[Federal Register Volume 63, Number 214 (Thursday, November 5, 1998)]
[Proposed Rules]
[Pages 59746-59750]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-29564]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 310, 314, and 600
[Docket No. 98N-0750]
RIN 0910-AB42
Electronic Reporting of Postmarketing Adverse Drug Reactions;
Request for Comments
AGENCY: Food and Drug Administration, HHS.
ACTION: Advance notice of proposed rulemaking.
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SUMMARY: The Food and Drug Administration (FDA) is announcing that it
is considering preparing a proposed rule that would require applicants,
manufacturers, packers, and distributors of marketed human drugs and
licensed biological products to submit postmarketing expedited
individual case safety reports and individual case safety reports
contained in periodic safety reports to the agency electronically using
standardized medical terminology, data elements, and electronic
transmission standards recommended by the International Conference on
Harmonization of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH). The proposed rule would help
harmonize reporting of postmarketing safety information worldwide and
expedite detection of safety problems for marketed drugs, thus
enhancing FDA's ability to protect and promote public health. FDA is
soliciting comments from interested persons to assist with the
development of the proposed rule. The agency is specifically seeking
comments on whether exemptions from any electronic safety reporting
requirements should be granted to any entity and, if so, the basis on
which they should be granted, the cost benefits or burdens of such
requirements, and timeframes for implementing the requirements.
DATES: Written information and comments by February 3, 1999.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,
Rockville MD 20852.
FOR FURTHER INFORMATION CONTACT: Thomas C. Kuchenberg, Center for Drug
Evaluation and Research (HFD-7), 5600 Fishers Lane, Rockville, MD
20857, 301-594-5621 (Internet electronic mail:
kuchenbergt@cder.fda.gov) or Marcel Salive, Center for Biologics
Evaluation and Research (HFM-220), 1401 Rockville Pike, Rockville, MD
20852, 301-827-3974 (Internet electronic mail: salive@cber.fda.gov).
SUPPLEMENTARY INFORMATION:
I. Background
A. International Harmonization
For several years, FDA has cooperated with industry associations
and the regulatory authorities of certain other nations to promote
international harmonization of regulatory requirements. Much of this
effort has been coordinated through ICH, which is facilitating 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 Industries
Associations, the Japanese Ministry of Health and Welfare, the Japanese
Pharmaceutical Manufacturers Association, the Centers for Drug
Evaluation and Research and Biologics Evaluation and Research at FDA,
and the Pharmaceutical Research and Manufacturers of America. The ICH
Secretariat, which coordinates the preparation of documentation, is
provided by the International Federation of Pharmaceutical
Manufacturers Associations (IFPMA).
The ICH Steering Committee includes representatives from each of
the ICH sponsors and the IFPMA, as well as observers from the World
Health Organization (WHO), the Canadian Therapeutic Products
Directorate, and the European Free Trade Area.
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 individual case safety reports and
periodic safety reports for human drugs and biological products. In the
Federal Register of March 1, 1995 (60 FR 11284), FDA published an ICH
final guidance entitled ``Clinical Safety Data Management: Definitions
and Standards for Expedited Reporting'' (the ICH E2A guidance). In the
Federal Register of May 19, 1997 (62 FR 27470), FDA published an ICH
final guidance entitled ``Clinical Safety Data Management: Periodic
Safety Update Reports for Marketed Drugs'' (the ICH E2C guidance).
Under the auspices of ICH, standards for electronic submission of
safety information have been developed, as described in the Appendices,
including a standard
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medical terminology for regulatory purposes, ICH M1 (see Appendix A in
section VII.A of this document); electronic standards for the transfer
of regulatory information, ICH M2 (see Appendix B in section VII.B of
this document); and standardized data elements for transmission of
individual case safety reports, ICH E2B format (see Appendix C in
section VII.C of this document). FDA believes the changes recommended
by ICH will result in more effective and efficient safety reporting to
regulatory authorities worldwide.
There is now international agreement on the major components for
standardizing electronic transmission of certain safety reports, and
worldwide implementation of this initiative has begun.
