Component Safety Reports
E. Postmarketing Periodic Safety Reporting
1. Traditional Periodic Safety Reports (TPSRs)
a. Narrative summary and analysis of individual case safety
reports
b. Individual case safety reports
c. Increased frequency reports
d. Safety-related actions to be taken
e. Summary tabulations
f. History of safety-related actions taken
g. Location of safety records
h. Contact person
2. Periodic Safety Update Reports (PSURs)
a. Title page, table of contents, and introduction
b. Worldwide marketing status
c. Actions taken for safety reasons
[[Page 12407]]
d. Changes to CCSI
e. Worldwide patient exposure
f. Individual case safety reports
i. Line listings
ii. Summary tabulations
g. Safety studies
h. Other information
i. Overall safety evaluation
j. Conclusion
k. Appendices
i. Company core data sheet
ii. U.S. labeling
iii. Spontaneous reports submitted to the applicant by an
individual other than a health care professional
iv. SADRs with unknown outcome
v. Class action lawsuits
vi. Lack of efficacy reports
vii. Information on resistance to antimicrobial drug products
viii. Medication errors
ix. U.S. patient exposure
x. Location of safety records
xi. Contact person
3. Interim Periodic Safety Reports (IPSRs)
4. Semiannual Submission of Individual Case Safety Reports
5. Reporting Requirements
a. Reporting intervals
b. Submission date
c. Cover letter
d. International birth date for combination products
F. Reporting Format
1. Forms Versus Narrative Format
2. Medical Dictionary for Regulatory Activities (MedDRA)
3. Single Form for Each Identifiable Patient
4. Contact Person
5. Computer-Generated Facsimile of FDA Form 3500A or Vaccine
Adverse Event Reporting System (VAERS) Form
6. Other Revisions
G. Patient Privacy
H. Recordkeeping
I. Abbreviated New Drug Application (ANDA) Products
J. Postmarketing Approved New Drug Application (NDA) and
Biologics License Application (BLA) Annual Reports
K. Safety Reporting for In Vivo Bioavailability and
Bioequivalence Studies
L. Proposed Implementation Scheme
IV. Environmental Impact
V. Analysis of Impacts
A. Background and Summary
B. Market Failure
C. Benefits
1. Expanded Safety Information
2. Improved Uniformity and Quality of Safety Information
3. Potential Savings from Reduced SADR-Related Hospitalizations
a. Reduced rate of SADR-related hospitalizations
b. Reduced rate of in-hospital SADRs
c. Indirect benefits of reducing the hospital costs of SADRs
d. Sum of SADR-related costs
4. Cost Savings and More Efficient Use of Resources
a. Savings related to maintaining and building data bases of
SADRs and intercompany transfers of drug safety data
b. Savings related to greater ease in entering into intercompany
agreements
c. Savings related to eventual international harmonization to
the PSUR format
d. Potential savings in clinical trial management
e. Leveraging specialized knowledge
f. Total benefits
D. Costs of Compliance
1. Costs of New Recordkeeping and Reporting Requirements
a. Number of reports
b. New time burden
i. Expedited reports
ii. Followup reports
iii. Blood products
iv. IND and bioavailability/bioequivalence safety reports
v. Semiannual submissions of postmarketing individual case
safety reports
vi. Postmarketing period safety reports (TPSR, PSUR, and IPSR)
vii. Other reports
c. Annual cost of the reporting and recordkeeping provisions
2. Costs of MedDRA
a. One-time costs
i. Planning and coordination
ii. Development of information technology support structure
iii. Purchase or development of an autoencoder
iv. Conversion of legacy safety data
v. Training of personnel
vi. Revision of standard operating procedures (SOPs)
b. Recurring costs
i. MedDRA core subscription
ii. MedDRA versions and quarterly updates
iii. Maintenance of existing dictionaries
E. Small Business Analysis
1. Need for and Objectives of the Rule
2. Description and Estimate of Small Entities
3. Projected Reporting, Recordkeeping, and Other Compliance
Requirements
a. Reporting and recordkeeping requirements
b. Implementing MedDRA
4. Alternatives and Steps to Minimize the Impact on Small
Entities
a. Do nothing
b. Do not require a medical dictionary
c. Do not require medication errors as expedited reports
d. Do not require blood establishments to submit reports for all
serious SADRs associated with blood collection and transfusion
e. Do not require certain bioavailability and bioequivalence
reports as expedited reports
f. Waivers for economic hardship
g. Small business outreach, training, and assistance
F. Unfunded Mandates Reform Act of 1995
G. References
VI. Paperwork Reduction Act of 1995
A. Expedited Safety Reporting
B. Periodic Safety Reports
C. Other Reports
D. Recordkeeping
VII. Executive Order 13132: Federalism
I. Previous Safety Reporting Rulemaking and Current Guidances
FDA has undertaken a major effort to clarify and revise its
regulations regarding pre- and postmarketing safety reporting for human
drug and biological products. Since 1990, several rules and guidances
have been issued regarding these regulations. Some of these guidances
have been issued by international organizations (i.e., ICH and CIOMS),
while others have been issued by FDA. In figure 1 of this document, FDA
illustrates how these rules and guidances relate to the current
proposed rule.
BILLING CODE 4160-01-P
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In the Federal Register of October 27, 1994 (59 FR 54046), FDA
published a proposed rule to amend its expedited and periodic pre- and
postmarketing safety reporting regulations for human drug and
biological products (the October 1994 proposal). In the Federal
Register of October 7, 1997 (62 FR 52237), FDA published a final rule
amending its expedited pre- and postmarketing safety reporting
regulations for human drug and biological products (the October 1997
final rule). The October 1997 final rule implemented certain
international standards recommended in an ICH guidance entitled
``Clinical Safety Data Management: Definitions and Standards for
Expedited Reporting'' (60 FR 11284, March 1, 1995) (the ICH E2A
guidance). FDA is now proposing additional amendments to its expedited
pre- and postmarketing safety reporting regulations based on
recommendations in the ICH E2A guidance that were not included in the
October 1994 proposal. Although the ICH E2A guidance pertains to
expedited safety reporting during the premarketing phase of drug
development, the agency has determined that many of the definitions and
standards also should apply to FDA's expedited postmarketing safety
reporting requirements.
The proposed amendments to the postmarketing periodic safety
reporting requirements in the October 1994 proposal were based on
recommendations in a CIOMS II report issued in 1992 (``International
Reporting of Periodic Drug-Safety Update Summaries'') (Ref. 28). As
explained in the October 1997 final rule, the agency decided not to
finalize these proposed amendments (62 FR 52237 and 52238) until FDA
considered ICH's recommendations on this topic. These recommendations
were published in an ICH final guidance entitled ``Clinical Safety Data
Management: Periodic Safety Update Reports for Marketed Drugs''
''(PSURs) (the ICH E2C guidance) (62 FR 27470, May 19, 1997). After
review of the ICH E2C guidance, FDA decided to repropose the
postmarketing periodic safety reporting amendments in the October 1994
proposal. These amendments are being reproposed in this rulemaking
based on recommendations in the ICH E2C guidance and comments submitted
in response to the October 1994 proposal.
An addendum to the ICH E2C guidance has been prepared by ICH based
on experience gained over the past 5 years in preparation of PSUR
reports by companies and review of them by regulators (the ICH V1 draft
guidance) (67 FR 79939; December 31, 2002). FDA is interested in
harmonizing, to the extent possible, its postmarketing periodic safety
reporting regulations with the recommendations in the ICH V1 draft
guidance. In this regard, FDA is interested in comment from the public
on whether the agency should implement these recommendations (e.g.,
permit use of summary bridging reports, include an executive summary in
PSURs, permit use of different versions of reference safety information
within a reporting interval or use of the version in effect at the end
of the reporting interval).
Some of the comments submitted in response to the October 1994
proposal noted that several of the proposed amendments to the
postmarketing periodic safety reporting regulations would result in
duplicative reporting of information currently required in
postmarketing approved new drug application (NDA) annual reports. The
comments questioned the value of submitting similar information to FDA
in two different reports and requested that the agency require
inclusion of this information in either one report or the other, but
not in both of them. In light of these comments, FDA is proposing to
revoke the requirement for safety-related information in postmarketing
approved NDA annual reports.
In the Federal Register of December 2, 1998 (63 FR 66632), FDA
issued a final rule amending its postmarketing approved NDA annual
reports regulations to require reporting of specific information
regarding studies in pediatric populations (the 1998 pediatric final
rule). The 1998 pediatric final rule also required a new annual report
for biological products with approved biologics license applications
(BLAs) that contains the same type of information on studies of
licensed biological products in pediatric populations. FDA is proposing
to amend the annual reporting requirements for licensed biological
products to revoke the requirement to submit safety-related information
in these reports. This proposal is consistent with the proposed
amendments to the postmarketing approved NDA annual reporting
requirements.
In the Federal Register of June 25, 1997 (62 FR 34166), FDA
published a final rule revoking the postmarketing safety reporting
requirement for submission of increased frequency reports in an
expedited manner (the increased frequency reports final rule). These
reports contained information regarding a significant increase in
frequency of an adverse drug experience (synonymous with adverse
experience) that is both serious and expected for marketed human drug
and licensed biological products. FDA is now proposing to amend its
regulations to require submission of increased frequency type
information for marketed human drugs and licensed biological products
in postmarketing periodic safety reports.
In the Federal Register of August 27, 1997 (62 FR 45425), FDA
published a notice of availability of a guidance for industry entitled
``Postmarketing Adverse Experience Reporting for Human Drug and
Licensed Biological Products; Clarification of What to Report'' (the
clarification guidance of 1997). This guidance clarifies the agency's
policy concerning certain postmarketing safety reporting requirements
for human drugs and licensed biological products. The guidance: (1)
Describes the information that should be obtained before an individual
case safety report (i.e., FDA Form 3500A, CIOMS I Form, Vaccine Adverse
Event Reporting System (VAERS) Form) of an adverse experience should be
considered for submission to FDA; (2) clarifies how solicited safety
information from planned contacts with patients should be handled; and
(3) informs applicants that FDA will entertain waiver requests for
periodic submission of individual case safety reports for adverse
experiences that are determined to be nonserious and expected.
FDA received 28 comments from medical centers, physicians, and
consumers regarding the clarification guidance of 1997. All of these
comments pertained to the item regarding waiver requests for periodic
submission of individual case safety reports for adverse experiences
that are determined to be nonserious and expected. The agency
considered these comments in developing this proposed rule. All of the
comments requested that FDA postpone granting these waivers until this
new policy receives more complete public scrutiny and debate. The
comments stated that the new waiver policy would deprive the public of
access to important safety information about adverse reactions to
approved drugs and biological products. The comments noted that, in
some cases, adverse reactions classified as ``nonserious'' may, in
fact, be related to very serious reactions. The comments also indicated
that the new waiver policy provides industry with an incentive to
classify serious reactions as ``nonserious'' so that the reactions
would not have to be reported to FDA.
