Expedited Safety Reporting Requirements for Human Drug and Biological Products

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 20, 310, 312, 314, and 600

[Docket No. 93N-0181]

RIN 0910-AA97

Expedited Safety Reporting Requirements for Human Drug and

Biological Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending its

expedited safety reporting regulations for human drug and biological

products to provide consistency with the elements of FDA Form 3500A for

use in pre- and postmarketing safety reporting;

[[Page 52238]]

implement definitions, reporting periods, formats, and standards as

recommended by the International Conference on Harmonisation of

Technical Requirements for Registration of Pharmaceuticals for Human

Use (ICH) and by the World Health Organization's Council for

International Organizations of Medical Sciences (CIOMS); require

applicants, manufacturers, packers, and distributors, as well as

licensed manufacturers and other manufacturers of biological products,

to develop written procedures for postmarketing safety monitoring and

reporting; state that FDA Form 3500A reports that FDA forwards to any

person subject to the postmarketing safety reporting requirements are

not required to be resubmitted to the agency; and make other revisions

to the regulations to provide uniformity with definitions and

procedures used in expedited pre- and postmarketing safety reporting

for human drug and biological products. These changes simplify and

facilitate expedited safety reporting and enhance agencywide

consistency in the collection of postmarketing safety data.

DATES: This regulation is effective April 6, 1998. Submit written

comments on the information collection provisions of this final rule by

December 8, 1997.

ADDRESSES: Submit written comments on the information collection

provisions of this final rule to the Dockets Management Branch (HFA-

305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23,

Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT:

For information concerning human drug products: Audrey A. Thomas,

Center for Drug Evaluation and Research (HFD-7), Food and Drug

Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-594-5625.

For information concerning human biological products: Valerie A.

Butler, Center for Biologics Evaluation and Research (HFM-17), Food and

Drug Administration, 1401 Rockville Pike, suite 200N, Rockville, MD

20852-1448, 301-594-3074.

SUPPLEMENTARY INFORMATION:

I. Introduction

In the Federal Register of October 27, 1994 (59 FR 54046), FDA

published a proposed rule to amend the regulations for expedited and

periodic pre- and postmarketing safety reporting for human drug and

biological products (hereinafter referred to as the October 1994

proposal). FDA also proposed to amend the requirements for clinical

study design and conduct and annual sponsor reporting in the

investigational new drug application (IND) regulations.

As explained in the October 1994 proposal, the amendments to the

safety reporting regulations are intended to provide consistency with

certain standardized definitions, procedures, and formats developed by

ICH and CIOMS (59 FR 54046 at 54047). In the Federal Register of July

9, 1993 (58 FR 37408), FDA published an ICH draft guideline entitled

``Clinical Safety Data Management: Definitions and Standards for

Expedited Reporting'' (hereinafter referred to as the draft ICH E2A

guideline). The public was given an opportunity to comment on the draft

ICH E2A guideline. After consideration of the comments received and

revisions to the draft guideline, ICH finalized the guideline. In the

Federal Register of March 1, 1995 (60 FR 11284), FDA published the ICH

final guideline (hereinafter referred to as the final ICH E2A

guideline). Although the final ICH E2A guideline pertains to expedited

safety reporting during the preapproval phase of drug development, for

consistency and simplicity many of the definitions, reporting periods,

formats, and standards also could apply to FDA's expedited

postmarketing safety reporting requirements.

In this final rule, FDA is amending its regulations for expedited

safety reporting to implement certain definitions, reporting periods,

and formats recommended in the final ICH E2A guideline. FDA is

considering other recommendations in the final ICH E2A guideline that

were not included in the October 1994 proposal and plans to propose

additional amendments to its expedited safety reporting regulations

shortly (e.g., pre- and postmarketing reporting of adverse drug

reactions rather than adverse drug experiences, submission of expedited

safety reports to FDA from clinical investigations based on the opinion

of either the sponsor or investigator).

FDA is delaying finalization of the proposed amendments to the

periodic postmarketing safety reporting regulations (59 FR 54046). The

proposed amendments were based, for the most part, on recommendations

developed by the CIOMS Working Group II (Ref. 1). ICH also developed

recommendations, based on the CIOMS Working Group II proposals, for

periodic postmarketing safety reporting. In the Federal Register of May

19, 1997 (62 FR 27470), FDA published an ICH final guideline entitled

``Clinical Safety Data Management: Periodic Safety Update Reports for

Marketed Drugs'' (hereinafter referred to as the ICH E2C guideline).

FDA will finalize the proposed amendments to the periodic postmarketing

safety reporting regulations after consideration of the provisions of

the ICH E2C guideline.

In light of the comments the agency received, FDA has reconsidered

the proposed amendments to the requirements for clinical study design

and conduct and annual sponsor reporting under the IND (59 FR 54046).

In general, the comments opposed the proposed amendments because the

current IND regulations protect the safety of the public in all but the

most unusual cases. Based on these general comments and others specific

to each of the proposed amendments, the agency has decided to withdraw

the proposed amendments to the IND requirements for clinical study

design and conduct and annual sponsor reporting. The agency will,

instead, develop a guidance document providing recommendations on study

design and monitoring of investigational drugs used to treat serious

and potentially fatal illnesses, with particular attention to detection

of adverse events that are similar to those caused by the underlying

disease. In developing the draft guidance document, FDA will consider

comments submitted in response to the proposed amendments and will

provide opportunity for public input on the document prior to its

implementation. Thus, in this final rule, FDA is withdrawing the

proposed amendments to the IND regulations (part 312 (21 CFR part 312))

at Secs. 312.23, the second sentence of 312.32(c)(1)(i), 312.33,

312.37, 312.42, 312.44, 312.56, and 312.64 (59 FR 54046 at 54057 to

54059).

In the Federal Register of June 25, 1997 (62 FR 34166), FDA

published a final rule to amend its regulations on expedited reporting

of postmarketing adverse experiences to revoke the requirement for

increased frequency reports as expedited reports for human drug and

licensed biological products. Thus, in this final rule, FDA is

withdrawing the proposed amendments to the increased frequency

reporting requirements published in the October 1994 proposal.

II. Background

In the Federal Register of June 3, 1993 (58 FR 31596), FDA

announced the availability of a new form for reporting single cases of

adverse events and product problems with medications, devices, and

other FDA-regulated medical products (hereinafter referred to as the

June 1993 notice). This form is available in two versions: FDA Form

3500 is for use by health care professionals and consumers for

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voluntary reporting; FDA Form 3500A is for use by any person subject to

FDA's mandatory safety reporting regulations. Adverse events associated

with vaccines continue to be reported to FDA and the Centers for

Disease Control and Prevention using the Vaccine Adverse Event

Reporting System (VAERS) form.

Under the existing regulations, manufacturers, packers, and

distributors; applicants of approved new and abbreviated marketing

applications for drugs and antibiotics; and licensed manufacturers and

other manufacturers of biological products must submit expedited

reports of postmarketing adverse drug experiences under 21 CFR 310.305,

314.80, 314.98, and 600.80. Sponsors of IND's must also submit

expedited reports, under Sec. 312.32, for adverse experiences

associated with the use of an investigational human drug or biological

product. Currently, there is no standard form for these IND expedited

safety reports.

FDA Forms 3500 and 3500A are part of FDA's Medical Products

Reporting Program (MedWatch) and are designed to facilitate safety

reporting for most FDA-regulated human medical products by the entire

health care community, including manufacturers, distributors, user

facilities, and health care professionals. FDA issued the new forms to

simplify and consolidate safety reporting for human drug products,

biologics, and medical devices, as well as other FDA-regulated medical

products. The new forms eliminate redundant or nonessential elements

from past reporting forms and clarify those areas that have caused

confusion.

In developing FDA Forms 3500 and 3500A, and in developing the

revisions to the expedited safety reporting regulations that are the

subject of this final rule, the agency considered several ICH and CIOMS

recommendations. These organizations were formed to facilitate

international consideration of issues, particularly safety issues,

concerning the use of both foreign and domestic data in the development

and use of drugs and biological products. ICH has worked to promote the

harmonization of technical requirements for the registration of

pharmaceutical products among three regions: The European Union, Japan,

and the United States. In addition, several CIOMS working groups have

served to coordinate and standardize the international reporting of

suspected postmarketing adverse drug reactions by pharmaceutical

manufacturers to regulatory authorities. FDA believes the changes

recommended by CIOMS and ICH will result in more effective and

efficient safety reporting to regulatory authorities worldwide.

III. Description of the Final Rule

This final rule amends parts 20, 310, 312, 314, and 600 (21 CFR

parts 20, 310, 312, 314, and 600) to revise definitions, requirements,

and procedures for expedited pre- and postmarketing safety reporting.

This rulemaking finalizes many of the expedited safety reporting

provisions as proposed in the October 1994 proposal. In addition, this

final rule reflects amendments to the October 1994 proposal that were

made in response to comments (discussed in section IV of this

document), including comments recommending greater consistency with the

ICH E2A guideline and uniformity between pre- and postmarketing safety

reporting definitions. This final rule also incorporates minor

revisions for clarity and further consistency. The major provisions of

the final rule are summarized as follows:

1. FDA Forms 3500/3500A. As proposed, the final rule permits

sponsors to submit IND safety reports, under Sec. 312.32(c)(1)(i), on

FDA Form 3500A rather than in a narrative format, and replaces, at

Secs. 310.305 and 314.80, Form FDA-1639 with FDA Form 3500A for use in

postmarketing safety reporting for human drug products. The final rule

also replaces, at Sec. 20.112, Form FDA-1639 with FDA Form 3500 for

voluntary drug experience reporting by physicians and hospitals. The

final rule, like the proposed rule, instructs applicants,

manufacturers, packers, and distributors to obtain approval from FDA's

MedWatch office before using an alternative reporting format for

postmarketing safety reporting under Secs. 310.305(d)(3)(ii) and

314.80(f)(3)(ii). Pre- and postmarketing safety reporting of foreign

events may continue to be reported to FDA on the CIOMS I form (Ref. 2).