B. Postmarketing Safety Reports
Under existing regulations, manufacturers, packers, distributors,
applicants of approved new and abbreviated marketing applications for
drugs, and licensed manufacturers of biological products must submit
expedited individual case safety reports of postmarketing adverse drug
experiences under Secs. 310.305, 314.80, 314.98, and 600.80 (21 CFR
310.305, 314.80, 314.98, and 600.80). Applicants and licensed
manufacturers must also submit periodic reports of postmarketing
adverse drug experiences under Secs. 314.80, 314.98, and 600.80.
Expedited individual case safety reports are required to be
submitted for each adverse drug experience that is both serious and
unexpected, whether foreign or domestic, as soon as possible, but in no
case later than 15 calendar days of initial receipt of the information
(Secs. 310.305(c)(1), 314.80(c)(1)(i), and 600.80(c)(1)(i)). Followup
reports to these expedited reports are required to be submitted within
15 calendar days of receipt of new information or as requested by FDA
(Secs. 310.305(c)(2), 314.80(c)(1)(ii), and 600.80(c)(1)(ii)).
Presently, periodic reports are required to be submitted at
quarterly intervals for 3 years from the date of approval of the
application and annually thereafter (Secs. 314.80(c)(2)(i) and
600.80(c)(2)(i)). The periodic report is required to contain: (1) A
narrative summary and analysis of the information in the report and an
analysis of the expedited individual case safety reports submitted
during the reporting interval, (2) individual case safety reports for
each adverse drug experience not previously reported, and (3) a history
of actions taken since the last periodic report (Secs. 314.80(c)(2)(ii)
and 600.80(c)(2)(ii)).
Each adverse drug experience is required to be submitted to the
agency on an FDA Form 3500A (Secs. 310.305(d), 314.80(f), and
600.80(f)). Foreign events may be submitted either on an FDA Form 3500A
or, if preferred, on a CIOMS (Council for International Organizations
of Medical Sciences) I form.
FDA is in the process of revising these regulations to be
consistent with safety reporting recommendations developed by ICH. In
the Federal Register of October 27, 1994 (59 FR 54046), FDA published a
proposed rule to amend its postmarketing expedited and periodic safety
reporting requirements, as well as others, to implement international
standards and to facilitate the reporting of adverse drug experiences.
In the Federal Register of October 7, 1997 (62 FR 52237), FDA published
a final rule amending its premarketing and postmarketing expedited
safety reporting regulations to implement certain recommendations in
the ICH E2A guidance on definitions and standards for expedited
reporting. At this time, the agency is considering other
recommendations in the ICH E2A guidance and plans to propose additional
amendments to its postmarketing expedited safety reporting regulations.
With regard to the amendments to the postmarketing periodic adverse
drug experience reporting requirements proposed on October 27, 1994,
FDA has decided to repropose these amendments based on recommendations
in the ICH E2C guidance on postmarketing periodic safety update
reports. In developing the reproposal, FDA will consider comments
submitted in response to the proposed rule of October 27, 1994,
regarding postmarketing periodic adverse experience reports.
II. Proposed Policy
FDA is considering preparing a proposed rule that would require
that applicants, manufacturers, packers and distributors of marketed
human drugs and licensed biological products submit postmarketing
expedited individual case safety reports and individual case safety
reports contained in periodic safety reports to the agency
electronically rather than on paper. The proposed rule would require
that the electronic submission of postmarketing expedited and periodic
individual case safety reports be precoded in the standardized M1
international medical terminology, use the E2B format, and be
transmitted using M2 specifications. FDA may also propose requiring
that textual materials contained within periodic safety reports (e.g.,
narrative summary and analyses, history of actions taken) be submitted
electronically.
In the Federal Register of March 20, 1997 (62 FR 13430), FDA
published a final rule in part 11 (21 CFR part 11) providing the
conditions under which the agency will accept electronic signatures,
electronic records, and handwritten signatures executed to electronic
records as equivalent to paper records and handwritten signatures
executed to paper records. Part 11 applies to any required records
submissions under the Federal Food, Drug, and Cosmetic Act, the Public
Health Service Act, or Title 21 of the Code of Federal Regulations.