Even though applicants may currently request waivers for submission
of individual case safety reports for nonserious, expected adverse
experiences, the agency should continue to receive information
regarding these experiences. The clarification guidance
[[Page 12410]]
of 1997 provides that summary tabulations of nonserious, expected
adverse experiences be included in postmarketing periodic safety
reports. If warranted, FDA could request submission of an individual
case safety report for any nonserious, expected adverse experience.
Thus, even if a waiver is granted, the agency will continue to receive
sufficient information to monitor the safety of marketed drugs and
licensed biological products. FDA is now proposing amendments to its
postmarketing periodic safety reporting regulations that would require
that nonserious, expected adverse experiences \1\ be submitted to the
agency in summary tabulations consistent with the clarification
guidance of 1997. At this time, FDA is also proposing to codify the
other recommendations in the clarification guidance of 1997 (i.e.,
require a minimum data set for individual case safety reports, describe
how solicited safety information from planned contacts with patients
must be handled).
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\1\ Adverse experiences are proposed to be called suspected
adverse drug reactions (SADRs) in this proposed rule; see section
III.A.1 of this document; the term ``adverse experiences'' or
``adverse drug experiences'' will be used in this document when
discussions pertain to FDA's current regulations and the term
``SADR'' will be used in this document when discussions pertain to
proposals in this rule.
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In the Federal Register of March 12, 2001 (66 FR 14391), FDA
published a notice of availability of a draft guidance for industry
entitled ``Postmarketing Safety Reporting for Human Drug and Biological
Products Including Vaccines'' (the draft guidance of 2001). The draft
guidance of 2001 represents the agency's current thinking on reporting
of postmarketing adverse drug experiences for human marketed drug and
biological products including vaccines in accordance with FDA's
postmarketing safety reporting regulations for these products in effect
at the time the draft guidance of 2001 was issued. The draft guidance
of 2001 consolidates the agency's existing guidances on this topic and
revises them based on the October 1997 final rule and the increased
frequency reports final rule. The draft guidance of 2001, once
finalized, will replace FDA's guidances entitled ``Postmarketing
Reporting of Adverse Drug Experiences'' (57 FR 61437, December 24,
1992) (the guidance of 1992), ``Adverse Experience Reporting for
Licensed Biological Products'' (the guidance of 1993), and the
clarification guidance of 1997. The agency will issue a final guidance
for industry on this topic after considering the comments received on
the draft guidance of 2001.
FDA is now proposing to codify certain expectations described in
the draft guidance of 2001 to improve the quality of postmarketing
safety reports submitted to the agency for human marketed drug and
biological products, and also to clarify certain postmarketing safety
reporting requirements. Once this proposed rule is finalized, the draft
guidance of 2001, as finalized, will be updated to provide industry
with assistance in fulfilling the new safety reporting requirements for
human marketed drug and biological products.
In June 2001, CIOMS issued a new report entitled ``Current
Challenges in Pharmacovigilance: Pragmatic Approaches'' (CIOMS V
report) (Ref. 29). This report provides recommendations for
simplification, clarification, and harmonization of certain drug safety
practices. Many of these recommendations serve to provide guidance for
industry and would not be subject to requirements of individual
regulatory authorities (e.g., FDA). Those that are the subject of our
proposed rule are essentially consistent with what we are proposing.
However, in some cases, there may be differences (see section III.A.6
of this document for discussion of use of active query and written
requests for acquisition of followup information).
In the Federal Register of November 5, 1998 (63 FR 59746), FDA
published an advance notice of proposed rulemaking announcing that it
is considering a proposal to require persons subject to the
postmarketing safety reporting regulations to submit postmarketing
expedited individual case safety reports and individual case safety
reports contained in postmarketing periodic safety reports to the
agency electronically using a standardized medical terminology,
standardized data elements, and electronic transmission standards
recommended by the ICH. Under the auspices of ICH, standard medical
terminology for regulatory purposes, MedDRA, the medical dictionary for
regulatory activities (ICH M1), has been developed (63 FR 59746 at
59748). On November 24, 1998, an international maintenance and support
services organization (MSSO) was established to maintain and update
MedDRA in response to medical/scientific advances and regulatory
changes and to serve as the licensing agent for distribution of MedDRA.
This proposed rule on safety reporting would require that postmarketing
individual case safety reports be coded using MedDRA prior to
submission to the agency. In a separate rulemaking, FDA plans to
propose that postmarketing individual case safety reports be submitted
to the agency electronically using standardized data elements and
electronic transmission standards. The proposed amendments for
electronic submissions are beyond the scope of this proposed rule.
II. Introduction
II.A. Persons Subject to the Safety Reporting Regulations
II.A.1. Premarketing Expedited Safety Reporting Regulations
Section 312.32 (21 CFR 312.32), requires expedited reports of
premarketing adverse experiences associated with the use of an
investigational human drug or biological product (see table 1).
Sponsors of INDs are subject to the premarketing expedited safety
reporting regulations.
Table 1.--Currently Required Premarketing Expedited Safety Reports
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Type of 21 CFR Persons with reporting
Safety report information section Submission timeframe responsibility
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Written IND safety report.... [sbull] Serious 312.32 15 calendar days......... Sponsors.
and unexpected
adverse
experience
associated with
the use of the
drug.
[sbull] Findings
from tests in
laboratory
animals that
suggest a
significant
risk for humans.
Telephone and facsimile Unexpected fatal 312.32 7 calendar days.......... Sponsors.
transmission safety report. or life-
threatening
experience
associated with
the use of the
drug.
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[[Page 12411]]
II.A.2. Postmarketing Safety Reporting Regulations
Sections 310.305, 314.80, 314.98, and 600.80 (21 CFR 310.305,
314.80, 314.98, and 600.80) require expedited reports of postmarketing
adverse drug experiences (see table 2). The following persons are
subject to these postmarketing expedited safety reporting regulations:
[sbull] Applicants with approved NDAs (Sec. 314.80) and
abbreviated new drug applications (ANDAs) (Sec. 314.98);
[sbull] Licensed manufacturers with approved BLAs (Sec. 600.80);
[sbull] Manufacturers, packers, and distributors (also shared
manufacturers, joint manufacturers, or any other participant involved
in divided manufacturing for Sec. 600.80) whose name appears on the
label of a product with an approved NDA, ANDA, or BLA (Sec. Sec.
314.80, 314.98 and 600.80); and
[sbull] Manufacturers, packers, and distributors whose name appears
on the label of a prescription drug product marketed without an
approved NDA or ANDA (Sec. 310.305). In this document, the term
``applicant'' will be used instead of the term ``licensed
manufacturer'' for persons with approved BLAs.
Table 2.--Currently Required Postmarketing Safety Reports
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Persons with reporting
Type of report Safety report Type of information 21 CFR section Submission timeframe responsibility
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Expedited report...... 15-day Alert report... Serious and 310.305, 314.80, 15 calendar days.............. Manufacturers \2\ and
unexpected adverse 314.98, 600.80. applicants \3\.
drug experience \1\.
15-day Alert report- New information for 310.305, 314.80, 15 calendar days.............. Manufacturers \2\ and
followup. 15-day Alert report. 314.98, 600.80. applicants \3\.
Reports to Serious adverse drug 310.305.............. 5 calendar days............... Packers and distributors.
manufacturer instead experiences \1\.
of FDA.
Reports to applicant Serious adverse 314.80, 314.98, 5 calendar days............... Manufacturers, packers,
instead of FDA. experiences \1\. 600.80. and distributors (Sec.
Sec. 314.80, 314.98,
and 600.80) and joint
manufacturers, shared
manufacturers, or any
participant involved in
divided manufacturing
(Sec. 600.80).
Expedited report...... Blood safety report... Fatalities........... 606.170.............. As soon as possible (oral or Blood establishments.
written) and 7 days (written).
Periodic report....... Periodic adverse drug [sbull] Narrative 314.80, 314.98, Quarterly for 3 years from the Applicants.
experience report. summary and analysis 600.80. date of U.S. approval of the
of adverse drug application and then annually
experiences that thereafter.
occurred during the
reporting interval
including 15-day
Alert reports
previously submitted
to FDA \1\.
[sbull] Individual
case safety report
for each adverse
drug experience not
submitted to FDA as
a 15-day Alert
report, excluding
reports from
postmarketing
studies, reports in
the scientific
literature, and
foreign marketing
experience \1\.
[sbull] History of
actions taken..
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\1\ For spontaneous reports, adverse drug experiences are submitted whether or not they are considered drug related; for study reports, adverse drug
experiences are submitted if there is a reasonable possibility that the drug caused the adverse drug experience.
\2\ Section 310.305 also includes packers and distributors.
\3\ Sections 314.80 and 314.98 also include manufacturers, packers and distributors. Section 600.80 also includes manufacturers, packers, distributors,
joint manufacturers, shared manufacturers, or any participant involved in divided manufacturing.
Applicants with approved NDAs, ANDAs, and BLAs must also submit
periodic reports of postmarketing adverse drug experiences under
Sec. Sec. 314.80, 314.98 and 600.80 (see table 2). Manufacturers of
prescription drug products marketed without an approved NDA or ANDA are
not required to submit periodic reports of postmarketing adverse drug
experiences (Sec. 310.305).
Existing regulations, under Sec. 606.170 (21 CFR 606.170), require
expedited reports of fatalities associated with
[[Page 12412]]
blood collection or transfusion (see table 2). The report must be
submitted to FDA by the collecting facility in the event of a donor
reaction and by the facility that performed the compatibility tests in
the event of a transfusion reaction.
Current safety reporting regulations under Sec. Sec. 310.305,
314.80, 314.98, 600.80 and 606.170, as well as the provisions of this
proposed rule, do not apply to voluntary reporting of adverse drug
experiences to companies or regulatory authorities (e.g., FDA) by an
individual (e.g., health care professional, consumer).
II.A.3. Terms Used in This Document
The terms ``sponsors,'' ``manufacturers,'' and ``applicants'' are
used in this proposed rule to describe, as appropriate, persons with
safety reporting responsibilities. ``Sponsors'' is used to describe
persons subject to the premarketing safety reporting regulations.
``Manufacturers'' is used, unless otherwise specified, to describe
persons subject to the postmarketing safety reporting regulations under
Sec. 310.305 for prescription drug products marketed without an
approved NDA or ANDA. ``Applicants'' is used to describe persons
subject to the postmarketing safety reporting regulations under
Sec. Sec. 314.80, 314.98, and 600.80 for products with an approved
NDA, ANDA, or BLA; for Sec. 600.80, ``applicants'' includes
participants involved in divided manufacturing.
II.B. Rationale for This Proposal
II.B.1. International Standards
Many of the amendments that are being proposed in this rulemaking
are intended to harmonize our safety reporting requirements with
international standards developed by CIOMS and ICH (see table 4 of this
document). These organizations were formed to facilitate international
consideration of issues, particularly safety issues, concerning the use
of global data in the development and use of drugs and biological
products.
The CIOMS working groups have been comprised of representatives
from regulatory authorities, including FDA, and the pharmaceutical
industry. These groups have worked to develop recommendations for
standardization of international reporting of postmarketing adverse
reactions by the pharmaceutical industry to regulatory authorities.