After consideration of the comments, the final rule, unlike the

proposed rule, permits use of the CIOMS I form for this purpose without

prior FDA approval.

2. Definitions. In response to comments, the proposed definition of

``serious'' at Secs. 310.305(b), 312.32(a), 314.80(a), and 600.80(a)

has been revised to make it consistent with the definition of

``serious'' in the final ICH E2A guideline and with the definition of

``serious'' used in FDA Form 3500A. To provide uniformity between the

pre- and postmarketing definitions of ``serious,'' the following

information has been removed from the current definition of ``serious

adverse experience'' at Sec. 312.32(a) and added as a reporting

requirement to the IND safety reporting regulations at

Sec. 312.32(c)(1)(i):

With respect to results obtained from tests in laboratory

animals, a serious adverse drug experience includes any experience

suggesting a significant risk for human subjects, including any

finding of mutagenicity, teratogenicity, or carcinogenicity.

This revision represents an organizational change that does not impose

a new burden because sponsors are already required to report such

information to FDA.

In response to comments, the final rule also amends the proposed

definitions of ``disability'' and ``life-threatening'' at

Secs. 310.305(b), 314.80(a), and 600.80(a) for consistency with the

final ICH E2A guideline and for clarity. In addition, the definition of

``disability'' has been added to the ``definitions'' section of the

premarketing safety reporting regulations at Sec. 312.32(a), and the

definition of ``life-threatening'' has been removed from the

``telephone safety report'' section of the premarketing safety

reporting regulations at Sec. 312.32(c)(2) and added to the

``definitions'' section of these regulations at Sec. 312.32(a). For

further clarity and consistency in reporting adverse drug experiences

that are life-threatening, FDA has decided to replace, at

Secs. 310.305(b), 312.32(a), 314.80(a), and 600.80(a), the word

``serious'' with ``severe'' so that the first sentence of the

definition of ``life-threatening'' includes the following: ``* * *,

i.e., [Life-threatening] does not include a reaction that, had it

occurred in a more severe form, might have caused death.'' As explained

in the final ICH E2A guideline, ``severe'' refers to the intensity

(severity) of a specific event (e.g., mild, moderate, or severe

myocardial infarction); the event itself may be of relatively minor

medical significance such as a severe headache. The term ``serious,''

however, is based on patient/event outcome or action criteria usually

associated with events that pose a threat to a patient's life or

functioning (e.g., an event that results in death or that is life-

threatening or requires inpatient hospitalization) (60 FR 11284 at

11285). FDA has also decided to remove the following sentence from this

definition: ``For example, drug-induced hepatitis that resolved without

evidence of hepatic failure would not be considered life-threatening

even though drug-induced hepatitis can be fatal.'' Use of hepatitis as

an example for life-threatening may be confusing because viral

transmission of certain types of hepatitis through blood products could

be life-

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threatening. To harmonize pre- and postmarketing safety reporting

definitions, FDA has decided to withdraw the examples listed in the

proposed postmarketing definition of ``life-threatening'' at

Secs. 310.305(b), 314.80(a), and 600.80(a). The agency has decided,

instead, to revise the guidances associated with this final rule to

include examples of life-threatening adverse drug experiences (CDER's

``Guideline for Postmarketing Reporting of Adverse Drug Experiences,''

March 1992 and CBER's ``Guideline for Adverse Experience Reporting for

Licensed Biological Products,'' October 1993).

In this final rule, FDA is incorporating minor changes to the

definition of ``unexpected'' adverse drug experience at

Secs. 310.305(b), 312.32(a), 314.80(a), and 600.80(a) to provide

uniformity between pre- and postmarketing safety reporting definitions

and consistency with the ICH E2A guideline.

The definition of ``unexpected'' adverse drug experience at

Secs. 310.305(b), 314.80(a), and 600.80(a) currently states:

* * * an adverse drug experience that is not listed in the

current labeling for the drug product and includes an event that may

be symptomatically and pathophysiologically related to an event

listed in the labeling, but differs from the event because of

greater severity or specificity. For example, under this definition,

hepatic necrosis would be unexpected (by virtue of greater severity)

if the labeling only referred to elevated hepatic enzymes or

hepatitis. Similarly, cerebral thromboembolism and cerebral

vasculitis would be unexpected (by virtue of greater specificity) if

the labeling only listed cerebral vascular accidents.

To clarify what must be reported to the agency as an ``unexpected

adverse drug experience,'' FDA is amending this definition by adding

the following sentence:

``Unexpected,'' as used in this definition, refers to an adverse

drug experience that has not been previously observed (i.e.,

included in the labeling) rather than from the perspective of such

experience not being anticipated from the pharmacological properties

of the pharmaceutical product.

This amendment is consistent with the discussion of ``expectedness of

an adverse drug reaction'' in the final ICH E2A guideline:

The purpose of expedited reporting is to make regulators,

investigators, and other appropriate people aware of new, important

information on serious reactions. Therefore, such reporting will

generally involve events previously unobserved or undocumented, and

a guideline is needed on how to define an event as ``unexpected'' or

``expected'' (expected/ unexpected from the perspective of

previously observed, not on the basis of what might be anticipated

from the pharmacological properties of a medicinal product).

The definition of ``unexpected adverse experience'' at

Sec. 312.32(a) currently states:

* * * any adverse experience that is not identified in nature,

severity, or frequency in the current investigator brochure; or, if

an investigator brochure is not required, that is not identified in

nature, severity, or freuquency [sic] in the risk information

described in the general investigational plan or elsewhere in the

current application, as amended.

For clarity and consistency, FDA is amending this definition to conform

with the definition of ``unexpected'' at Secs. 310.305(b), 314.80(a),

and 600.80(a) by removing the references to frequency, replacing the

word ``nature'' with the word ``specificity,'' adding examples of

unexpected adverse drug experiences, and making other minor revisions.

The revised definition at Sec. 312.32(a) states:

Unexpected adverse drug experience: Any adverse drug experience,

the specificity or severity of which is not consistent with the

current investigator brochure; or if an investigator brochure is not

required or available, the specificity or severity of which is not

consistent with the risk information described in the general

investigational plan or elsewhere in the current application, as

amended. For example, under this definition, hepatic necrosis would

be unexpected (by virtue of greater severity) if the investigator

brochure only referred to elevated hepatic enzymes or hepatitis.

Similarly, cerebral thromboembolism and cerebral vasculitis would be

unexpected (by virtue of greater specificity) if the investigator

brochure only listed cerebral vascular accidents. ``Unexpected,'' as

used in this definition, refers to an adverse drug experience that

has not been previously observed (e.g., included in the investigator

brochure) rather than from the perspective of such experience not

being anticipated from the pharmacological properties of the

pharmaceutical product.

3. IND Safety Reports. As proposed, the final rule revises the time

period for submitting written IND safety reports, under

Sec. 312.32(c)(1) and (d)(3), from 10 working days to 15 calendar days,

and revises the time period for submitting telephone IND safety

reports, under Sec. 312.32(c)(2), from 3 working days to 7 calendar

days. The final rule also permits telephone safety reports to be made

by facsimile transmission under Sec. 312.32(c)(2). The final rule, as

proposed with minor revisions for clarity, also states, at

Sec. 312.32(c)(1)(i), that FDA may require sponsors to submit

additional data.

In response to comments, FDA is making minor revisions to its IND

safety reporting regulations to provide greater consistency with the

final ICH E2A guideline. Currently, the requirement at Sec. 312.32(b)

states:

The sponsor shall promptly review all information relevant to

the safety of the drug obtained or otherwise received by the sponsor

from any source, foreign or domestic, including information derived

from clinical investigations, animal investigations, commercial

marketing experience, reports in the scientific literature, and

unpublished scientific papers.

To clarify the phrase ``any source,'' FDA is adding ``epidemiological

investigations'' and ``foreign regulatory authorities that have not

already been previously reported to the agency by the sponsor'' to the

list of examples in Sec. 312.32(b). This revision does not impose a new

burden because sponsors are already required to review all information

relevant to the safety of the drug obtained or otherwise received by

the sponsor from any source, foreign or domestic. The amendment

clarifies for sponsors the type of safety information that must be

examined for determination of whether information should be submitted

to the agency in IND safety reports. This revision is consistent with

the final ICH E2A guideline (60 FR 11284 at 11285 and 11286):

[Expedited reporting] applies to reports from spontaneous

sources and from any type of clinical or epidemiological

investigation, independent of design or purpose.

The agency does not expect sponsors to search adverse drug experience

data bases generated by regulatory authorities for safety information

or to submit to FDA adverse drug experience reports submitted to them

by FDA.

FDA is also amending its IND safety reporting regulations at

Sec. 312.32(c)(1)(i), as noted above, by adding, with minor revisions,

language that is being moved from the current definition of ``serious

adverse experience'' at Sec. 312.32(a):

any finding from tests in laboratory animals that suggests a

significant risk for human subjects including reports of

mutagenicity, teratogenicity, or carcinogenicity.

