[Federal Register: November 5, 1998 (Volume 63, Number 214)]

[Proposed Rules]

[Page 59746-59750]

From the Federal Register Online via GPO Access [wais.access.gpo.gov]

[DOCID:fr05no98-30]

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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