ICH was organized to provide an opportunity for tripartite
harmonization initiatives to be developed with input from regulatory
and industry representatives. 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. The six ICH sponsors are the European
Commission; the European Federation of Pharmaceutical Industry
Associations; the Japanese Ministry of Health and Welfare; the Japanese
Pharmaceutical Manufacturers Association; FDA; and the Pharmaceutical
Research and Manufacturers of America.
One ICH initiative is to harmonize certain safety reporting
requirements of the three regions. Through the ICH process,
recommendations have been developed regarding the content, format, and
reporting frequency for expedited and periodic safety reports for human
drugs and biological products (the ICH E2A and E2C guidances). In
addition, a standard medical terminology for regulatory purposes,
MedDRA, has been developed (ICH M1). Worldwide implementation of this
initiative is in process. FDA, which has been actively involved in the
development of these recommendations, has implemented some of them (the
October 1997 final rule) and is proposing to implement others in this
rulemaking.
FDA believes the changes recommended by ICH and CIOMS will result
in more effective and efficient safety reporting to regulatory
authorities worldwide. For example, postmarketing periodic safety
reports are, for the most part, currently submitted to regulatory
authorities in the three regions at different times with different
formats and content. International harmonization efforts are beginning
to decrease some of these differences, but harmonization of the format
and content, as well as the reporting frequency, of these reports by
all countries in the three regions is essential to eliminate
unnecessary reporting burdens on industry so that companies can focus
on the safety profiles of their products and not on the different
reporting requirements of different regions. The PSUR recommended for
postmarketing periodic safety reporting in the ICH E2C guidance
provides regulatory authorities with a comprehensive overview of the
safety profile of a product along with other relevant information such
as estimates of worldwide patient exposure and worldwide marketing
status of the product. In this rulemaking, FDA is proposing to require
submission of PSURs for certain products (see sections III.E.2 and
III.E.5.a of this document). FDA is also interested in receipt of
additional information and is proposing to require that such
information be submitted with these reports as appendices (e.g., copy
of current U.S. approved labeling, information on medication errors,
resistance to antimicrobial drug products and class action lawsuits)
(see section III.E.2.k of this document). Thus, companies can prepare
the same core document for all three regions and any additional
information required by FDA would simply be attached to this document.
Another international harmonization effort is standardization of
medical terminology used for regulatory purposes. As noted previously,
ICH has developed MedDRA for this purpose. Currently, companies use
various medical terminologies for safety reporting purposes (e.g.,
WHO's Adverse Reaction Terminology (WHOART), Coding Symbols for a
Thesaurus of Adverse Reaction Terms (COSTART), Japan's Adverse Reaction
Terminology (J-ART)). The established terminologies have been
criticized for a number of reasons, including: Lack of specificity,
limited data retrieval options, and an inability to effectively handle
complex combinations of signs and symptoms (syndromes). In addition,
use of different terminologies at different stages in the development
and use of products complicates data retrieval and analysis of
information and makes it difficult to effectively cross-reference data
through the lifetime of a product. Internationally, communication is
impaired between regulatory authorities because of the delays and
distortions caused by the translation of data from one terminology to
another.
Use of different terminologies also has significant consequences
for pharmaceutical firms. Companies operating in more than one
jurisdiction have had to adjust to subsidiaries or clinical research
organizations that use different terminologies because of variations in
data submission requirements. The difficulty of analyzing data
comprehensively may be compounded by use of incompatible terminologies
and could lead to delays in recognizing potential public health
problems.
For these reasons, it is critical that a single medical terminology
be used internationally for coding postmarketing safety reports. FDA is
proposing to use MedDRA for this purpose (see section III.F.2 of this
document). MedDRA is the best choice because it was developed with
input from regulatory authorities and industry and the problems
associated with the other terminologies were taken into consideration
during development of MedDRA. Some companies have begun to voluntarily
[[Page 12413]]
submit their postmarketing safety reports to FDA coded using MedDRA.
Even though FDA is proposing to use MedDRA as the standard medical
terminology for reporting purposes under this rule, the agency
recognizes that alternative standard classification systems for
clinical information exist in the United States and supports the
national health data standardization initiatives underway in the United
States under the Health Insurance Portability and Accountability Act.
Although this proposed rule does not impose reporting requirements
on health care providers, the agency recognizes that clinicians,
medical centers, hospitals and others may report safety information to
pharmaceutical companies. These third parties may employ clinical
terminology standards that differ from those proposed here. Therefore,
the agency invites comment on the unintended potential impact of this
proposed rule on those parties not subject to FDA's safety reporting
requirements. The agency also invites comment on the potential
strategies and approaches for facilitating seamless cross-standard
communications, such as mapping between alternative terminologies and
MedDRA.
II.B.2. Quality of Postmarketing Safety Reports
In light of the recommendations of ICH and CIOMS, FDA has reviewed
its postmarketing safety reporting regulations for human drugs and
licensed biological products and identified additional changes that the
agency believes would further enhance surveillance of marketed
products. Many of the postmarketing safety reports that FDA receives
are complete and of very high quality. Others are incomplete, of
mediocre or poor quality or both, making it difficult to ascertain the
significance of these reports. In the latter cases, FDA is
unnecessarily spending considerable amounts of time trying to collect
additional information for the reports.
To address this problem, FDA is proposing amendments to its
postmarketing safety reporting requirements. For most of these
amendments, a risk-based approach is being proposed (i.e., greater
emphasis and effort would be required for reports of serious adverse
drug experiences while less information would be required for
nonserious adverse drug experiences (adverse drug experiences proposed
to be called SADRs in this proposed rule; see section III.A.1 of this
document)). For example, FDA is proposing that complete information be
submitted for reports of serious SADRs (see section III.C.5 of this
document). If complete information is not available, in some cases, a
followup report would be required (e.g., for serious, unexpected SADRs)
(see section III.D.6 of this document). On the other hand, for SADRs
that are determined to be nonserious, not as much information would
need to be acquired (see section III.C.5 of this document).
Another amendment would require direct contact with the initial
reporter of an SADR by a health care professional at the company for
collection of certain postmarketing safety information (e.g.,
collection of followup information for a serious SADR) (see section
III.A.6 of this document). Currently, some companies use this approach
for collecting information, whereas others send the initial reporter a
letter. The latter case is a passive approach which, in FDA's
experience, results in limited acquisition of new information. In most
cases, the initial reporter simply does not respond to the letter.
Instead, using an active approach, as proposed by FDA, companies would
more likely obtain the additional information needed for an SADR. Thus,
use of this approach should result in submission of higher quality
reports to FDA for review.
Another amendment would require that a licensed physician at the
company be responsible for the content of postmarketing safety reports
submitted to FDA (see sections III.E.1.h, III.E.2.k.xi, and II.F.4 of
this document). As in the previous examples, some companies currently
use licensed physicians for this purpose, whereas others have their
postmarketing safety reports prepared and submitted by clerical
personnel with no health care training. The medical significance of
postmarketing safety reports warrants review by a licensed physician.
The agency believes that licensed physicians would ensure submission of
high quality reports to FDA that articulately conveys all clinically
relevant information associated with an SADR.
II.B.3. New Postmarketing Expedited Safety Reports
FDA currently requires postmarketing expedited safety reports for
serious and unexpected adverse drug experiences (adverse drug
experiences proposed to be called SADRs in this proposed rule; see
section III.A.1 of this document). To facilitate identification of
significant safety problems, FDA is proposing that additional safety
information be submitted expeditiously to the agency for marketed drugs
and biological products. Some of this information is currently
submitted to the agency but not in an expedited manner. In other cases,
the information is not currently required to be submitted to the
agency.
II.B.3.a. Medication errors. In 1999, the Institute of Medicine
(IOM) issued a report, ``To Err is Human: Building a Safer Health
System,'' that cited studies and articles estimating the number of
Americans dying each year as a result of medical mistakes to be between
44,000 and 98,000 (Ref. 10). The IOM report concluded that preventable
adverse drug events impose significant medical, personal, and economic
costs to the United States.
Requiring medication errors to be reported in an expedited manner
to a centralized location would provide a systematic approach for
collecting comprehensive information on these errors and result in
timely assessment of the information. Various organizations and health
care professional associations, including the 1999 IOM report, have
advocated mandatory medication error reporting efforts, as well as
encouragement of voluntary efforts, aimed at making sure the system
continues to be made safer for patients. Such a system would provide
the public with a higher level of protection by assuring that the most
serious errors are investigated and reported, and that appropriate
followup action is taken both by FDA and the company whose product is
associated with the error. Second, it would provide companies with an
incentive to improve patient safety regarding medication errors
associated with their products. Finally, it would require that FDA and
the pharmaceutical industry make some level of investment in preventing
medication errors and improving patient safety. In some instances,
information gathered through this type of a reporting system and
analyzed for root causes can lead to various changes within the health
care system to prevent or minimize recurrence.
Currently, FDA maintains both a voluntary adverse event reporting
system for health care professionals, through MedWatch (the Medical
Products Reporting Program), and a mandatory adverse event reporting
system for companies subject to the agency's postmarketing safety
reporting regulations. Through these systems, FDA receives only about
3,000 reports of medication errors annually. FDA believes that these
safety reporting systems do not adequately address the nature and
extent of problems caused by medication errors. In most cases, safety
reports associated with a medication error are not identified in the
report as being associated with an error. Instead, the report only
highlights the effect of
[[Page 12414]]
the medication error (e.g., patient experienced a seizure). This
information is not sufficient for FDA to identify medication errors
that could be avoided in the future. For cases that involve a
medication error, the safety report needs to be identified as a
suspected medication error so that the report can be appropriately
analyzed and addressed. FDA concludes that an explicit requirement for
reporting medication errors by companies subject to the agency's
postmarketing safety reporting regulations is needed to adequately
assess and respond to the problem.
FDA is therefore proposing to require that these companies submit
to the agency expeditiously all domestic reports of actual and
potential medication errors (see section III.D.5 of this document). FDA
would review information about suspected medication errors to determine
an appropriate risk management plan (e.g., changes to the proprietary
name, labels, labeling or packaging of the drug or biological product
or educational initiatives to protect public health). This proposal,
which is consistent with one of the Department of Health and Human
Services' major health initiatives, would allow FDA to form the
framework for building a comprehensive risk assessment and management
system for preventable SADRs. This proposal is also responsive to the
1999 IOM report, which states that ``the Food and Drug Administration
(FDA) should increase attention to the safe use of drugs in both pre-
and postmarketing process'' by ``establishing appropriate responses to
problems identified through post-marketing surveillance, especially for
concerns that are perceived to require immediate response to protect
the safety of patients.''
II.B.3.b. Unexpected SADRs with unknown outcome. FDA is also
proposing to require that companies subject to the agency's
postmarketing safety reporting regulations submit to FDA in an
expedited report SADRs that are unexpected and for which a
determination of serious or nonserious cannot be made (i.e., SADR with
unknown outcome) (see section III.D.3 of this document). This
information is currently submitted to FDA, but, in most cases, not in
an expedited manner. A company that receives a report of an adverse
drug experience is able, in most cases, to determine if it is serious
or nonserious (i.e., whether it meets the regulatory definition of
serious), but in some cases, this may not be possible. Currently, most
companies that are not able to make this determination designate the
adverse drug experience as nonserious and include it in their next
quarterly or annual postmarketing periodic safety report. In some of
these cases, the adverse drug experience is, in fact, serious even
though the company was not able to make this determination. FDA needs
to receive reports of SADRs with unknown outcome expeditiously if the
SADR is unexpected so that the agency can evaluate the report in light
of other data and information available to FDA to attempt to determine
if the SADR is serious. FDA would do this by comparing information on
the unexpected SADR with unknown outcome with information on other
similar unexpected SADRs with a known serious outcome that are on file
with the agency.