Part 11 provides that for records required to be maintained but not
submitted to the agency, electronic records and accompanying signatures
may be used in lieu of traditional records and signatures provided
certain requirements are met. Electronic records and accompanying
signatures that are submitted to the agency must meet the requirements
of part 11 and must also be identified in public docket number 92S-0251
as the type of submission the agency is prepared to accept
electronically. It is important to note that the use of electronic
records, as well as their submission to FDA under part 11, is
voluntary.
However, for a number of reasons, FDA believes that it is essential
to mandate the electronic submission of postmarketing expedited and
periodic individual case safety reports as well as the use of
international standards for electronic safety reporting.
The rapid identification and dissemination of information about
emerging problems with individual drugs or harmful drug interactions is
central to the agency's mission to protect and promote public health
and safety. First, receipt of safety information electronically will
vastly increase FDA's ability to quickly analyze data and identify
emerging safety problems. Second, the agency believes that use of
international standards for electronic safety reporting will eliminate
the costs to industry associated with maintaining multiple systems
designed to meet the needs of different terminologies, data elements,
and electronic transmission standards of different regulatory
authorities, and would thereby greatly enhance the utility of the
system. Third, electronic submissions will improve the speed and
efficiency of industry and agency operations and enhance the quality of
the safety data.
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III. Solicitation of Comments
All interested persons are invited to submit to FDA their comments
on any aspect of this advance notice of proposed rulemaking (ANPRM). In
particular, FDA is seeking public comment on the following subjects:
1. Exemptions
The agency believes that the electronic reporting of postmarketing
individual case safety reports will be welcomed by most of industry.
The agency is aware, however, that some entities may have difficulty
adapting existing systems to the requirements of a mandatory
standardized electronic reporting system. The agency seeks guidance on
whether exemptions should be granted and, if so, what considerations
should be used to determine whether requesting entities may continue
submitting postmarketing individual case safety reports in a paper
format and whether any such exemptions should continue indefinitely or
be terminated after a certain period of time.
In the Federal Register of October 30, 1997 (62 FR 58647), the
Securities and Exchange Commission (SEC) published a final rule stating
that it would no longer accept paper copies of filings and required
filers to submit information electronically unless certain requirements
for a temporary or continuing hardship were met. Filers may claim or
request, as appropriate, hardship exemptions based on certain criteria,
including: Technical difficulties in filing and undue burden and
expense of conversion to electronic format. A temporary hardship
exemption, generally for unanticipated technical difficulties, is
available automatically, but submission of a paper copy of the filing
must be followed, within 6 business days, by a confirming electronic
copy. A continuing hardship exemption is also available but must be
granted by the SEC. It may be granted for a specific period (after
which a confirming electronic copy of the paper copy must be filed) or
for an indefinite period.
FDA is seeking specific comments on whether a similar exemption
provision would be appropriate for electronic reporting for
postmarketing individual case safety reports.
2. Cost Benefits and Burdens
The agency is interested in comments on the impact of a mandatory
standardized electronic reporting requirement on different segments of
regulated industry. For example, how will such a requirement affect
manufacturers of different type and size over the short term during
implementation and over the long term once systems are established? FDA
is also interested in information on the benefits that industry could
derive from a mandatory standardized electronic reporting requirement
(e.g., reduced paperwork burden, reduced errors, increased convenience
and more timely receipt of information).
3. Timeframes for Implementation
The SEC model, described in section III.1 of this document, phased
companies into its electronic filing system over a 4-year period, with
small business filers being the last to be required to file
electronically. The agency is seeking comments on whether a similar
implementation plan, based on the size of a firm, would be appropriate
for electronic reporting of postmarketing individual case safety
reports and, if not, how it should be modified, and what criteria
should be used to define an implementation plan.
4. OMB Circular A-130
Section 8a(3) of OMB circular A-130 cites a policy to encourage
agencies to explore the use of automated techniques for the collection
of information and conditions conducive to the use of those techniques.