This revision represents an organizational change that does not impose

any new burden because sponsors are currently required to report such

information to FDA. For clarity and consistency, FDA is amending

Sec. 312.32(c)(1)(i) to state that reports from animal studies and

epidemiological studies must be submitted in a narrative format rather

than on FDA Form 3500A because FDA Form 3500A has been designed for

reporting of adverse experience information from an individual patient.

4. Postmarketing 15-day Alert and Followup Reports. As proposed,

the final rule revises, at Secs. 310.305(c), 314.80(c), and 600.80(c),

the time period for submitting postmarketing Alert reports from 15

working days to 15 calendar days. For clarity, the final rule is being

amended, at Sec. 310.305(c)(1)(i),

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to state that the 15 calendar day timeframe for reporting adverse drug

experiences on marketed prescription drugs for human use without

approved new drug applications (NDA's) begins upon initial receipt of

the information by the person whose name appears on the label. In

addition, the final rule at Secs. 310.305(c)(2), 314.80(c)(1)(ii), and

600.80(c)(1)(ii), as proposed, advises any person subject to the

reporting requirements under Secs. 310.305(c), 314.80(c), and

600.80(c), who has been unable to obtain additional information for

adverse drug experiences that are the subject of postmarketing 15-day

Alert reports, to maintain records of their unsuccessful attempts to

seek additional information. For clarity, the final rule is being

amended, at Sec. 310.305(c)(2), to state that 15-day Alert reports and

followups to them must be submitted under separate cover.

The final rule specifies, like the proposed rule, at

Secs. 310.305(c)(6), 314.80(b), and 600.80(b), that no one subject to

this rule is required to resubmit to the agency reports of adverse drug

experiences that the agency has forwarded to them. For clarity, the

final rule is being amended, at Secs. 310.305(c)(6), 314.80(b), and

600.80(b), to emphasize that followup reports must be submitted for

reports received from the agency. The final rule also requires, at

Secs. 310.305(a), 314.80(b), and 600.80(b), any person subject to the

reporting requirements under Secs. 310.305(c), 314.80(c), and 600.80(c)

to develop written procedures for the postmarketing surveillance,

receipt, evaluation, and reporting of adverse drug experiences to FDA.

In response to comments, the final rule permits persons subject to the

reporting requirements under Secs. 310.305(c), 314.80(c), and 600.80(c)

to submit reports of serious adverse drug experiences to a

manufacturer, applicant, or licensed manufacturer of a final biological

product instead of FDA in 5 calendar days, instead of 3 calendar days

as proposed.

In this final rule, FDA is also amending the postmarketing

expedited reporting regulations, at Secs. 314.80(c)(1)(i) and

600.80(c)(1)(i), by replacing, in the first sentence, the phrase

``regardless of source'' with the phrase ``whether foreign or

domestic.'' This amendment is consistent with Secs. 314.80(b) and

600.80(b) which describe adverse drug experience information that must

be reviewed by applicants and licensed manufacturers:

Each applicant (Any person having a product license) * * * shall

promptly review all adverse drug experience information (pertaining

to its product) obtained or otherwise received by the applicant

(licensed manufacturer) from any source, foreign or domestic,

including * * *.

FDA is making this revision to clarify that 15-day Alert reports are to

be submitted for appropriate foreign as well as domestic adverse drug

experiences.

5. Implementation Schedule. The effective date for this final rule

has been extended to 180 days after its publication in the Federal

Register to allow sufficient time for the agency to comply with the

provisions of the Paperwork Reduction Act of 1995. Any person subject

to FDA's mandatory safety reporting requirements may comply with the

provisions of this final rule prior to its effective date.

6. Guidances. In the Federal Register of February 27, 1997 (62 FR

8961), FDA published a notice of a guidance document entitled ``Good

Guidance Practices (GGP's),'' in which FDA announced that notices of

draft and final guidances will be provided both in the Federal Register

and on the FDA World Wide Web (WWW) home page (http://www.fda.gov) (62

FR 8961 at 8965). In this final rule, FDA is amending its postmarketing

safety reporting regulations at Secs. 314.80(j) and 600.80(j) to remove

reference to guidelines prepared by the agency for submission of

reports of adverse drug experiences and suggested followup

investigation of these reports. FDA is also withdrawing its proposed

amendments of October 27, 1994, regarding the availability of adverse

experience reporting guidelines under Secs. 310.305(g), 314.80(j), and

600.80(j). FDA is making these amendments because the guidance document

of February 27, 1997, describes processes for timely notification of

availability of draft and final guidance documents and it is no longer

necessary for the agency to include reference to these documents in its

postmarketing safety reporting regulations.

At the present time, FDA is in the process of revising guidances

pertaining to this final rule (CDER's ``Guideline for Postmarketing

Reporting of Adverse Drug Experiences,'' March 1992 and CBER's

``Guideline for Adverse Experience Reporting for Licensed Biological

Products,'' October 1993) to provide persons with the agency's current

thinking on reporting of postmarketing adverse drug experiences. The

agency will provide notice of availability of any draft or final

guidance document pertaining to these regulations in the Federal

Register and on the FDA WWW home page.

IV. Comments on the Proposed Rule

FDA received 57 comments on the proposed rule from representatives

of pharmaceutical companies, health care professional and

pharmaceutical associations, academic and government institutions, and

individuals. The comments addressed all aspects of the October 1994

proposal, including those areas that are not being finalized in this

final rule. In general, the comments endorsed FDA's efforts in the

proposal to support global harmonization through the adoption of

certain ICH and CIOMS recommendations. However, many comments described

areas where the proposed regulations did not conform to the

international guidelines, and recommended that the proposal be revised

to be more consistent. The agency also received comments recommending

uniformity between its pre- and postmarketing safety reporting

definitions. In response to these comments, FDA, as described in

section III of this document, is amending its regulations to implement

additional provisions recommended in the final ICH E2A guideline and to

provide uniformity in its safety reporting definitions.

A discussion of the comments pertaining to this final rule and the

agency's responses follows.

A. Definition of Disability

FDA proposed to define ``disability,'' in Secs. 310.305(b),

314.80(a), and 600.80(a), as ``a substantial disruption of a person's

ability to carry out normal life functions.''

1. Eight comments requested clarification of this definition. One

comment asked whether it included missing work because of an adverse

experience, quitting a job, an inability to get out of bed, or a

decrease in earning capacity. Another comment asked if it included

nausea, vomiting, and diarrhea that would keep a person home from work.

One questioned whether the proposed definition included events such as

migraine headaches, severe influenza, or accidental trauma (e.g.,

sprained ankle). Another comment contended that if the proposed

definition is intended to mean the substantial disruption of normal

life functions, then such a condition would require hospitalization or

the in-house use of life-support equipment.

FDA proposed to include the definition of ``disability'' in the

regulations to enable reporters to determine when a ``serious'' adverse

drug experience occurs. The extent of a disability required for a

serious adverse drug experience is described in the

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definition of ``serious'' by the phrase ``* * * results in persistent

or significant disability/incapacity * * *.'' Thus, only a persistent

or significant or incapacitating disability is intended. The type of

disability that would constitute a serious adverse drug experience is

also described in the final ICH E2A guideline, which states that a

serious adverse drug experience is based on events that pose a threat

to a patient's life or functioning and not on events of relatively

minor medical significance (60 FR 11284 at 11285). Thus, disability is

not intended to include experiences of relatively minor medical

significance such as headache, nausea, vomiting, diarrhea, influenza,

and accidental trauma (e.g., sprained ankle).

For clarity, FDA has revised the proposed definition of

``disability'' by substituting the words ``to conduct'' for the words

``to carry out.''

To assure a consistent interpretation of serious adverse drug

experience in premarketing and postmarketing safety reporting, FDA has

decided to revise the ``definitions'' section of the IND safety reports

regulation, at Sec. 312.32(a), by adding the definition of

``disability'' that is used in the postmarketing safety reporting

regulations at Secs. 310.305(b), 314.80(a), and 600.80(a).

B. Definition of Life-Threatening

FDA proposed to define ``life-threatening,'' in Secs. 310.305(b),

314.80(a), and 600.80(a), as follows:

[T]hat the patient was, in the view of the initial reporter, at

immediate risk of death from the adverse experience as it occurred.

It does not include an adverse experience that, had it occurred in a

more serious form, might have caused death. For example, product-

induced hepatitis that resolved without evidence of hepatic failure

would not be considered life-threatening even though hepatitis of a

more severe nature can be fatal. Similarly, an allergic reaction

resulting in angioedema of the face would not be life-threatening,

even though angioedema of the larynx, allergic bronchospasm, or

anaphylaxis can be fatal.

2. Five comments opposed the use of the phrase ``in the view of the

initial reporter.'' The comments stated that the initial reporter could

be a lay person whose judgment of what constitutes an ``immediate risk

of death'' may be contrary to an evaluation by a medically

knowledgeable source. Several comments suggested alternative language

for the definition to minimize inaccurate reporting of events. One

comment requested deletion of the word ``initial.'' Another suggested

changing the phrase ``initial reporter'' to ``a health care

professional directly associated with the care of the patient,'' while

a third recommended changing the word ``reporter'' to ``health care

provider who reports the adverse experience.''