II.B.3.c. Always expedited reports. FDA is also proposing that
companies subject to the agency's postmarketing safety reporting
regulations always submit to FDA in an expedited report certain SADRs,
which may jeopardize the patient or subject and/or require medical or
surgical intervention to treat the patient or subject (e.g.,
ventricular fibrillation, liver necrosis, transmission of an infectious
agent by an approved product) (see section III.D.4 of this document).
Currently, all of these adverse drug experiences are submitted to the
agency for review, but only some of them are submitted in an expedited
safety report (i.e., if the adverse drug experience is serious and
unexpected). FDA is proposing that all of them be submitted
expeditiously whether the SADR is unexpected or expected and whether or
not the SADR leads to a serious outcome. This is because of the medical
gravity of these SADRs. For example, even though the labeling for a
product indicates that ventricular fibrillation may be associated with
use of the product and thus not subject to expedited reporting to FDA
(i.e., SADR is expected), the agency needs to review each new report of
ventricular fibrillation for this product as quickly as possible to
ascertain if there is a qualitative or quantitative change in the
nature of the SADR. Information from these reports could result in
either new studies being undertaken to evaluate the SADR or appropriate
regulatory action by FDA (e.g., labeling change, distribution of Dear
Health Care Professional letter, restriction on distribution of
product, withdrawal of product from the market).
II.B.3.d. Blood and blood component safety reports. With regard to
blood and blood components (e.g., red blood cells, plasma, platelets,
cryoprecipitated AHF), FDA is proposing that blood establishments
submit reports to the agency for all serious SADRs associated with
blood collection and transfusion, in addition to their current
requirement at Sec. 606.170(b) (21 CFR 606.170(b)) to submit reports
of fatalities (see section III.D.12 of this document). This proposed
safety reporting requirement would not impose significant new burdens
on blood establishments. This is because under Sec. 606.170(a) (21 CFR
606.170(a)) blood collection and transfusion facilities are currently
required to conduct investigations and prepare and maintain reports of
all adverse events associated either with the collection or transfusion
of blood or blood components. The proposal would simply require that
reports of serious SADRs that are currently maintained by the facility,
be submitted to the agency within 45 calendar days of occurrence rather
than only having these reports be reviewed by FDA at the time of an
inspection. Thus, not all serious SADRs are reported to FDA for blood
and blood components. FDA believes that it is critical that we receive
all such reports to enhance donor safety and also to ensure the safety,
purity and potency of blood and blood components for administration to
patients.
In the past, the agency has received some voluntary reports that
have helped to identify errors in manufacturing and defects in products
used to collect blood. For example, in 1997, FDA received reports from
a blood establishment of allergic adverse reactions to red blood cells
that had been leukoreduced using a bedside filtration method in
hematology or oncology patients receiving multiple transfusions. The
reactions were related to several lots of Hemasure Leukonet filters.
The symptoms included bilateral conjunctival edema, severe headaches,
eye pain, nausea sometimes associated with vomiting and joint pain.
After investigation and analysis of the reports by FDA, the
manufacturer discontinued production of the filter. Voluntary reporting
of the adverse reactions by the blood establishment brought the issue
to the attention of FDA. However, the time to resolution may have been
shortened had these been required to be reported to FDA from all blood
centers.
With regard to the safety of donors, FDA review of adverse event
reports is important and has resulted in detection and correction of
problematic collection procedures. During an inspection, FDA field
officers identified a blood collection center that had numerous donors
with vasovagal reactions that required treatment by emergency medical
personnel. In some of these cases, the donors had to be transported to
a hospital emergency room for treatment. Upon investigation, FDA
[[Page 12415]]
determined that the center had failed to establish a lower limit for
blood pressure measurements for donors as required by 21 CFR 640.3. Had
these serious adverse events been required to be reported to FDA,
immediate analysis of them is likely to have identified the problem
sooner.
Thus, required reporting of all serious SADRs related to blood
collection and transfusion would enhance FDA's ability to take
appropriate action to protect the blood supply more consistently.
Currently, there is no assurance that FDA will receive reports of
serious SADRs that have the potential to adversely affect both the
donors and recipients of the nation's blood supply. Such information is
essential for evaluating the agency's scientific and regulatory
policies and for monitoring industry practices and their implications
on blood safety.
II.B.4. Bioavailability and Bioequivalence Studies Not Subject to
an Investigational New Drug Application (IND).
FDA is also proposing to amend its bioavailability and
bioequivalence regulations under part 320 (21 CFR part 320) (see
section III.K of this document). Under the existing regulations at
Sec. 320.31, persons conducting a bioavailability or bioequivalence
study in humans are only required to comply with the IND requirements
of part 312 (21 CFR part 312) for certain products or for certain types
of studies. This proposed rule would require submission of expedited
safety reports for serious, unexpected adverse experiences (adverse
experiences proposed to be called SADRs in this proposed rule; see
section III.A.1 of this document) as prescribed under Sec. 312.32 for
human bioavailability and bioequivalence studies that are not being
conducted under an IND. FDA believes that bioavailability and
bioequivalence studies that are not being conducted under an IND are,
in general, safe. However, the agency is occasionally made aware of
safety-related information associated with these types of studies. This
information could either reflect a problem with the drug product being
evaluated or with the study design being used. Timely review of
serious, unexpected SADRs from these studies is critical to ensure the
safety of study subjects. FDA would use this information to determine
if the study design needs to be altered or if the study needs to be
stopped.
II.C. New Safety Reporting Abbreviations
Table 3 provides a list of new safety reporting abbreviations that
are used in this document.
Table 3.--New Safety Reporting Abbreviations
----------------------------------------------------------------------------------------------------------------
Reference in section III of this
Phrase Abbreviation document
----------------------------------------------------------------------------------------------------------------
Company core safety information........ CCSI......................... A.9
Interim periodic safety report......... IPSR......................... E.3
Medical dictionary for regulatory MedDRA....................... F.2
activities.
Periodic safety update report.......... PSUR......................... E.2
Suspected adverse drug reaction........ SADR......................... A.1
Traditional periodic safety report..... TPSR......................... E.1
----------------------------------------------------------------------------------------------------------------
II.D. Highlights of Proposed Changes to FDA's Safety Reporting
Regulations
Specific changes to FDA's safety reporting requirements, as
described in this proposed rule, are identified in table 4.
Table 4.--Highlights of Proposed Changes to FDA's Safety Reporting Requirements
----------------------------------------------------------------------------------------------------------------
Proposed Change (reference in section III Is the change based on ICH (ICH
21 CFR Section of this document) guidance)?
----------------------------------------------------------------------------------------------------------------
Changes apply to: 310.305, [sbull] ``Associated with the use of the Yes (E2A)
312.32, 314.80, 314.98, and drug'' and ``adverse drug experience''
600.80.\1\ changed to ``suspected adverse drug
reaction (SADR)'' and ``adverse
experience'' changed to ``suspected
adverse reaction (SAR)'' (A.1).
[sbull] Minimum data set required for all Yes (E2A)
individual case safety reports of SADRs
(A.5, B.2.a, C.5, E.4).
[sbull] Reporting requirements for lack of Yes (E2A and E2C)
efficacy reports revised (B.2.c, C.7, D.2,
E.1.c, E.2.h, E.2.k.vi).
[sbull] Sources of safety information No
revised (B.1, C.2, D.8).
[sbull] Individual case safety reports from Yes (E2A)
clinical trials based on opinion of either
the sponsor/applicant or investigator
(B.2.b, B.3, C.6).
[sbull] Narrative format required for No
safety reports of overall findings or data
in the aggregate (B.2.d, F.1).
Changes only apply to 312.32.... [sbull] Determination of a life-threatening Yes (E2A)
SADR based on opinion of either sponsor or
investigator (A.2).
[sbull] Expedited reports of findings from Yes (E2A)
tests in laboratory animals revised to
include other information sufficient to
consider product administration changes
(B.2.c).
Changes only apply to 310.305, New Safety Reports......................... Yes (E2A)
314.80, 314.98, 600.80. [sbull] Expedited report for information
sufficient to consider product
administration changes (D.2).
[sbull] Expedited report for unexpected No
SADRs with unknown outcome (A.3, D.3).
[[Page 12416]]
[sbull] Always expedited reports for No
certain medically significant SADRs
whether unexpected or expected and whether
or not the SADR leads to a serious outcome
(D.4).
[sbull] Expedited report for medication No
errors (D.5).
[sbull] 30-day followup report for initial No
serious and unexpected SADR reports,
always expedited reports, and medication
error reports that do not contain a full
data set (D.6).
Other Changes.............................. No
[sbull] Active query required to acquire
certain safety information (A.6, C.5, D.6,
D.7).
[sbull] Full data set required for reports No
of serious SADRs, always expedited
reports, and medication error reports
(A.5, C.5, D.1, D.4, D.5, E.4).
[sbull] Safety reporting requirements for No
contractors and shared manufacturers (A.4,
D.9).
Changes only apply to 310.305, [sbull] Reporting requirements for Yes (E2A and E2C)
314.80, 314.98, and 600.80. spontaneous reports codified (A.7, C.6).
[sbull] Supporting documentation required No
for expedited reports concerning a death
or hospitalization (D.7).
[sbull] FDA request for submission of No
safety reports at times other than
prescribed by regulations (C.4).
[sbull] Individual case safety reports Yes (M1)
required to be coded using MedDRA (F.2)..
[sbull] SADR information from class action No
lawsuits (A.7, E.1.e, E.2.k.v, E.3).
[sbull] Contact person for postmarketing No
safety reports (E.1.h, E.2.k.xi, E.3, F.4).
[sbull] Use of computer-generated facsimile No
of FDA Form 3500A or VAERS form permitted
without approval by FDA (F.5).
[sbull] Location of safety records (D.10, No
E.1.g, E.2.k.x, E.3).
[sbull] FDA request for submission of No
safety related records (D.7, H)..
Changes only to apply to 314.80, New or Revised Safety Reports.............. No
314.98 and 600.80. [sbull] Semiannual submission of certain No
spontaneously reported individual case
safety reports (E.4, E.5.a).
[sbull] TPSR, PSUR, or IPSR for No
applications approved prior to January 1,
1998 (E.1, E.2, E.3, E.5.a).
[sbull] PSUR/IPSR for applications approved Yes (E2C)
on or after January 1, 1998 (E.2, E.3,
E.5.a).
[sbull] PSUR/IPSR for pediatric use No
supplements (E.5.a).
Other Changes.............................. Yes (E2C)
[sbull] Periodicity of periodic safety
reports (E.5.a, I).