Section 8a(3) reads as follows:
Electronic Information Collection. Agencies shall use electronic
collection techniques where such techniques reduce burden on the
public, increase efficiency of government programs, reduce costs to
the government and the public, and/or provide better service to the
public. Conditions favorable to electronic collection include:
(a) The information collection seeks a large volume of data and/
or reaches a large proportion of the public;
(b) The information collection recurs frequently;
(c) The structure, format, and/or definition of the information
sought by the information collection does not change significantly
over several years;
(d) The agency routinely converts the information collected into
electronic format;
(e) A substantial number of the affected public are known to
have ready access to the necessary information technology and to
maintain the information in electronic form;
(f) Conversion to electronic reporting, if mandatory, will not
impose substantial costs or other adverse effects on the public,
especially State and local governments and small business entities.
FDA is soliciting comments on whether a proposed rule consistent
with the objectives discussed in this ANPRM would advance the
objectives of the policy stated in the OMB circular.
If FDA develops a proposed rule for electronic reporting of
postmarketing individual case safety reports, it will take into
consideration comments submitted in response to this ANPRM.
IV. Executive Order 12866 Analysis
In any rulemaking proposed as a result of comments received on this
ANPRM, FDA will examine the economic implications of the proposed rule
as required by Executive Order 12866, which directs agencies to assess
all costs and benefits of available regulatory alternatives. Executive
Order 12866 classifies a rule as significant if it meets any one of a
number of specified conditions, including having an annual effect on
the economy of $100 million or adversely affecting in a material way a
sector of the economy, competition, or jobs, or if it raises novel
legal or policy issues. In any rulemaking, the agency will examine the
potential costs and potential benefits of the proposed rule. FDA
requests information that would aid the agency in responding to the
Executive Order.
V. Regulatory Flexibility Analysis
If a rule has a significant economic impact on a substantial number
of small entities, the Regulatory Flexibility Act (5 U.S.C. 601-612)
requires agencies to analyze options that would minimize the economic
impact of that rule on small entities. FDA requests information
regarding the impact on small entities of the three subjects identified
in section III of this document.
VI. Comments
Interested persons may on or before February 3, 1999, submit to the
Dockets Management Branch (address above) written comments regarding
this ANPRM. Two copies of any comments are to be submitted, except that
individuals may submit one copy. Comments are to be identified with the
docket number found in brackets in the heading of this document.
Received comments may be seen in the office above between 9 a.m. and 4
p.m., Monday through Friday.
VII. Appendices
A. Appendix A: M1 Medical Terminology
Most organizations currently process their regulatory data using
an international adverse drug reaction (ADR) terminology in combination
with a morbidity terminology. In Europe, many users combine the World
Health Organization's Adverse Reaction Terminology with the ninth
revision of the International Classification of Diseases (ICD-9). In
the United States, Coding Symbols for a Thesaurus of Adverse Reaction
Terms with Clinical Modification of ICD-9 (ICD-9-CM) is
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very commonly used, and Japan has developed its own version of these
ADR terminologies, J-Art and MEDIS.
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.
A medical terminology designed for regulatory purposes was
recognized as necessary by industry and regulatory authorities to
support the computerization and transmission of information related to
many aspects of the regulation of medical products. In October 1994,
the ICH Steering Committee introduced a multidisciplinary communication
initiative to establish an international medical terminology for
regulatory purposes (M1).
In November 1994, the ICH Steering Committee released a draft (or
alpha) version of the M1 terminology for review and evaluation. The
alpha version was made available free of charge to all national
regulatory entities participating in the WHO International Drug
Monitoring Program and, on request, to pharmaceutical companies and
contract research organizations. More than 600 electronic copies were
distributed with a testing guide which provided suggestions on how the
terminology could be evaluated.