FDA declines to amend the proposed definition of ``life-

threatening'' by deleting or revising the phrase ``in the view of the

initial reporter.'' As explained in the June 1993 notice (58 FR 31596

and 31604), FDA encourages health care professionals and consumers to

report adverse drug experiences to manufacturers. FDA Form 3500A

includes a section for identifying the ``initial reporter'' and for

indicating the reporter's occupation and whether the person is a health

care professional. Thus, the manufacturer and FDA will know whether the

adverse drug experience report came from a lay person or a health care

professional and can take that information into account when evaluating

the report.

Current IND safety reporting regulations for telephone reports

define a ``life-threatening'' experience at Sec. 312.32(c)(2), as:

* * * that the patient was, in the view of the investigator, at

immediate (emphasis added) risk of death from the reaction as it

occurred, i.e., it does not include a reaction that, had it occurred

in a more serious form, might have caused death. For example, drug-

induced hepatitis that resolved without evidence of hepatic failure

would not be considered life-threatening even though drug-induced

hepatitis can be fatal.

FDA has decided, on its own initiative, to remove the definition of

``life-threatening'' from the telephone safety reports section, at

Sec. 312.32(c)(2), and add it to the general ``definitions'' section of

Sec. 312.32, at Sec. 312.32(a). This action will clarify that reporting

of life-threatening events apply to both written and telephone IND

safety reports. FDA has also replaced ``serious'' with ``severe'' in

the definition of ``life-threatening'' to make it consistent with the

final ICH E2A guideline. FDA has also decided, on its own initiative,

to add the words ``or subject'' after ``patient'' in this definition to

clarify that IND safety reports apply to healthy subjects as well as

patients. FDA has also removed the last sentence in the definition of

``life-threatening'' under Sec. 312.32 (and the last two sentences in

the proposed postmarketing definition of ``life-threatening'' under

Secs. 310.305(b), 314.80(a), and 600.80(a)), as noted in section III of

this document, to minimize confusion. The revised definition of ``life-

threatening adverse drug experience'' in the IND safety reporting

regulations at Sec. 312.32(a) reads as follows:

Any adverse drug experience that places the patient or subject,

in the view of the investigator, at immediate risk of death from the

reaction as it occurred, i.e., it does not include a reaction that,

had it occurred in a more severe form, might have caused death.

C. Definition of Serious

FDA proposed to revise the definition of ``serious,'' in

Secs. 310.305(b), 312.32(a), 314.80(a), and 600.80(a), to read as

follows:

Serious means an adverse drug experience occurring at any dose

that is fatal or life-threatening, results in persistent or

significant disability/incapacity, requires or prolongs inpatient

hospitalization, necessitates medical or surgical intervention to

preclude permanent impairment of a body function or permanent damage

to a body structure, or is a congenital anomaly.

3. Twenty-five comments opposed all or parts of the phrase

``necessitates medical or surgical intervention to preclude permanent

impairment of a body function or permanent damage to a body

structure.'' Nine comments stated that this phrase makes the U.S.

definition of ``serious'' inconsistent with harmonized safety reporting

standards such as the ICH E2A and E6 guidelines and with the CIOMS II

report. One comment said that although the phrase was included to

provide a consistent definition of what constitutes a serious adverse

event for all FDA-regulated products, it causes inconsistency between

United States and international reporting requirements. Another comment

said that the difference in definitions between the United States and

the international community will cause confusion and additional expense

for manufacturers who are complying with the reporting requirements of

several countries. One comment stated that if the definition is

finalized as proposed, preparation and submission of a single

postmarketing periodic report worldwide will not be possible. Another

comment said that a definition as important as ``serious'' should be

internationally consistent in order to be easy to learn, quote, and

recognize in global clinical development and medical safety. One

comment noted that it would be especially difficult to implement the

proposed criterion of ``medical/surgical intervention'' during the

course of an ongoing clinical study.

Ten comments recommended deletion of the phrase. Eleven comments

requested clarification of the phrase because it is too vague and

misinterpretation would result in overreporting or underreporting of

adverse events. Another comment suggested that the phrase be reworded

as an ``unusual and potentially serious experience that necessitates

any medical or surgical intervention.'' One comment recommended

adopting the approach in the final ICH E2A guideline of including

``medical and surgical intervention''

[[Page 52243]]

within the area of ``other important medical events.'' The comment

indicated that the guideline leaves the determination of whether or not

such an event is serious to medical and scientific judgment.

As explained in the June 1993 notice (58 FR 31596), FDA Forms 3500

and 3500A are designed to encourage and facilitate the reporting of

adverse events and product problems for most FDA-regulated human

medical products by the entire health care community, including

manufacturers, distributors, user facilities, and health care

professionals. This includes reporting of adverse events and product

problems with human drug products, biologics, and medical devices, as

well as other FDA-regulated medical products.

FDA adopted several recommendations from ICH and CIOMS in

developing the definitions used in the forms and in the proposed

amendments to the safety reporting regulations for human drug and

biological products. The agency believes that certain standardized

definitions, procedures, and formats proposed by ICH and CIOMS will

result in more effective and efficient safety reporting to regulatory

authorities worldwide. The agency proposed to amend the definition of

``serious'' to have a consistent definition of what constitutes a

serious adverse drug experience for all FDA-regulated products and to

avoid confusion about what events should be reported to regulatory

authorities worldwide.

FDA agrees with the comments that the differences between the

definition of serious, as proposed, and the definition recommended in

the final ICH E2A guideline and in the CIOMS II report may create

confusion about what events to report as serious. Therefore, the agency

has revised the definition of ``serious'' to be consistent with the

final ICH E2A guideline (60 FR 11284 at 11285) and FDA Forms 3500 and

3500A. The revised definition states:

Any adverse drug experience occurring at any dose that results

in any of the following outcomes: Death, a life-threatening adverse

drug experience, inpatient hospitalization or prolongation of

existing hospitalization, a persistent or significant disability/

incapacity, or a congenital anomaly/birth defect. Important medical

events that may not result in death, be life-threatening, or require

hospitalization may be considered a serious adverse drug experience

when, based upon appropriate medical judgment, they may jeopardize

the patient or subject and may require medical or surgical

intervention to prevent one of the outcomes listed in this

definition. Examples of such medical events include allergic

bronchospasm requiring intensive treatment in an emergency room or

at home, blood dyscrasias or convulsions that do not result in

inpatient hospitalization, or the development of drug dependency or

drug abuse.

The term ``serious'' is defined similarly in the final ICH E2A

guideline (60 FR 11284 at 11285) as:

A serious adverse event (experience) or reaction is any untoward

medical occurrence that at any dose:

Results in death,

Is life-threatening,

* * *

Requires inpatient hospitalization or prolongation of

existing hospitalization,

Results in persistent or significant disability/

incapacity, or

Is a congenital anomaly/birth defect.

Medical and scientific judgment should be exercised in deciding

whether expedited reporting is appropriate in other situations, such

as important medical events that may not be immediately life-

threatening or result in death or hospitalization but may jeopardize

the patient or may require intervention to prevent one of the other

outcomes listed in the definition above. These should also usually

be considered serious.

Examples of such events are intensive treatment in an emergency

room or at home for allergic bronchospasm; blood dyscrasias or

convulsions that do not result in hospitalization; or development of

drug dependency or drug abuse.

The revised definition of ``serious'' is also consistent with

section B.2 of FDA Forms 3500 and 3500A, which directs persons

completing the forms to indicate which of the following outcomes is

attributed to the adverse event: ``death, life-threatening,

hospitalization--initial or prolonged, disability, congenital anomaly,

required intervention to prevent permanent impairment/damage, or

other.''

In order to make the definition of ``serious'' in the premarketing

safety reporting regulations at Sec. 312.32(a) uniform with the revised

definition of ``serious'' in the postmarketing safety reporting

regulations at Secs. 310.305(b), 314.80(a), and 600.80(a), FDA is

removing the following sentence from the current definition of

``serious'' at Sec. 312.32(a), and adding it, with minor revisions, to

the IND written safety reporting requirements under

Sec. 312.32(c)(1)(i):

With respect to results obtained from tests in laboratory

animals, a serious adverse drug experience includes any experience

suggesting a significant risk for human subjects, including any

finding of mutagenicity, teratogenicity, or carcinogenicity.

4. One comment requested adding the phrase ``including overdose and

underdose'' after the phrase ``occurring at any dose'' in the

definition of ``serious'' in order to eliminate confusion. Otherwise,

the comment claimed, adverse outcomes associated with underdoses may be

interpreted as a lack of therapeutic effect rather than an adverse drug

experience.

FDA declines to amend the definition of ``serious'' to include the

phrase ``including overdose or underdose.'' Use of the phrase

``occurring at any dose'' in the revised definition of ``serious'' will

ensure that serious adverse drug experiences occurring at any dose,

including an overdose or an underdose, must be reported.

5. Five comments asked for examples of what is considered serious.

One comment asked whether intravenous (IV) treatment for dehydration

without hospital admission or the use of IV antibiotics, blood

products, or dialysis would be considered serious.

FDA advises that use of IV fluids, antibiotics, or blood products,

or dialysis may or may not be serious, depending on why they are being

used. A decision using medical judgment should be made based on the

circumstances surrounding each case. As stated in the revised

definition of ``serious'', other examples include allergic bronchospasm

requiring intensive treatment in an emergency room or at home, blood

dyscrasias or convulsions that do not result in inpatient

hospitalization, and the development of drug dependency or drug abuse.