[sbull] Submission date for periodic safety Yes (E2C)
reports (A.10, E.5.b, I).
[sbull] CCSI for determination of listed Yes (E2C)
and unlisted SADRs for certain periodic
safety reports (A.9, E.2, E.3, E.4).
[sbull] Information in addition to the No
minimum data set not required to be
acquired for nonserious SADRs, except for
nonserious SADRs resulting from a
medication error, which require a full
data set (A.3, C.5, E.4).
[sbull] Individual case safety reports No
forwarded to applicant by FDA required to
be included in comprehensive safety
analysis (C.2).
[sbull] Information on resistance to No
antimicrobial drug products (E.2.k.vii,
E.3).
[sbull] Number of copies of periodic safety No
reports required to be submitted to FDA
(C.3).
Change only applies to 314.81 [sbull] Requirement to submit safety- No
and 601.28 \2\. related information in postmarketing
annual report revoked (J).
Change only applies to 312.64(b) [sbull] Investigator safety reporting No
\3\. requirements revised.
Change only applies to 320.31(d) [sbull] Submission of expedited safety No
\4\. reports required for human bioequivalence
and bioavailability studies which are
exempt from submission of an IND (K).
Change only applies to 606.170 [sbull] All serious SARs required to be No
\5\. submitted to FDA for blood and blood
products (D.12).
----------------------------------------------------------------------------------------------------------------
\1\ Section 310.305 describes postmarketing safety reporting regulations for prescription drug products marketed
for human use without an approved application; Sec. 312.32 describes premarketing safety reporting
regulations for investigational drugs and biological products; Sec. 314.80 describes postmarketing safety
reporting regulations for human drugs with approved NDAs; Sec. 314.98 describes postmarketing safety
reporting regulations for human drugs with approved ANDAs; and Sec. 600.80 describes postmarketing safety
reporting regulations for human licensed biological products with approved BLAs.
\2\ Section 314.81 describes postmarketing annual reporting regulations for human marketed drugs with approved
NDAs; Sec. 601.28 describes postmarketing annual reporting regulations for pediatric studies of human
licensed biological products with approved BLAs.
\3\ Section 312.64(b) describes requirements for safety reporting to sponsors by investigators.
\4\ Section 320.31 (d) describes bioequivalence and bioavailability requirements for studies which are exempt
from submission of an IND.
\5\ Section 606.170 describes safety reporting and recordkeeping requirements for blood and blood products.
[[Page 12417]]
III. Description of the Proposed Rule
III.A. Definitions
III.A.1. Suspected Adverse Drug Reaction (SADR)
FDA's existing premarketing safety reporting regulations in Sec.
312.32(a) define ``associated with the use of the drug'' to mean:
``There is a reasonable possibility that the experience may have been
caused by the drug.''
FDA's existing postmarketing safety reporting regulations in
Sec. Sec. 310.305(b), 314.80(a), and 600.80(a) define ``adverse drug
experience (``adverse experience'' for Sec. 600.80(a))'' to mean:
Any adverse event associated with the use of a drug
(``biological product'' for Sec. 600.80(a)) in humans, whether or
not considered drug (``product'' for Sec. 600.80(a)) related,
including the following: An adverse event occurring in the course of
the use of a drug (``biological'' for Sec. 600.80(a)) product in
professional practice; an adverse event occurring from drug overdose
(``from overdose of the product'' for Sec. 600.80(a)) whether
accidental or intentional; an adverse event occurring from drug
abuse (``from abuse of the product'' for Sec. 600.80(a)), an
adverse event occurring from drug withdrawal (``from withdrawal of
the product'' for Sec. 600.80(a)); and any failure of expected
pharmacological action.
Proposed Sec. 312.32(a) would replace the term ``associated with
the use of the drug'' with the term ``suspected adverse drug reaction
(SADR).'' Proposed Sec. Sec. 310.305(a) and 314.80(a) would replace
the term ``adverse drug experience'' with the term ``suspected adverse
drug reaction (SADR)'' (see section III.C.1 of this document regarding
reorganization of Sec. 310.305). Proposed Sec. 600.80(a) would
replace the term ``adverse experience'' with the term ``suspected
adverse reaction (SAR).'' In this document the term ``adverse drug
experience'' is synonymous with the term ``adverse experience'' and the
abbreviation ``SADR'' will be used for both ``SADR'' and ``SAR,''
except when reference is only being made to an ``SAR,'' in which case
the abbreviation ``SAR'' will be used. Proposed Sec. Sec. 310.305(a),
312.32(a), 314.80(a), and 600.80(a) would also replace the definitions
for ``associated with the use of the drug,'' ``adverse drug
experience'' and ``adverse experience'' with the following definition
for ``SADR'':
A noxious and unintended response to any dose of a drug
(``biological'' for proposed Sec. 600.80(a)) product for which
there is a reasonable possibility that the product caused the
response. In this definition, the phrase ``a reasonable
possibility'' means that the relationship cannot be ruled out.
The phrase ``the relationship cannot be ruled out'' clarifies which
individual cases would be reported to FDA. Classifying a case as
``probably related,'' ``possibly related,'' ``remotely related,'' or
``unlikely related'' to the drug or biological product would signify
that a causal relationship between the product and an adverse event
could not be ruled out and, thus, the adverse event would be considered
an SADR. For example, in some cases an adverse event may most probably
have occurred as a result of a patient's underlying disease and not as
a result of a drug or biological product the patient was taking, but it
cannot usually be said with certainty that the product did not cause
the adverse event. Therefore, such an adverse event would be classified
as an SADR because there would be at least a ``reasonable possibility''
that the drug or biological product may have caused the adverse event.
Of course, this classification would not establish causality
(attributability) by itself, it would only indicate that causality
could not be ruled out with certainty.
These proposed changes are consistent with the ICH E2A guidance (60
FR 11284 at 11285), which defines ``adverse drug reaction'' as:
All noxious and unintended responses to a medicinal product
related to any dose should be considered adverse drug reactions. The
phrase ``response to medicinal products'' means that a causal
relationship between a medicinal product and an adverse event is at
least a reasonable possibility, i.e., the relationship cannot be
ruled out.
These proposed amendments would harmonize the agency's premarketing
and postmarketing safety reporting definition for SADR, as well as
safety reporting worldwide.
Even though FDA has harmonized its proposed definition of SADR with
the definition of adverse drug reaction recommended by ICH, the agency
would like comment on an alternative definition for SADR: ``A noxious
and unintended response to any dose of a drug product for which a
relationship between the product and the response to the product cannot
be ruled out''. The alternative and proposed definitions for SADR have
the same meaning (i.e., a response to a product is an SADR unless one
is sure that the product did not cause the response). The difference
between these definitions is that the alternative definition of SADR
does not include the phrase ``a reasonable possibility.'' This is
because use of this phrase is potentially confusing. The phrase ``a
reasonable possibility'' might be interpreted differently than the
phrase ``the relationship cannot be ruled out.'' The agency defines ``a
reasonable possibility'' as ``the relationship cannot be ruled out'' to
be consistent with ICH. FDA seeks comment as to whether the agency
should use the alternative definition of SADR instead of the proposed
definition of SADR. The agency also requests comment from sponsors,
manufacturers and applicants if their interpretation of these
definitions is different than FDA's interpretation.
As explained in the following paragraphs, FDA believes that the
proposed definition of SADR would not affect the number of safety
reports that are currently submitted to FDA from spontaneous sources,
but it could increase the number of safety reports that would be
submitted from clinical studies. FDA seeks comment as to whether use of
the proposed or alternative definition of SADR would lead to
significant increases in reporting to the agency beyond what FDA has
identified in the following paragraphs. FDA is particularly interested
in learning of examples of events beyond those identified by the agency
that are not currently reported to FDA but would be required to be
reported under these definitions.
Although FDA is proposing to remove the definition for ``adverse
drug experience'' from its postmarketing safety reporting regulations
and replace it with the proposed definition for ``SADR,'' this change
would not affect the number of safety reports from spontaneous sources
that would be submitted to the agency because every spontaneous report
currently must be submitted to FDA, irrespective of whether the
manufacturer or applicant considers it to be drug related (see current
definition of adverse drug experience at Sec. Sec. 310.305(c),
314.80(c), and 600.80(c)). Under this proposed rule, every spontaneous
report would continue to be submitted to FDA, because, for spontaneous
reports, manufacturers and applicants would always be required to
assume, for safety reporting purposes only, that there was at least a
reasonable possibility in the opinion of the initial reporter that the
drug or biological product caused the spontaneously reported event (see
sections III.A.7 and III.C.6 of this document for the proposed
definition of spontaneous report and for discussion of the proposed
reporting requirement for SADRs from spontaneous sources).
On the other hand, with regard to clinical studies of
investigational and marketed drugs and biological products, the
proposed definition of SADR is likely to result in an increase in the
number of safety reports that are currently submitted to FDA from some
[[Page 12418]]
studies. Current regulations at Sec. Sec. 310.305(c)(1)(ii),
312.32(c)(1), 314.80(e)(1), and 600.80(e)(1) require that serious,
unexpected adverse experiences from a study be reported to FDA only if
there is a reasonable possibility that the drug caused the adverse
experience. The phrase ``reasonable possibility'' is typically
interpreted by sponsors, manufacturers and applicants to mean that
there is a possible causal relationship between an adverse experience
and a drug or biological product. It would not include adverse
experiences considered to be unlikely or remotely related to the
product. The proposed definition of SADR maintains the phrase
``reasonable possibility'' as part of the definition, but defines the
phrase to mean that the relationship between a product and a response
to the product cannot be ruled out. In some cases, this proposed change
would result in submission of more safety reports to FDA. For example,
under the current regulations if a sponsor or applicant concludes that
the existence of a causal relationship between a drug and an adverse
event is unlikely or remote, but not impossible, (e.g., because the
event is a recognized consequence of the patient's underlying disease)
it would not submit a safety report to FDA. In contrast, under the
proposed rule, the sponsor or applicant would be required to submit a
safety report to the agency for this SADR, because, although the
relationship of the adverse event to the drug is unlikely or remote
because of the patient's underlying disease, a causal relationship
cannot, nonetheless, be ruled out. FDA is proposing the new definition
for SADR to minimize situations in which an adverse event that proves
ultimately to be due to a drug or biological product is not reported as
soon as possible to the agency because the etiology of the adverse
event is attributed to the patient's underlying disease by the sponsor,
manufacturer or applicant (e.g., a patient's hepatic deterioration is
judged to be related to the patient's viral hepatitis and not to the
hepatotoxicity of the drug the patient received.)
FDA recognizes, however, that particularly for those patients who
have certain diseases (e.g., fatal diseases such as cancer), the
proposed definition of SADR may result in submission of numerous safety
reports to the agency for which the reported SADR is not informative as
a single report because it is very likely to have been a consequence of
the patient's disease. This would be true, for example, for most non-
acute deaths in a clinical trial evaluating a drug in cancer patients.