In March 1995, the M1 ICH working group met to evaluate the results
of the alpha test, review proposals submitted by potential users
participating in the alpha test, and evaluate suggested changes. Since
1995, the working group has: (1) Refined and documented the definitions
of the levels in the structural hierarchy; (2) reviewed and established
the scope of the terminology; (3) reviewed terms and codes of the
established terminologies, made necessary linkages and deletions, and
included the most recent versions of the current terminologies to
facilitate the transfer of historical data; (4) reviewed the results of
the extensive and systematic Organ Class reviews performed in the
United States and Japan; and (5) made necessary changes to facilitate
data analysis and presentation.
Over time, it is essential that the M1 medical terminology be
maintained and updated in response to medical/scientific advances and
regulatory changes. An international maintenance and service
organization (MSSO) is being established to provide this function as
well as serve as the licensing agent for the distribution of the M1
medical terminology. It is anticipated that the MSSO will begin
licensing the M1 medical terminology in the near future.
B. Appendix B: Electronic Transmission Standards
The ICH Steering Committee recognized the need for rapid
communication of regulatory information between pharmaceutical
manufacturers and regulatory authorities and, in particular, the need
for the electronic communication of safety information. The ICH
Steering Committee also noted that rapid communication required
universal standards and that separate, uncoordinated initiatives
launched in various countries could compromise the benefits of
electronic communication and jeopardize the harmonization process. As a
result, the ICH Multidisciplinary Group 2 (M2) Expert Working Group
(EWG) was established in October 1994 to recommend electronic standards
and provide solutions to facilitate international electronic
communication in the three ICH regions.
The M2 EWG recommended various open international standards that
allow for the worldwide transmission of information regardless of the
technical infrastructure. The electronic standards for the transfer of
regulatory information (ESTRI) gateway is designed to ensure reliable
regulatory communications by using certain common electronic elements.
The M2 EWG recommended the following:
1. Physical Media
Use of 3.5 inch floppy disk (ISO 8860) (1 and 2) and CD-ROM 640 MB
(ISO 9660) as standard media for physical data storage and
transferability across heterogenous computer platforms.
2. Network Messaging
Use of the Internet (STP/MIME) and X400 as network messaging
standards that will provide for the efficient transport of heterogenous
data formats and complex documents among the three ICH regions.
3. Electronic Document Format
Use of the Portable Document Format (PDF) as the interchange format
for the transfer of certain types of documents.
4. Secure Electronic Data Interchange (EDI) Over the Internet
Use of Templar, a standards-based solution that facilitates the
transmission of secure EDI over the Internet in all three ICH regions.
In addition, the M2 EWG facilitated the implementation of E2B data
elements by defining an attribute list and deriving a relational view
that allows for transmission of all types of individual case safety
reports, regardless of source and destination. The E2B/M2 attribute
list will form the basis for defining E2B data elements in various
structured formats such as standard generalized markup language (SGML).
C. Appendix C: E2B Data Elements for Transmission of Individual Case
Safety Reports
In the Federal Register of October 1, 1996 (61 FR 51287), FDA
published a draft guidance entitled ``Data Elements for Transmission of
Individual Case Safety Reports.'' The notice gave interested parties an
opportunity to submit comments by December 30, 1996. After
consideration of the comments received and revisions to the guidance, a
final draft was submitted to the ICH Steering Committee and endorsed by
the three participating regulatory parties on July 17, 1997. The final
guidance entitled ``E2B Data Elements for Transmission of Individual
Case Safety Reports'' (ICH E2B guidance) was published in the Federal
Register of January 15, 1998.
The guidance is intended to facilitate the standardization of data
elements for transmission of individual case safety reports. The format
for individual case safety reports includes provisions for transmitting
all the relevant data elements useful to assess an individual ADR or
adverse event report. The data elements are sufficiently comprehensive
to cover complex reports from most sources, different data sets, and
transmission situations or requirements. In many, if not most,
instances a
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substantial number of the data elements will not be known, but as much
information as possible should be provided. The minimum information for
the transmission of a safety report should include an identifiable
patient, an identifiable reporter, a reaction/event, and a suspect drug
or biological product.
Dated: October 6, 1998.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 98-29564 Filed 11-4-98; 8:45 am]
BILLING CODE 4160-01-F