6. Five comments requested clarification of the following sentence

in the preamble to the proposed rule under the discussion of the

definition of ``serious'': ``FDA notes that a serious adverse

experience would not include the discontinuation of therapy, changes in

dosage, or routine treatment with a prescription medication'' (59 FR

54046 at 54048). One comment stated that the sentence should also be

included in the codified definition of ``serious'' because the

qualifiers are extremely important in limiting the range of events not

considered serious. Three comments asked for clarification of the

phrase ``routine treatment with a prescription medication.'' One of

these comments noted that treatment with any new medication could

potentially be considered a medical intervention and therefore could be

classified as serious. Another comment requested clarification of the

phrase ``would not include discontinuation of therapy'' because it

implies that discontinuation of therapy in response to a clinically

significant rise in serum aminotransferases or serum creatinine would

not be considered intervention and therefore would not be serious.

FDA declines to revise the definition of ``serious'' to include

examples of events not considered serious. FDA

[[Page 52244]]

clarifies that discontinuation of therapy, changes in dosage, and

routine treatment with a prescription medication are not in themselves

serious events but may occur as the result of a serious event.

7. Several comments discussed the use of the words ``persistent''

and ``permanent'' in the definition of ``serious''. One comment

requested rewording the phrase ``persistent or significant disability''

to read ``permanent or persistent disability.'' Another comment

suggested that the term ``permanent disability'' in the current

definition of ``serious'' should be retained because replacing

``permanent'' with ``persistent'' does not further define disability.

The comment noted that a condition like influenza might be

significantly incapacitating but may not qualify as a serious event.

Three comments recommended changing the word ``permanent'' to

``persistent'' in the phrase ``preclude permanent impairment of a body

function or permanent damage to a body system.'' One comment requested

that the phrase ``persistent or significant disability'' be used

instead of ``permanent or significant disability'' in the definition of

``serious'' in proposed Sec. 312.32(a) in order to be consistent with

proposed Secs. 310.305(b), 314.80(a), and 600.80(a).

As explained in the preamble to the October 1994 proposal (59 FR

54046 at 54047), FDA is revising the phrase ``is permanently

disabling'' to ``results in a persistent or significant disability/

incapacity'' in order to clarify that a disability need not be

permanent to be considered a serious adverse drug experience. Thus, FDA

declines to substitute the phrase ``permanent or persistent

disability'' for ``persistent or significant disability'' or retain

``permanent disability.'' In addition, FDA has corrected the

typographical error in proposed Sec. 312.32(a) by revising ``permanent

or significant disability'' to read ``persistent or significant

disability.''

8. One comment requested the addition of the word ``immediately''

before ``life-threatening'' in the definition of ``serious''. The

comment stated that although ``immediate'' is stated in the definition

of ``life-threatening'', it is not indicated on FDA Form 3500 or 3500A.

As a result, reporters may interpret ``life-threatening'' to mean

``potentially'' life-threatening rather than ``immediately'' life-

threatening.

FDA declines to revise the definition of ``serious'' to add the

word ``immediately'' before ``life-threatening'' because the phrase

``at immediate risk of death'' is part of the definition of ``life-

threatening adverse drug experience.'' Although the word

``immediately'' does not appear before the word ``life-threatening'' on

FDA Forms 3500 and 3500A, the MedWatch ``FDA Desk Guide for Adverse

Event and Product Problem Reporting'' explains that a life-threatening

adverse event would be immediate.

D. IND Safety Reports--Written

FDA proposed to revise the requirements for submitting written IND

safety reports, under Sec. 312.32(c)(1) and (d)(3), by altering the

time period for submitting such reports from 10 working days to 15

calendar days. In addition, FDA proposed to permit sponsors to submit

written IND safety reports to the agency by using FDA Form 3500A or in

a narrative format. If a sponsor chose to use FDA Form 3500A,

additional narrative data might be required if the agency determined

that insufficient data were submitted on the form.

9. Three comments expressed support for the 15 calendar days

timeframe. One comment commended FDA for requiring the same timeframe

for both pre- and postmarketing expedited reporting. Two other comments

requested that the timeframe be increased to 20 calendar days, while

another comment recommended any period longer than 15 calendar days.

The comments stated that 15 calendar days would not provide enough time

for the submission of reports or for contacting non-U.S. physicians.

One comment noted that a longer timeframe would permit better review

and reporting of serious adverse experiences.

As explained in the October 1994 proposal (59 FR 54046 at 54051),

FDA believes that the extended timeframe is sufficient for sponsors to

gather appropriate data to help initially interpret the reports before

submitting them to FDA. This timeframe is also consistent with the 15

calendar day period in the final ICH E2A guideline (60 FR 11284 at

11286).

10. Although one comment expressed support for use of FDA Form

3500A for written IND safety reports because it would provide

consistency with the form for postmarketing reports, another comment

requested that the form not be required for these reports because of

limited space for describing narrative information.

FDA notes that it is not ``requiring'' use of FDA Form 3500A for

written IND safety reports. Reporters may use the form or,

alternatively, may submit these reports in a narrative format. In

addition, as explained in the June 1993 notice announcing the

availability of the form, reporters may use additional blank sheets of

paper, referenced to the section of the form being described, to

complete any narrative sections of the form.

In the June 1993 notice (58 FR 31596 at 31598), FDA also stated

that companies may use the CIOMS I form for reporting foreign events

after obtaining FDA approval. FDA has decided, based on comments to its

postmarketing safety reporting regulations (see section IV.F of this

document), to amend Sec. 312.32(c)(1) to permit use of the CIOMS I form

for reporting foreign events without prior approval. FDA has decided to

take this action to expedite reporting of foreign events and harmonize

its pre- and postmarketing safety reporting regulations.

11. One comment requested clarification about what sponsors must

include in a written IND safety report. The comment also requested

guidance on how often a report should be submitted and whether one is

required every time a new case is reported.

Under Sec. 312.32(b), as amended in this final rule, FDA requires

that the sponsor must promptly review all information relevant to the

safety of the drug obtained or otherwise received by the sponsor from

any source, foreign or domestic, including information derived from any

clinical or epidemiological investigations, animal investigations,

commercial marketing experience, reports in the scientific literature,

and unpublished scientific papers, as well as reports from foreign

regulatory authorities that have not already been previously reported

to the agency by the sponsor. This requirement qualifies for sponsors

the type of safety information that must be examined for determination

of whether the information should be included in IND safety reports.

As noted earlier, FDA is amending its IND safety reports

regulations, at Sec. 312.32, by moving, for organizational purposes,

certain information from the current definition of ``serious adverse

experience,'' at Sec. 312.32(a), to the written IND safety reports

section, at Sec. 312.32(c)(1)(i). Under Sec. 312.32(c)(1)(i), as

revised in this final rule, sponsors must submit written IND safety

reports to FDA and all participating investigators within 15 calendar

days after the sponsor's receipt of information on any adverse

experience associated with the use of the drug that is both serious and

unexpected; or any finding from tests in laboratory animals that

suggests a significant risk for human subjects including reports of

[[Page 52245]]

mutagenicity, teratogenicity, or carcinogenicity.

FDA advises sponsors, as described in greater detail in the final

ICH E2A guideline (60 FR 11284 at 11285 and 11286), to submit in

written IND safety reports as much information as possible on a case.

In some instances, information for final description and evaluation of

a case report may not be available within 15 calendar days.

Nevertheless, initial reports should be submitted within this timeframe

when the following minimum criteria are met: An identifiable patient; a

suspected medicinal product; an identifiable reporter; and an adverse

event or outcome that can be identified as serious and unexpected, and

for which, in clinical investigation cases, there is a reasonable

suspected causal relationship between the investigational product and

the adverse event (i.e., the causal relationship cannot be ruled out).

For reportable events that occur during a ``blinded'' clinical

investigation, sponsors should only break the blind for the subject in

question. Sponsors should consult with the FDA review division

responsible for their IND in situations in which the sponsor believes

that breaking the blind would compromise their study (e.g., when a

fatal or other serious outcome is the primary efficacy endpoint in a

clinical investigation). Reportable events attributed to a specific

dosage form, formulation, or route of administration should be cross-

referenced to other IND's for the drug. Reportable events associated

with a particular population or for a specific indication should also

be cross-referenced to other IND's for the drug.

FDA expects sponsors to submit written IND safety reports every

time the sponsor receives or otherwise obtains information about a

serious and unexpected adverse experience associated with the use of

the drug until the current investigator brochure or, if the

investigator brochure is not required, until the risk information

described in the general investigational plan or elsewhere in the

current application is amended. This is consistent with the final ICH

E2A guideline (60 FR 11284 at 11285): ``Until source documents are

amended, expedited reporting is required for additional occurrences of

the reaction.''

12. One comment asked when a written safety report would be due if

the 15th day occurs on a weekend or holiday.

FDA advises that if the 15th calendar day occurs on a weekend or

U.S. Federal holiday, the written safety report would be due the 1st

working day after the weekend or U.S. Federal holiday.

E. IND Safety Reports--Telephone

FDA proposed to revise the requirements for submitting IND safety

reports by telephone, under Sec. 312.32(c)(2), by altering the time

period for submitting such reports from 3 working days to 7 calendar

days. FDA also proposed to allow telephone safety reports to be made by

facsimile transmission.

13. Two comments expressed support for the 7 calendar day

timeframe. Other comments requested longer timeframes because 7 days

does not provide a significant difference from the current time period,

and because additional time is needed for contacting non-U.S.

physicians. One comment asked for a timeframe of 10 calendar days, and

another requested any period longer than 7 calendar days.