These deaths would have to be reported to FDA as SADRs because a
relationship between the drug and the deaths could not be ruled out
with certainty. Because such ``over-reporting'' may make it more
difficult for FDA and the sponsor, manufacturer or applicant to
recognize adverse events that are really caused by a drug or biological
product, the agency wants to minimize receipt of this type of safety
report, but in a way that does not compromise receipt of useful safety
reports that are perceived as remotely related to an administered drug
or biological product but that occur, in fact, as a result of the
product. If sponsors, manufacturers or applicants believe that, in a
specific situation, there is an alternative way(s) to handle adverse
events occurring during clinical studies that would minimize ``over-
reporting'' while assuring that reporting of SADRs would not be
compromised, they are invited to propose any such alternative(s)
reporting method to the agency. In such situations, if FDA does not
oppose the proposed alternative reporting method, the sponsor,
manufacturer or applicant would be permitted to report SADRs to the
agency according to the alternative method. For example, one such
alternative would be to include in study protocols or other
documentation a list of known consequences of the disease that would
not be submitted to FDA in an expedited manner as individual case
safety reports (e.g., events that are the endpoints of the study).
These adverse events would, however, be monitored by the sponsor,
manufacturer, or applicant and, if they indicated in the aggregate by
comparison to a control group or historical experience, that the
product in the clinical study may be causing these events, the
information would be submitted to FDA in an expedited manner as an
information sufficient to consider product administration changes
report (see sections III.B.2.c and III.D.2 of this document for
discussion of this type of report). FDA invites comment from the public
on this alternative and requests suggestions for other alternatives as
well that would minimize ``over-reporting'' of uninformative events and
assure submission of meaningful reports of unexpected events. FDA also
invites comment on reporting of these types of clinical events that
occur in studies not being conducted under an IND (e.g., drug or
biological product is marketed in the United States for a particular
indication and being investigated in a clinical trial abroad for the
same or other indication).
The proposed definition of SADR may result in submission to FDA of
some reports from clinical studies and the scientific literature in
which the reported SADR is suspected to be associated with the product,
but, in fact, it is ultimately demonstrated not to be due to the
product. This is also true for reports from spontaneous sources in
which manufacturers and applicants must always assume, for safety
reporting purposes, that there is at least a reasonable possibility
that the drug or biological product caused the spontaneously reported
event and submit the report to FDA. Thus, SADR reports are required to
be submitted to FDA based on a suspected, not established, causal
relationship between an adverse event and a drug. This type of
reporting program allows the agency to determine more quickly which
SADRs warrant regulatory action by FDA to protect public health (e.g.,
change in product labeling, withdrawal of product from the market). FDA
receives hundreds of thousands of such reports each year, most of which
do not result in any regulatory action. But for those reports that do
represent a significant change in the benefit-to-risk profile of a
product, this system is critical for developing a signal necessitating
further evaluation of an SADR.
Some members of the public have maintained that submission of
voluntary SADR reports by health care professionals or consumers to
manufacturers or to FDA might be discouraged because of concern that a
person or entity might be implicated in a product liability action. In
addition, industry has expressed its concern that these reports, taken
out of context and used in a manner for which they were never intended,
can create a product liability vulnerability. FDA is concerned that
such liability misuse of these reports could imperil the credibility
and functionality of this critical public health reporting system.
Our current safety reporting regulations at Sec. Sec. 310.305(g),
312.32(e), 314.80(k), and 600.80(l) provide manufacturers, applicants,
and sponsors with a disclaimer that permits them to deny that the
safety report or other information required to be submitted to FDA
under these regulatory provisions constitutes an admission that the
drug or biological product caused or contributed to an adverse effect.
For example, Sec. 314.80(k) currently reads in pertinent part:
Disclaimer. A report or information submitted by an applicant
under this section (and any release by FDA of that report or
information) does not necessarily reflect a
[[Page 12419]]
conclusion by the applicant or FDA that the report or information
constitutes an admission that the drug caused or contributed to an
adverse effect. An applicant need not admit, and may deny, that the
report or information submitted under this section constitutes an
admission that the drug caused or contributed to an adverse effect.
Additionally, a ``disclaimer'' is included on the first page of the
voluntary reporting form used by health care professionals and
consumers, FDA Form 3500, stating ``Submission of a report does not
constitute an admission that medical personnel or the product caused or
contributed to the event.'' A similar disclaimer is included on the
mandatory reporting form used by manufacturers and applicants, FDA Form
3500A. In its notice of availability announcing FDA Form 3500 and
3500A, the agency reiterated that ``Although the underlying information
may be relevant to product liability issues, submitting the form
itself, as is clearly stated on the form, does not constitute an
admission that the product caused the adverse event'' (58 FR 31596 at
31600, June 3, 1993).
FDA seeks comment as to whether these ``disclaimers'' are
sufficient to protect manufacturers, applicants, and sponsors, from the
use of SADR reports in product liability actions. For instance, perhaps
the agency should consider also prohibiting use of SADR reports the
agency receives in product liability actions. Accordingly, FDA seeks
comment on the need for any further action to promote submission of
SADR reports to the agency and guard against their misuse, as well as
FDA's legal authority to take any such action.
FDA is proposing to remove the current provisions in Sec. Sec.
310.305(c)(1)(ii), 314.80(e)(1), and 600.80(e)(1). The agency is
proposing this amendment because the information contained in these
paragraphs is included in the proposed definition of SADR.
III.A.2. A Life-Threatening SADR
FDA's existing premarketing safety reporting regulations at Sec.
312.32(a) define a life-threatening adverse drug experience as:
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.
FDA is proposing to amend this definition by adding the phrase ``or
sponsor'' after the word ``investigator.'' Thus, reports of life-
threatening SADRs would be based on the opinion of either the
investigator or sponsor. In some cases, the opinions of the
investigator and sponsor may be discordant. In these situations, the
sponsor would submit an IND safety report to FDA for the life-
threatening SADR and include in the report the reason(s) for any
differences in opinions. This proposed revision is consistent with the
ICH E2A guidance (60 FR 11286): ``Causality assessment is required for
clinical investigation cases. All cases judged by either the reporting
health care professional or the sponsor as having a reasonable
suspected causal relationship to the medicinal product qualify as ADR's
[adverse drug reactions].''
FDA's existing postmarketing safety reporting regulations at
Sec. Sec. 310.305(b), 314.80(a), and 600.80(a) define a ``life-
threatening adverse drug experience'' as:
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.
Proposed Sec. Sec. 310.305(a), 312.32(a), 314.80(a), and 600.80(a)
would amend the premarketing and postmarketing definition of life-
threatening adverse drug experience by making minor revisions. FDA is
proposing to move the phrase ``places the patient'' (``patient or
subject'' for proposed Sec. 312.32(a)) before the phrase ``at
immediate risk of death'' and also to replace the phrase ``adverse drug
experience'' with the abbreviation ``SADR.''
III.A.3. Serious SADR, Nonserious SADR, and SADR With Unknown Outcome
FDA's existing premarketing and postmarketing safety reporting
regulations at Sec. Sec. 310.305(b), 312.32(a), 314.80(a), and
600.80(a) define a serious adverse drug experience as:
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. * * *
Proposed Sec. Sec. 310.305(a), 312.32(a), 314.80(a), and 600.80(a)
would amend this definition by removing the phrase ``occurring at any
dose,'' because the proposed definition of SADR includes the phrase
``response to any dose of a drug (``biological'' for proposed Sec.
600.80(a)) product'' and it is unnecessary to refer to ``any dose'' in
both definitions. FDA is also proposing to amend this definition by
replacing the phrase ``adverse drug experience'' with the abbreviation
``SADR'' for consistency as proposed previously.
Under proposed Sec. Sec. 310.305(a), 314.80(a), and 600.80(a), FDA
would amend its postmarketing safety reporting regulations to define
the term ``nonserious SADR'' to mean: ``Any SADR that is determined not
to be a serious SADR.'' FDA is proposing to add this definition to
clarify what constitutes a nonserious SADR. SADRs would only be
classified as ``nonserious'' if manufacturers and applicants have
determined that the reaction does not meet the definition of a serious
SADR. If the outcome for an SADR is not known, a determination of
seriousness cannot be made; the SADR would not default to a
``nonserious'' designation, but would rather be classified as an ``SADR
with unknown outcome'' as described below.
Under proposed Sec. Sec. 310.305(a), 314.80(a), and 600.80(a), FDA
would amend its postmarketing safety reporting regulations to define
the term ``SADR with unknown outcome'' to mean: ``An SADR that cannot
be classified, after active query, as either serious or nonserious.''
FDA is proposing to define this term to describe those SADRs for which
an outcome (i.e., classification as either serious or nonserious)
cannot be determined. FDA believes that, in most cases, manufacturers
and applicants are usually able to determine the outcome of an SADR.
However, in a few cases, this may not be possible, even after active
query, and these SADRs would be designated as ``SADR with unknown
outcome'' (see section III.A.6 of this document for proposed definition
of active query).
III.A.4. Contractor
Under proposed Sec. 310.305(a), FDA would amend its postmarketing
safety reporting regulations to define the term ``contractor'' to mean:
Any person (e.g., packer or distributor whether or not its name
appears on the label of the product; licensee; contract research
organization) that has entered into a contract with the manufacturer
to manufacture, pack, sell, distribute, or develop the drug or to
maintain, create, or submit records regarding SADRs or medication
errors.
Under proposed Sec. 314.80(a), the term ``contractor'' is defined
as persons (e.g., manufacturer, packer, or distributor whether or not
its name appears on the label of the product; licensee; contract
research organization) that have entered into a contract with the
applicant. Under proposed Sec. 600.80(a), the term ``contractor'' is
defined as persons (e.g.,
[[Page 12420]]
manufacturer, joint manufacturer, packer, or distributor whether or not
its name appears on the label of the product; licensee; contract
research organization) that have entered into a contract with the
applicant (includes participants involved in divided manufacturing).
FDA would define this term to specify which contractors would be
subject to the agency's postmarketing safety reporting requirements
under proposed Sec. Sec. 310.305(c)(2)(xi), 314.80(c)(2)(x), and
600.80(c)(2)(x) (see section III.D.9 of this document). Persons under
contract to manufacture, pack, sell, distribute, or develop the drug or
licensed biological product, or to maintain, create, or submit records
regarding SADRs or medication errors (whether or not the medication
error results in an SADR; see section III.A.8 of this document) would
have postmarketing safety reporting responsibilities.
III.A.5. Minimum Data Set and Full Data Set for an Individual Case
Safety Report
Proposed Sec. Sec. 310.305(a), 312.32(a), 314.80(a), and
600.80(a), would amend FDA's premarketing and postmarketing safety
reporting regulations to define the term ``minimum data set.'' A
``minimum data set'' for an individual case safety report of an SADR
would include: an identifiable patient, an identifiable reporter, a
suspect drug (biological for proposed Sec. 600.80(a)) product, and an
SADR.
Proposed Sec. Sec. 310.305(a), 314.80(a), and 600.80(a), would
also amend FDA's postmarketing safety reporting regulations to define
the term ``full data set.'' A ``full data set'' for a postmarketing
individual case safety report would include:
Completion of all the applicable elements on FDA Form 3500A (or
the Vaccine Adverse Event Reporting System (VAERS) form for proposed
Sec. 600.80(a)) (or on a Council for International Organizations of
Medical Sciences (CIOMS) I form for reports of foreign SADRs)
including a concise medical narrative of the case (i.e., an accurate
summary of the relevant data and information pertaining to an SADR
or medication error).