FDA declines to lengthen the timeframe for IND safety reports by

telephone or facsimile transmission. FDA believes it is important that

unexpected fatal or life-threatening experiences associated with the

use of the drug be reported to the agency as expeditiously as possible.

A 7 calendar day timeframe is reasonable for these types of reports.

This timeframe is also consistent with recommendations in the final ICH

E2A guideline (60 FR 11284 at 11286).

14. Three comments supported FDA's proposal to accept telephone

safety reports by ``facsimile transmission.'' The comments also

requested that FDA permit transmission of these reports by other

electronic mechanisms such as Internet or electronic mail systems.

In the Federal Register of March 20, 1997 (62 FR 13430), FDA

published a final rule that permits the agency to accept electronic

records, electronic signatures, and handwritten signatures executed to

electronic records as generally equivalent to paper records and

handwritten signatures executed on paper. FDA stated in this final rule

that it will announce in the Federal Register when it is prepared to

accept certain submissions in electronic format only. At the present

time, FDA is not prepared to accept electronic submission of IND safety

reports, but is developing a system to accept such submissions in the

future.

15. One comment requested that FDA restore the phrase ``in the

clinical studies conducted under the IND'' to the language in

Sec. 312.32(c)(2) for telephone safety reports of any unexpected fatal

or life-threatening experience associated with the use of the drug. The

phrase did not appear in the October 27, 1994, proposed revisions to

this section.

It is FDA's intention not to restrict telephone safety reports of

any unexpected fatal or life-threatening experience associated with the

use of the drug to clinical studies conducted under the IND. As stated

under Sec. 312.32(b), as revised in this final rule, the sponsor shall

promptly review all information relevant to the safety of the drug

obtained or otherwise received by the sponsor from any source, foreign

or domestic, including information derived from any clinical or

epidemiological investigations, animal investigations, commercial

marketing experience, reports in the scientific literature, and

unpublished scientific papers, as well as reports from foreign

regulatory authorities that have not already been previously reported

to the agency by the sponsor. Thus, the sponsor is responsible for

notifying FDA by telephone or facsimile transmission, as soon as

possible, but in no event later than 7 calendar days, of any unexpected

fatal or life-threatening experience associated with the use of the

drug from any source. This requirement is consistent with the final ICH

E2A guideline (60 FR 11284 at 11286):

Information obtained by a sponsor or manufacturer on serious,

unexpected reports from any source should be submitted on an

expedited basis to appropriate regulatory authorities if the minimum

criteria for expedited reporting can be met.

F. Postmarketing Alert and Followup Reports

FDA proposed to amend Secs. 310.305(c), 314.80(c), and 600.80(c) by

reorganizing, renumbering, and retitling the paragraphs in these

sections to distinguish between postmarketing 15-day Alert reports and

followups to these reports. FDA also proposed to distinguish between

the reporting intervals for postmarketing 15-day Alert reports and the

intervals proposed for postmarketing periodic reports. In addition, FDA

proposed to amend Secs. 310.305(c)(1) through (c)(4), 314.80(c)(1)(i)

through (c)(1)(iv), and 600.80(c)(1)(i) through (c)(1)(iv), to alter

the time period for submitting postmarketing 15-day Alert reports and

followup reports from 15 working days to 15 calendar days.

16. Twelve comments stated that the 15 calendar day timeframe is

overly burdensome. One comment noted that the change from 15 working

days to 15 calendar days would result in approximately one-third (6

days) less time for preparation of reports for submission to FDA.

Another comment indicated that, although the proposed

[[Page 52246]]

timeframe is in accord with the final ICH E2A guideline, it would cause

significant disruption in reporting schedules and would probably result

in incomplete reports. Another comment stated that the revised

timeframe would not provide international companies with sufficient

time to receive and translate foreign reports. One comment said that

the proposed timeframe incorrectly assumes that reporters are

universally accessible anywhere in the world. Six comments offered

suggestions for alternative timeframes. Three comments recommended 20

calendar days, one recommended 21 calendar days, and another

recommended 22 calendar days. Two of the comments encouraged retention

of the 15 working day timeframe currently required by FDA.

FDA declines to revise its proposed 15 calendar day timeframe for

postmarketing Alert reports. The agency proposed to revise the

reporting period from 15 working days to 15 calendar days to provide

consistency in pre- and postmarketing safety reporting timeframes for

products and to decrease misunderstandings with reporting requirements

by stating all timeframes in terms of calendar days. This timeframe is

consistent with the 15 calendar day reporting timeframe in the final

ICH E2A guideline (60 FR 11284 at 11286) and consistent with the change

in timeframe set forth in this final rule at Sec. 312.32(c)(1) and

(d)(3) for IND safety reporting of serious and unexpected experiences.

This timeframe is sufficient for persons subject to the postmarketing

safety reporting requirements to gather appropriate data and initially

interpret reports before submitting them to the agency.

In this final rule, FDA is amending its postmarketing expedited

safety reporting regulations, at Sec. 310.305(c)(1)(i), by adding the

following phrase to the end of the first sentence: ``by the person

whose name appears on the label.'' FDA is making this revision to

clarify when the 15 calendar day timeframe begins for marketed

prescription drugs for human use without approved new drug

applications. This change is consistent with current language under

Secs. 314.80(c)(1)(i) and 600.80(c)(1)(i) for marketed prescription

drugs for human use with approved NDA's and for licensed biological

products. Under Sec. 314.80(c)(1)(i), 15-day Alert reports must be

submitted no later than 15 calendar days of initial receipt of

information by the applicant. Under Sec. 600.80(c)(1)(i), such reports

must be submitted within the same timeframe based on initial receipt of

information by the licensed manufacturer.

17. Two comments requested that they be permitted to use the CIOMS

I form for reporting foreign events as an alternative to FDA Form 3500A

without obtaining prior FDA approval. In addition, the comments

preferred using the CIOMS I form instead of FDA Form 3500A for all

adverse drug experience reporting worldwide.

In the June 1993 notice, the agency stated that reporters may use

the CIOMS I form for reporting foreign events with prior FDA approval.

FDA has considered the comments and has decided to revise

Secs. 310.305, 314.80, and 600.80 to permit the use of the CIOMS I form

for reports of foreign events without first obtaining prior FDA

approval. FDA is taking this action to expedite the reporting of

foreign events.

FDA will continue to require use of FDA Form 3500A for reports of

domestic events. FDA Form 3500A is more comprehensive than the CIOMS I

form and includes elements recommended by the final ICH E2A guideline

that are not part of the CIOMS I form (60 FR 11284 at 11287). For

example, the following items are included in FDA Form 3500A and

requested in the ICH E2A guideline but are not included in the CIOMS I

form: Body weight, the terms ``congenital anomaly'' and ``other''

(identifiers of adverse event outcomes), the lot number and dosage

strength of suspected medicinal product(s), details on the event

reporter, and the regulatory code number (e.g., IND/NDA number).

18. One comment requested that FDA accept postmarketing 15-day

Alert and followup reports through electronic transmission.

As explained above, FDA has published a final rule to permit the

agency to accept electronic records, electronic signatures, and

handwritten signatures executed to electronic records as generally

equivalent to paper records and handwritten signatures executed on

paper (62 FR 13430). At the present time, FDA is not prepared to accept

electronic submission of 15-day Alert reports, but is developing a

system to accept such submissions in the future.

G. Written Procedures for Monitoring Adverse Drug Experiences

FDA proposed to amend Secs. 310.305(a), 314.80(b), and 600.80(b) to

require that any person subject to the reporting requirements under

Secs. 310.305(c), 314.80(c), and 600.80(c) develop written procedures

for the surveillance, receipt, evaluation, and reporting of adverse

drug experiences to FDA.

19. One comment opposed this amendment. The comment stated that

these written procedures are customary and usual in the industry and,

if made part of a regulation, could be potentially burdensome to

manufacturers and would permit FDA to dictate internal procedures.

FDA declines to withdraw this proposed amendment. As explained in

the preamble to the October 1994 proposal (59 FR 54046 at 54053), this

requirement would improve postmarketing surveillance by applicants and

manufacturers and would enhance an applicant's and a manufacturer's

ability to evaluate and report adverse drug experiences to the agency.

In addition, because such written procedures are usual and customary,

FDA believes that this provision would not impose a new burden on

applicants and manufacturers.

20. One comment stated that it is inappropriate to require packers

and distributors to develop written procedures for the surveillance,

receipt, evaluation, and reporting of adverse drug experiences to FDA

if they elect to submit these reports to the manufacturer.

Under Secs. 310.305(c)(1)(i), 314.80(c)(1)(iv), and

600.80(c)(1)(iv), packers and distributors are subject to the reporting

requirements if their name appears on the label of a marketed

prescription drug product or licensed biological product. A packer or

distributor who elects to submit adverse drug experience reports to an

applicant, manufacturer, or licensed manufacturer of a final biological

product under Secs. 310.305(c)(4), 314.80(c)(1)(iv), and

600.80(c)(1)(iv) must include information about making such an election

in their written procedures, as well as procedures for recordkeeping

required to be maintained under these regulations. For the reasons

explained in the October 1994 proposal (59 FR 54046 at 54053), it is

appropriate to require that these packers and distributors develop

written procedures to ensure that they comply with these regulations.

21. One comment requested that FDA specify the minimum requirements

for a company's written procedures for reporting adverse drug

experiences.

FDA declines to specify minimum requirements for written reporting

procedures. As explained in the October 1994 proposal (59 FR 54046 at

54053), written procedures for handling adverse drug experiences are

customary and usual in the pharmaceutical industry. In

[[Page 52247]]

addition, such procedures have been required for many years by FDA's

current good manufacturing practice (CGMP) regulations for finished

pharmaceuticals (21 CFR 211.198).

H. Submission of Postmarketing 15-day Alert Reports by Persons Other

Than Applicants, Manufacturers, and Licensed Manufacturers of a Final

Biological Product

Current postmarketing safety reporting regulations, at

Sec. 310.305(c)(5), permit packers and distributors to submit reports

of serious adverse drug experiences to the manufacturer instead of FDA.

Under Sec. 314.80(c)(1)(iii), manufacturers, packers, and distributors

may submit these reports to the applicant. Under

Sec. 600.80(c)(1)(iii), packers, distributors, and manufacturers other

than licensed manufacturers of the final biological product may submit

these reports to the licensed manufacturer of the final product.

Currently, these reports must be submitted within 3 working days of

their receipt. FDA proposed to revise this timeframe to 3 calendar

days. The manufacturer, applicant, and licensed manufacturer of the

final biological product would then comply with the requirements

described in this section by submitting the report to FDA as soon as

possible, but in no case later than 15 calendar days of initial receipt

of the information.

22. Five comments opposed changing 3 working days to 3 calendar

days because the new timeframe is overly burdensome, especially if the

period includes holidays or weekends. One comment said that

manufacturers, packers, distributors, and shared and joint

manufacturers would probably submit these reports directly to FDA in

order to utilize the longer timeframe. This would result in duplicative

reporting to the agency. The comments suggested alternative timeframes.

Three comments recommended 5 calendar days, one recommended 7 calendar

days, and another recommended that the current requirement of 3 working

days be maintained.

FDA agrees with the comments and has revised the final rule at

Secs. 310.305(c)(4), 314.80(c)(1)(iv), and 600.80(c)(1)(iv) to permit

manufacturers, packers, and distributors, as well as manufacturers,

packers, distributors, shared manufacturers, joint manufacturers, and

any other participant involved in divided manufacturing of a biological

product, to submit reports of serious adverse drug experiences to the

manufacturer, applicant, or licensed manufacturer of the final

biological product in 5 calendar days.

23. One comment requested that the regulations state that

manufacturers should not submit to FDA reports it receives from a

reporter, if the reporter has submitted the report to FDA.

FDA declines to revise its regulations to exempt manufacturers from

submitting safety reports to FDA that it receives from a voluntary

reporter who has submitted the report to FDA, regardless of whether the

reporter is a physician, pharmacist, or other health care professional,

or a consumer. The agency requires manufacturers to submit such reports

to FDA to ensure that the agency receives all safety reports. However,

as now stated at Secs. 310.305(c)(6), 314.80(b), and 600.80(b), no one

subject to the postmarketing safety reporting regulations at

Secs. 310.305(c), 314.80(c), and 600.80(c) is required to resubmit to

the agency FDA Form 3500A reports that the agency has forwarded to

them.

I. General Comments

24. One comment asked whether the Federal Register notices

announcing the availability of FDA Forms 3500 and 3500A had been

withdrawn, revised, or replaced by the October 1994 proposal. The

comment indicated that the effective date for FDA Form 3500A was put on

hold pending revision of the regulations for safety reporting.

The June 1993 notice (58 FR 31596), announced the availability of

FDA Forms 3500 and 3500A. The use of FDA Form 3500 was effective

immediately, while the use of FDA Form 3500A was scheduled to be

effective on November 30, 1993. Manufacturers, medical device

distributors, and user facilities were encouraged to begin using the

form immediately. In the Federal Register of December 3, 1993 (58 FR

64001), FDA extended the effective date for use of FDA Form 3500A until

FDA issues a final rule amending the regulations to require the use of

the form. This final rule makes the requirement for use of FDA Form

3500A effective on April 6, 1998.

25. Four comments requested that FDA publish guidelines to explain

the proposed regulations. Two of the comments asked whether a draft

guideline could be published with an opportunity for public comment

before publication of the final rule.

In the Federal Register of March 1, 1995 (60 FR 11284), FDA

published the final ICH E2A guideline ``Clinical Safety Data

Management: Definitions and Standards for Expedited Reporting.''

Concerning the opportunity for comment on guidances, on July 9, 1993

(58 FR 37408), FDA published the draft ICH E2A guideline for public

comment.

As described under section III of this document, FDA is in the

process of revising guidances pertaining to this final rule and will

provide opportunity for public comment and notice of availability of

any draft or final guidance documents in the Federal Register and on

FDA's WWW home page, under the GGP's (62 FR 8961).

26. One comment asked whether information on the United Kingdom

Medicines Control Agency's Medical Dictionary for Drug Regulatory

Affairs would be incorporated into the final rule.

This terminology was not discussed in the proposed rule and will

not be incorporated into this final rule. At the September 1994 CIOMS

meeting, it was agreed that this terminology would be the basis for the

development of a new international medical terminology to support

classification of terms relating to all aspects of drug regulation. In

July 1997, ICH developed a final consensus guideline on this topic (ICH

M1). At this time, FDA is considering the ICH M1 document.

V. Environmental Impact

The agency has determined under 21 CFR 25.30(h) that this action is

of a type that does not individually or cumulatively have a significant

effect on the human environment. Therefore, neither an environmental

assessment nor an environmental impact statement is required.

VI. Analysis of Impacts

The agency has considered the potential economic impact of this

final rule under Executive Order 12866, the Regulatory Flexibility Act

(5 U.S.C. 601-612), as amended by Subtitle D of the Small Business

Regulatory Fairness Act of 1996 (Pub. L. 104-721), and the Unfunded

Mandates Reform Act of 1995 (Pub. L. 104-4). Executive Order 12866

directs agencies to assess all costs and benefits of available

regulatory alternatives and, when regulation is necessary, to select

regulatory approaches that maximize net benefits (including potential

economic, environmental, public health and safety, and other

advantages; distributive impacts; and equity). The agency believes that

this final rule is consistent with the regulatory philosophy and

principles identified in the Executive Order. In addition, the final

rule is not a significant regulatory action as defined by the Executive

Order and so is not subject to review under the Executive Order.

[[Page 52248]]

The Regulatory Flexibility Act requires agencies to analyze

regulatory options that would minimize any significant impact of a rule

on small entities. The agency certifies that the final rule will not

have a significant economic impact on a substantial number of small

entities. According to the Small Business Administration, manufacturers

of medicinals and botanicals or pharmaceutical preparations with 750 or

less employees, and manufacturers of diagnostic substances or

biological products with 500 or less employees are considered a small

business. As discussed in section VII of this document, modifications

and additions to the recordkeeping requirements will not result in a

change in industry's current recordkeeping burden hours. Therefore,

under the Regulatory Flexibility Act, no further analysis is needed.

The final rule will also not impose annual expenditures of $100

million or more on either State, local, and tribal governments in

aggregate, or on the private sector. Therefore, a written statement and

economic analysis is not required as prescribed under section 202(a) of

the Unfunded Mandates Reform Act of 1995.

VII. Paperwork Reduction Act of 1995

This final rule contains information collection provisions that are

subject to review by the Office of Management and Budget (OMB) under

the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). The title,

description, and respondent description of the information collection

provisions are shown below.

Title: Expedited Safety Reporting Requirements for Human Drug and

Biological Products; Final Rule.

Description: FDA is amending its current expedited safety reporting

requirements to replace current Form FDA-1639 with new FDA Form 3500A;

to revise certain definitions, reporting periods and formats; to

require applicants, manufacturers, packers, and distributors, as well

as licensed manufacturers and other manufacturers of biological

products to develop written procedures for postmarketing safety

monitoring and reporting of adverse drug experiences to FDA; and to

make other revisions to provide uniformity to the expedited pre- and

postmarketing safety reporting regulations. These changes will simplify

and facilitate expedited safety reporting and enhance agencywide

consistency in the collection of postmarketing safety data.

Respondent Description: Businesses and other for-profit

organizations, State or local governments, Federal agencies, and

nonprofit institutions.

FDA believes that this final rule will not result in any increase

in paperwork burden as compared to current expedited safety reporting

requirements. The new requirement under Secs. 310.305(a), 314.80(b),

and 600.80(b), that persons subject to the postmarketing safety

reporting requirements develop written procedures for the surveillance,

receipt, evaluation, and reporting to FDA of adverse drug experiences,

does not impose a new burden because it codifies a practice that is

already customary and usual in the pharmaceutical industry for handling

adverse drug experiences.

The new recordkeeping requirements under Secs. 310.305(c)(2),

314.80(c)(1)(ii), and 600.80(c)(1)(ii), that persons subject to the

postmarketing safety reporting requirements maintain records of

unsuccessful attempts to obtain additional followup information on 15-

day Alert reports, do not result in a change in the burden. Current

regulations provide for submission of a followup report describing

steps taken to seek additional information and the reasons why it could

not be obtained; FDA estimates that the effort needed to file this

existing information will be, at worst, no more than the effort that

would have been required to submit it to FDA.

The new language in Sec. 312.32(b) explicitly requiring that

sponsors review: (1) Information derived from any epidemiological

investigations, or (2) reports from foreign regulatory authorities that

have not already been previously reported to the agency by the sponsor

does not impose a new burden because this amendment is only a

clarification. Sponsors are already required to review all information

relevant to the safety of the drug obtained or otherwise received by

the sponsor from any source, foreign or domestic.