The proposed rule would define these terms to clarify the type of
information that manufacturers and applicants would be required to
submit to FDA for SADRs and medication errors. The proposed rule would,
as described below, require at least a minimum data set for all
individual case safety reports, except for certain reports of
medication errors (see sections III.B.2.a and III.C.5 of this
document). In addition, a full data set would be required for
postmarketing individual case safety reports of serious SADRs, always
expedited reports, and medication error reports (see sections III.C.5,
III.D.1, III.D.4, III.D.5, and III.E.4 of this document). Reports of
nonserious SADRs with a minimum data set would include all safety
information received or otherwise obtained by the manufacturer or
applicant for the SADR. However, except for reports of nonserious SADRs
resulting from a medication error, information in addition to the
minimum data set would not be required to be acquired by the
manufacturer or applicant (see sections III.C.5 and III.E.4 of this
document). Manufacturers and applicants would be required to submit a
full data set for reports of nonserious SADRs resulting from a
medication error (see sections III.C.5 and III.D.5 of this document).
As noted previously, for each individual case safety report, a
suspect product would be required to be identified. Reports from
blinded clinical studies (i.e., the sponsor and investigator are
blinded to individual patient treatment) should be submitted to FDA
only after the code is broken for the patient or subject that
experiences an SADR. The blind should be broken for each patient or
subject who experiences a serious, unexpected SADR unless arrangements
have been made otherwise with the FDA review division that has
responsibility for review of the IND (e.g., the protocol or other
documentation clearly defines specific alternative arrangements for
maintaining the blind). Exceptions to breaking the blind for a study
usually involve situations in which mortality or certain serious
morbidities are indeed the clinical endpoint of the study. This is
consistent with the discussion of managing blinded therapy cases in the
ICH E2A guidance (60 FR 11266):
* * * Although it is advantageous to retain the blind for all
patients prior to final study analysis, when a serious adverse
reaction is judged reportable on an expedited basis, it is
recommended that the blind be broken only for the specific patient
by the sponsor even if the investigator has not broken the blind. *
* * However, when a fatal or other ``serious'' outcome is the
primary efficacy endpoint in a clinical investigation, the integrity
of the clinical investigation may be compromised if the blind is
broken. Under these and similar circumstances, it may be appropriate
to reach agreement with regulatory authorities in advance concerning
serious events that would be treated as disease-related and not
subject to routine expedited reporting.
In addition to the exception for breaking the blind mentioned above,
FDA is also interested in considering whether the blind should be
broken for other serious SADRs that are not the clinical endpoint of
the study, but occur at a rate high enough that the overall study blind
would be threatened if each such case were individually unblinded. FDA
invites comment from the public on how reporting of these SADRs should
be handled.
III.A.6. Active Query
Under proposed Sec. Sec. 310.305(a), 314.80(a), and 600.80(a), FDA
would amend its postmarketing safety reporting regulations to define
the term ``active query'' to mean:
Direct verbal contact (i.e., in person or by telephone or other
interactive means such as a videoconference) with the initial
reporter of a suspected adverse drug reaction (SADR) or medication
error by a health care professional (e.g., physician, physician
assistant, pharmacist, dentist, nurse, any individual with some form
of health care training) representing the manufacturer (applicant
for proposed Sec. Sec. 314.80(a) and 600.80(a)). For SADRs, active
query entails, at a minimum, a focused line of questioning designed
to capture clinically relevant information associated with the drug
product (licensed biological product for proposed Sec. 600.80(a))
and the SADR, including, but not limited to, information such as
baseline data, patient history, physical exam, diagnostic results,
and supportive lab results.
The agency would define this term to describe the process that
manufacturers and applicants would be required to use to acquire safety
information expeditiously. Active query would be used to:
[sbull] Determine whether an SADR is serious or nonserious if the
manufacturer or applicant is not able to immediately make this
determination (see section III.C.5 of this document),
[sbull] Obtain at least the minimum data set for all SADRs and the
minimum information for medication errors that do not result in an SADR
if the manufacturer or applicant is not able to immediately obtain this
information (see section III.C.5 of this document),
[sbull] Obtain a full data set for individual case safety reports
of serious SADRs, always expedited reports, and medication error
reports if a full data set is not available for the report (see section
III.C.5 of this document), and
[sbull] Obtain supporting documentation for a report of a death or
hospitalization (e.g., autopsy report, hospital discharge summary) (see
section III.D.7 of this document).
Active query would entail direct verbal contact either in person or
by telephone or other interactive means (e.g., a videoconference) with
the initial reporter of an SADR or medication error. FDA believes that,
in many cases, use of active query during initial contact with these
reporters would provide
[[Page 12421]]
manufacturers and applicants with adequate safety information and could
eliminate or decrease followup time expended by manufacturers,
applicants, and the agency. The agency does not believe that it is
sufficient for manufacturers and applicants just to send a letter to
reporters of SADRs and medication errors requesting further
information. These reporters could, however, submit written materials
to manufacturers and applicants to clarify or provide support for
verbal discussions.
Even though the agency is not proposing that manufacturers and
applicants request followup information for SADR and medication error
reports in writing, the CIOMS V report describes instances when it
might be appropriate to do so. FDA seeks comment as to whether the
agency should permit written requests for followup information and, if
so, in which situations should these requests be permitted.
Active query would be conducted by a health care professional, such
as a physician, physician's assistant, pharmacist, dentist, nurse, or
any individual with some form of health care training. The agency
believes that a health care professional would be able to understand
better the medical consequences of a case and ask reporters of SADRs
and medication errors appropriate questions to acquire more complete
safety information effectively and rapidly.
The proposed definition of active query would provide that, at a
minimum, a focused line of questioning be used to acquire further
information on SADRs. For this purpose, questions would be designed to
capture clinically relevant information associated with the drug or
licensed biological product and the SADR. This information would
include, but would not be limited to, baseline data, patient history,
physical exam, diagnostic results, and supportive lab results.
III.A.7. Spontaneous Report
Under proposed Sec. Sec. 310.305(a), 314.80(a), and 600.80(a), FDA
would amend its postmarketing safety reporting regulations to define
the term ``spontaneous report'' to mean:
A communication from an individual (e.g., health care
professional, consumer) to a company or regulatory authority that
describes an SADR or medication error. It does not include cases
identified from information solicited by the manufacturer or
contractor (applicant or contractor for proposed Sec. 314.80(a);
applicant, shared manufacturer, or contractor for proposed Sec.
600.80(a)), such as individual case safety reports or findings
derived from a study, company-sponsored patient support program,
disease management program, patient registry, including pregnancy
registries, or any organized data collection scheme. It also does
not include information compiled in support of class action
lawsuits.
The agency would define this term to clarify which reports would be
considered ``spontaneous.'' Over the years, changes in marketing
practices in the United States have led to expanded contacts between
consumers and manufacturers, applicants, contractors, and shared
manufacturers. This has resulted in the acquisition of new types of
solicited safety information. Under the proposed rule, only unsolicited
safety information from an individual, such as a health care
professional or consumer, to a company or regulatory authority would be
considered a ``spontaneous report.''
Cases identified from information solicited by companies, such as
individual case safety reports or findings obtained from a study,
company-sponsored patient support program, disease management program,
patient registry, including pregnancy registries, or any organized data
collection scheme would not be considered spontaneous. Instead, safety
information from these sources would be considered ``study''
information and would be handled according to the postmarketing safety
reporting requirements for a ``study.'' As proposed, study information
would be subject to reporting as discussed below:
[sbull] Expedited reports for serious and unexpected SADRs from a
study (see section III.D.1 of this document),
[sbull] Expedited reports for information from a study that would
be sufficient to consider product administration changes (see section
III.D.2 of this document),
[sbull] Expedited reports for an unexpected SADR with unknown
outcome from a study (see section III.D.3 of this document),
[sbull] Always expedited reports from a study (see section III.D.4
of this document),
[sbull] Medication error reports from a study (see section III.D.5
of this document),
[sbull] Summary tabulations of all serious SADRs from studies or
individual patient INDs in PSURs (see section III.E.2.f.ii of this
document), and
[sbull] Discussion of important safety information from studies in
PSURs and IPSRs (see sections III.E.2.g and III.E.3 of this document).
The proposed rule would consider SADR information compiled in
support of class action lawsuits to be neither spontaneous nor
``study'' information. FDA believes that the vast majority of SADR
information from class action lawsuits is duplicative (i.e., the same
SADR information is reported by multiple individuals). In many cases,
information in addition to the minimum data set is not available for
these SADR reports and followup is unlikely to result in acquisition of
new information. For these reasons, the agency is proposing to require
in TPSRs, PSURs and IPSRs summary information for SADRs from class
action lawsuits (see sections III.E.1.e, III.E.2.k.v, and III.E.3 of
this document).
Any safety information obtained from an individual (e.g., health
care professional, consumer) who has initiated contact with a company
or regulatory authority would be considered spontaneous. For example,
if an individual calls a company and asks if a particular SADR has been
observed with one of the company's drug or licensed biological products
because the individual or someone the individual knows has experienced
such an SADR, the call would be considered spontaneous. The agency
would consider these calls spontaneous because the individual making
the call has a belief or suspicion that the drug or licensed biological
product may have caused the SADR.
The proposed definition for spontaneous report is consistent with
the definition of ``spontaneous report or spontaneous notification'' in
the ICH E2C guidance (62 FR 27475)):
An unsolicited communication to a company, regulatory authority,
or other organization that describes an adverse reaction in a
patient given one or more medicinal products and which does not
derive from a study or any organized data collection scheme.
III.A.8. Medication Error
Proposed Sec. Sec. 310.305(a), 314.80(a), and 600.80(a) would
amend FDA's postmarketing safety reporting regulations to define the
terms ``medication error,'' ``actual medication error,'' and
``potential medication error.'' A ``medication error'' would be defined
as:
Any preventable event that may cause or lead to inappropriate
medication use or patient harm while the medication is in the
control of the health care professional, patient, or consumer. Such
events may be related to professional practice, health care
products, procedures, and systems including: Prescribing; order
communication; product labeling, packaging, and nomenclature;
compounding; dispensing; distribution; administration; education;
monitoring; and use.
[[Page 12422]]
An ``actual medication error'' would be defined as:
A medication error that involves an identifiable patient whether
the error was prevented prior to administration of the product or,
if the product was administered, whether the error results in a
serious SADR, nonserious SADR, or no SADR.
A ``potential medication error'' would be defined as:
An individual case safety report of information or complaint
about product name, labeling, or packaging similarities that does
not involve a patient.
The proposed rule would define these terms to clarify what would be
considered a medication error. The proposed definition for ``medication
error'' was developed by the National Coordinating Council for
Medication Error Reporting and Prevention, of which FDA is a member.
FDA would not consider a case in which a patient deliberately took an
overdose of a drug to be a ``medication error'' because the agency does
not believe that this type of situation is ``preventable.'' Instead, it
would be considered a ``non-accidental overdose.''
The proposed definitions for actual and potential medication errors
were developed by FDA. Actual medication errors involve an identifiable
patient whether or not the product is administered and, if the product
is administered, whether or not an SADR occurs. Potential medication
errors do not involve a patient, but rather describe information or
complaint about product name, labeling, or packaging similarities that
could result in a medication error in the future.
III.A.9. Company Core Data Sheet, Company Core Safety Information
(CCSI), Listed SADR, Unlisted SADR, and Unexpected SADR
Proposed Sec. Sec. 314.80(a) and 600.80(a) would amend FDA's
postmarketing safety reporting regulations to define the terms
``company core data sheet,'' ``company core safety information
(CCSI),'' ``listed SADR,'' and ``unlisted SADR.'' The ``company core
data sheet'' would be defined as:
A document prepared by the applicant containing, in addition to
safety information, material relating to indications, dosing,
pharmacology, and other information concerning the drug substance
(biological product for proposed Sec. 600.80(a)). The only purpose
of this document is to provide the company core safety information
(CCSI) for periodic safety update reports (PSURs), interim periodic
safety reports (IPSRs), and certain individual case safety reports--
semiannual submissions (i.e., if PSURs are submitted for the
product).
The ``CCSI'' would be defined as:
All relevant safety information contained in the company core
data sheet that the applicant proposes to include in the approved
product labeling in all countries where the applicant markets the
drug substance (biological product for proposed Sec. 600.80(a)). It
is the reference information by which an SADR is determined to be
``listed'' or ``unlisted'' for PSURs, IPSRs, and certain individual
case safety reports--semiannual submissions (i.e., if PSURs are
submitted for the product).
A ``listed SADR'' would be defined as: ``an SADR whose nature,
specificity, severity, and outcome are consistent with the information
in the CCSI.''
An ``unlisted SADR'' would be defined as: ``an SADR whose nature,
specificity, severity, or outcome is not consistent with the
information included in the CCSI.''
The proposed rule would define these terms to help applicants
determine which SADRs must be reported in PSURs, IPSRs, and certain
individual case safety reports--semiannual submissions (i.e., if PSURs
are submitted for the product) (see sections III.E.2, III.E.3, and
III.E.4 of this document). For this purpose, the CCSI would be used as
the reference document by which an SADR would be judged as ``listed''
or ``unlisted.''
Company core data sheets would usually be prepared by applicants
for a drug substance rather than a drug product because postmarketing
PSURs and IPSRs would be based on a drug substance. Under the existing
regulations at Sec. 314.3(b) (21 CFR 314.3(b)), a drug substance is
defined as:
An active ingredient that is intended to furnish pharmacological
activity or other direct effect in the diagnosis, cure, mitigation,
treatment, or prevention of disease or to affect the structure or
any function of the human body, but does not include intermediates
use[d] in the synthesis of such ingredient.
Under these same regulations, a drug product is defined as:
a finished dosage form, for example, tablet, capsule, or solution,
that contains a drug substance, generally, but not necessarily, in
association with one or more other ingredients.
Thus, drug substances refer to active moieties of drug products.
In the United States, the company core data sheet would be used
only to provide the CCSI for a drug or biological product to determine
whether an SADR is listed or unlisted. Company core data sheets would
not require approval from FDA, unlike the U.S. labeling for a marketed
drug or licensed biological product which does require approval from
FDA. Company core data sheets would not be used in the United States as
the labeling for an approved drug or licensed biological product. FDA
believes that preparation of a company core data sheet would not impose
a new burden on most applicants because it codifies a common practice
in the pharmaceutical industry (see the ICH E2C guidance, 62 FR 27470
at 27472).
Postmarketing PSURs may be submitted by applicants to multiple
countries, and the drug or licensed biological product may have
different approved labeling in the different countries. The CCSI for
the product should not be a compilation of all the safety information
contained in the various approved labelings for the product. Instead,
the CCSI should contain the critical safety information for the product
that would be relevant in all countries where the product is approved
for marketing. In some cases, the CCSI and an approved labeling for the
product would contain the same safety information (i.e., all the safety
information in an approved labeling for the product is relevant in all
countries where the product is approved for marketing or the product is
only approved for marketing in one country). In other cases, an
approved labeling for a product may contain more safety information
than the CCSI for the product because the labeling may contain safety
information specific to the country in which the product is approved
for marketing (e.g., safety information regarding a specific indication
for which the product is approved for marketing in one country but not
other countries). In these cases, the use of the CCSI as the reference
document for determining whether an SADR is listed or unlisted for the
postmarketing PSURs may result in overreporting of some SADRs to FDA as
``unlisted'' when they actually are ``expected'' by the approved U.S.
labeling.
This proposal would not affect the reference document used to
determine expectedness (i.e., unexpected or expected SADR) for SADRs
reported in premarketing IND safety reports, postmarketing expedited
reports, postmarketing TPSRs, and certain postmarketing individual case
safety reports--semiannual submissions (i.e., if TPSRs are submitted
for the product) (see table 5 and sections III.B, III.D, III.E.1, and
III.E.4 of this document). Under the existing regulations at Sec. Sec.
310.305(b), 314.80(a), and 600.80(a), the definition of ``unexpected
adverse drug experience'' designates the current approved labeling for
the drug or licensed biological product as the reference document to be
used to determine what would be considered
[[Page 12423]]
``unexpected.'' Proposed Sec. Sec. 310.305(a), 314.80(a), and
600.80(a) would include in the definition of ``unexpected SADR'' the
abbreviation ``U.S.'' before the word ``labeling'' to clarify that the
approved U.S. labeling would be used to determine whether or not an
SADR is ``unexpected.'' FDA would also amend this definition by
replacing the word ``event'' with the word ``reaction'' and by
clarifying that the phrase ``differ from the event because of greater
severity or specificity'' refers to a ``labeled reaction.'' Under
proposed Sec. Sec. 310.305(a), 312.32(a), 314.80(a), and 600.80(a),
the agency would also replace the word ``listed'' with the word
``included'' in the definition of ``unexpected SADR'' to minimize
confusion with ``listed SADRs'' in the CCSI. FDA would also revise the
sentence ``Unexpected, as used in this definition, refers to an SADR
that has not been previously observed * * * rather than from the
perspective of such reaction not being anticipated from the
pharmacological properties of the drug product'' in this definition for
clarity.
Table 5.--Proposed Reference Documents for Safety Reports
------------------------------------------------------------------------
Marketing status Safety report Reference document
------------------------------------------------------------------------
Premarketing................ IND safety report... Investigator's
brochure. If not
available, risk
information in
general
investigational
plan or elsewhere
in the current
application.
Postmarketing............... Expedited reports... U.S. labeling.
TPSRs............... U.S. labeling.
PSURs and IPSRs..... CCSI.
Individual case
safety reports--
semiannual
submission:
If TPSR is U.S. labeling.
submitted for
the product.
If PSUR is CCSI.
submitted for
the product.
------------------------------------------------------------------------
These proposed amendments are consistent with the ICH E2C guidance
(62 FR 27470 at 27472):
For purposes of periodic safety reporting, CCSI forms the basis
for determining whether an ADR is already Listed or is still
Unlisted, terms that are introduced to distinguish them from the
usual terminology of ``expectedness'' or ``labeledness'' that is
used in association with official labeling. Thus, the local approved
product information continues to be the reference document upon
which labeledness/expectedness is based for the purpose of local
expedited postmarketing safety reporting.
Under proposed Sec. Sec. 310.305(a), 312.32(a), 314.80(a), and
600.80(a), FDA would include the following sentence in the definition
of ``unexpected SADR:''
SADRs that are mentioned in the U.S. labeling (investigator's
brochure for proposed Sec. 312.32(a)) as occurring with a class of
drugs (products for proposed Sec. 600.80(a)) but not specifically
mentioned as occurring with the particular drug (product for
proposed Sec. 600.80(a)) are considered unexpected.
This information is currently included in the draft guidance of
2001. FDA is now proposing to codify this information to clarify which
SADRs would be considered ``unexpected.''
III.A.10. Data Lock Point and International Birth Date
Proposed Sec. Sec. 314.80(a) and 600.80(a) would amend FDA's
postmarketing safety reporting requirements to define the terms ``data
lock point'' and ``international birth date.'' The ``data lock point''
would be defined as:
The date designated as the cut-off date for data to be included
in a postmarketing periodic safety report.
The ``international birth date'' would be defined as:
The date the first regulatory authority in the world approved
the first marketing application for a human drug product containing
the drug substance (human biological product for proposed Sec.
600.80(a)).
The agency would define these terms to help standardize the
submission date (i.e., month and day of submission) for postmarketing
periodic safety reports (i.e., PSURs, IPSRs, TPSRs, individual case
safety reports--semiannual submissions). The data lock point would
signify the end of a reporting period for data to be included in a
specific postmarketing periodic safety report. The month and day of the
international birth date would serve as a reference point for
determining the data lock point. On the date of the data lock point,
safety information that is available to applicants would be reviewed
and evaluated prior to being submitted to FDA. Postmarketing periodic
safety reports would be submitted to FDA within 60 days of the data
lock point (see section III.E.5.b of this document). For example, for a
drug or biological product approved by FDA on June 15 with a 6-month
periodic reporting period and an international birth date of April 1,
the first data lock point would be October 1, which is less than 6
months after FDA approval, but is the 6-month anniversary of the
international birth date. Therefore, the first postmarketing periodic
safety report would cover the period from April 1 through October 1
even though the product had only been approved in the United States on
June 15. The second periodic report would cover the period from October
2 through April 1.
An international birth date would be determined and declared by
applicants. Applicants would determine an international birth date for
a product based on the date of approval of the first marketing
application in the world for a human drug product containing the drug
substance or a biological product. A single international birth date
would encompass all different dosage forms, formulations, or uses
(e.g., indications, routes of administration, populations) of a drug
substance or licensed biological product. Thus, postmarketing periodic
safety reports for different drug products containing the same drug
substance would be submitted to FDA at the same time.
The month and day of the international birth date would be used, as
noted previously, to determine the data lock point (i.e., month and
day) for postmarketing periodic safety reports. It would not, except as
noted below, be used to determine the frequency for submission of these
reports (i.e., 6-month intervals or multiples of 6 months). Instead,
the date (i.e., year) of U.S. approval of the application for the drug
or biological product (e.g., NDA, ANDA, BLA) would be used to determine
the frequency for submission of postmarketing periodic safety reports
to FDA (see section III.E.5.a of this document). The international
birth date would be used to determine both the data lock point and
reporting frequency for postmarketing periodic safety reports only when
the U.S. approval date is used to determine the international birth
date (e.g., FDA is the first
[[Page 12424]]
regulatory authority in the world to approve the human drug product
containing the drug substance or biological product for marketing).
The use of a standardized submission date (i.e., month and day),
which is consistent with the ICH E2C guidance (62 FR 27470 at 27472),
would enable applicants to submit a single core report (PSUR excluding
appendices) to regulatory authorities worldwide. Currently, different
regulatory authorities require submission of postmarketing periodic
safety reports on varying time schedules. Th