Although the October 1994 proposal provided a 90-day comment period

under the Paperwork Reduction Act of 1980, FDA is providing an

additional opportunity for public comment under the Paperwork Reduction

Act of 1995, which was enacted after the expiration of the comment

period and applies to this final rule. Therefore, FDA now invites

comments on: (1) Whether the proposed collection of information is

necessary for the proper performance of FDA's functions, including

whether the information will have practical utility; (2) the accuracy

of FDA's estimate of the burden of the proposed collection of

information, including the validity of the methodology and assumptions

used; (3) ways to enhance the quality, utility, and clarity of the

information to be collected; and (4) ways to minimize the burden of the

collection of information on respondents, including through the use of

automated collection techniques, when appropriate, and other forms of

information technology. Individuals and organizations may submit

comments on the information collection provisions of this final rule by

December 8, 1997. Comments should be directed to the Dockets Management

Branch (address above).

At the close of the 60-day comment period, FDA will review the

comments received, revise the information collection provisions as

necessary, and submit these provisions to OMB for review and approval.

FDA will publish a notice in the Federal Register when the information

collection provisions are submitted to OMB, and an opportunity for

public comment to OMB will be provided at that time. Prior to the

effective date of this final rule, FDA will publish a notice in the

Federal Register of OMB's decision to approve, modify, or disapprove

the information collection provisions. An agency may not conduct or

sponsor, and a person is not required to respond to, a collection of

information unless it displays a currently valid OMB control number.

VIII. References

The following references have been placed on display at the Dockets

Management Branch (address above) and may be seen by interested persons

between 9 a.m. and 4 p.m., Monday through Friday.

1. International Reporting of Periodic Drug-Safety Update

Summaries, Final Report of CIOMS Working Group II, 1992.

2. International Reporting of Adverse Drug Reactions, Final

Report of CIOMS Working Group I, 1990.

List of Subjects

21 CFR Part 20

Confidential business information, Courts, Freedom of information,

Government employees.

21 CFR Part 310

Administrative practice and procedure, Drugs, Labeling, Medical

devices, Reporting and recordkeeping requirements.

21 CFR Part 312

Drugs, Exports, Imports, Investigations, Labeling, Medical

research, Reporting and recordkeeping requirements, Safety.

[[Page 52249]]

21 CFR Part 314

Administrative practice and procedure, Confidential business

information, Drugs, Reporting and recordkeeping requirements.

21 CFR Part 600

Biologics, Reporting and recordkeeping requirements.

Therefore, under the Federal Food, Drug, and Cosmetic Act, the

Public Health Service Act, and under authority delegated to the

Commissioner of Food and Drugs, 21 CFR parts 20, 310, 312, 314, and 600

are amended as follows:

PART 20--PUBLIC INFORMATION

1. The authority citation for 21 CFR part 20 continues to read as

follows:

Authority: Secs. 201-903 of the Federal Food, Drug, and Cosmetic

Act (21 U.S.C. 321-393); secs. 301, 302, 303, 307, 310, 311, 351,

352, 354-360F, 361, 362, 1701-1706, 2101 of the Public Health

Service Act (42 U.S.C. 241, 242, 242a, 242l, 242n, 243, 262, 263,

263b-263n, 264, 265, 300u-300u-5, 300aa-1); 5 U.S.C. 552; 18 U.S.C.

1905; 19 U.S.C. 2531-2582; 21 U.S.C. 1401-1403.

Sec. 20.112 [Amended]

2. Section 20.112 Voluntary drug experience reports submitted by

physicians and hospitals is amended in paragraph (a) by removing the

words ``Form FDA-1639'' and adding in their place ``FDA Form 3500''.

PART 310--NEW DRUGS

3. The authority citation for 21 CFR part 310 continues to read as

follows:

Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 512-

516, 520, 601(a), 701, 704, 705, 721 of the Federal Food, Drug, and

Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357,

360b-360f, 360j, 361(a), 371, 374, 375, 379e); secs. 215, 301,

302(a), 351, 354-360F of the Public Health Service Act (42 U.S.C.

216, 241, 242(a), 262, 263b-263n).

4. Section 310.305 is amended by adding a new sentence at the end

of paragraph (a); by revising paragraphs (b), (c), (d)(1), (d)(3)(ii),

and (d)(4); by removing in paragraph (d)(2), the introductory text of

paragraph (d)(3), and paragraph (d)(3)(i) the words ``Form FDA-1639''

or ``FDA-1639'' and adding in their place ``FDA Form 3500A'' to read as

follows:

Sec. 310.305 Records and reports concerning adverse drug experiences

on marketed prescription drugs for human use without approved new drug

applications.

(a) * * * Any person subject to the reporting requirements of

paragraph (c) of this section shall also develop written procedures for

the surveillance, receipt, evaluation, and reporting of postmarketing

adverse drug experiences to FDA.

(b) Definitions. The following definitions of terms apply to this

section:

Adverse drug experience. Any adverse event associated with the use

of a drug in humans, whether or not considered drug related, including

the following: An adverse event occurring in the course of the use of a

drug product in professional practice; an adverse event occurring from

drug overdose whether accidental or intentional; an adverse event

occurring from drug abuse; an adverse event occurring from drug

withdrawal; and any failure of expected pharmacological action.

Disability. A substantial disruption of a person's ability to

conduct normal life functions.

Life-threatening adverse drug experience. Any adverse drug

experience that places the patient, in the view of the initial

reporter, at immediate risk of death from the adverse drug experience

as it occurred, i.e., it does not include an adverse drug experience

that, had it occurred in a more severe form, might have caused death.

Serious adverse drug experience. Any adverse drug experience

occurring at any dose that results in any of the following outcomes:

Death, a life-threatening adverse drug experience, inpatient

hospitalization or prolongation of existing hospitalization, a

persistent or significant disability/ incapacity, or a congenital

anomaly/birth defect. Important medical events that may not result in

death, be life-threatening, or require hospitalization may be

considered a serious adverse drug experience when, based upon

appropriate medical judgment, they may jeopardize the patient or

subject and may require medical or surgical intervention to prevent one

of the outcomes listed in this definition. Examples of such medical

events include allergic bronchospasm requiring intensive treatment in

an emergency room or at home, blood dyscrasias or convulsions that do

not result in inpatient hospitalization, or the development of drug

dependency or drug abuse.

Unexpected adverse drug experience. Any adverse drug experience

that is not listed in the current labeling for the drug product. This

includes events that may be symptomatically and pathophysiologically

related to an event listed in the labeling, but differ from the event

because of greater severity or specificity. For example, under this

definition, hepatic necrosis would be unexpected (by virtue of greater

severity) if the labeling only referred to elevated hepatic enzymes or

hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis

would be unexpected (by virtue of greater specificity) if the labeling

only listed cerebral vascular accidents. ``Unexpected,'' as used in

this definition, refers to an adverse drug experience that has not been

previously observed (i.e., included in the labeling) rather than from

the perspective of such experience not being anticipated from the

pharmacological properties of the pharmaceutical product.

(c) Reporting requirements. Each person identified in paragraph

(c)(1)(i) of this section shall report to FDA adverse drug experience

information as described in this section and shall submit one copy of

each report to the Division of Pharmacovigilance and Epidemiology (HFD-

730), Center for Drug Evaluation and Research, Food and Drug

Administration, 5600 Fishers Lane, Rockville, MD 20857.

(1) Postmarketing 15-day ``Alert reports''. (i) Any person whose

name appears on the label of a marketed prescription drug product as

its manufacturer, packer, or distributor shall report to FDA each

adverse drug experience received or otherwise obtained that is both

serious and unexpected as soon as possible, but in no case later than

15 calendar days of initial receipt of the information by the person

whose name appears on the label. Each report shall be accompanied by a

copy of the current labeling for the drug product.

(ii) A person identified in paragraph (c)(1)(i) of this section is

not required to submit a 15-day ``Alert report'' for an adverse drug

experience obtained from a postmarketing study (whether or not

conducted under an investigational new drug application) unless the

applicant concludes that there is a reasonable possibility that the

drug caused the adverse experience.

(2) Postmarketing 15-day ``Alert reports''--followup. Each person

identified in paragraph (c)(1)(i) of this section shall promptly

investigate all serious, unexpected adverse drug experiences that are

the subject of these postmarketing 15-day Alert reports and shall

submit followup reports within 15 calendar days of receipt of new

information or as requested by FDA. If additional information is not

obtainable, records should be maintained of the unsuccessful steps

taken to seek additional information. Postmarketing 15-day Alert

reports and followups to them shall be submitted under separate cover.

[[Page 52250]]

(3) Submission of reports. To avoid unnecessary duplication in the

submission of, and followup to, reports required in this section, a

packer's or distributor's obligations may be met by submission of all

reports of serious adverse drug experiences to the manufacturer of the

drug product. If a packer or distributor elects to submit these adverse

drug experience reports to the manufacturer rather than to FDA, it

shall submit each report to the manufacturer within 5 calendar days of

its receipt by the packer or distributor, and the manufacturer shall

then comply with the requirements of this section even if its name does

not appear on the label of the drug product. Under this circumstance,

the packer or distributor shall maintain a record of this action which

shall include:

(i) A copy of each adverse drug experience report;

(ii) The date the report was received by the packer or distributor;

(iii) The date the report was submitted to the manufacturer; and

(iv) The name and address of the manufacturer.

(4) Each report submitted to FDA under this section shall bear

prominent identification as to its contents, i.e., ``15-day Alert

report,'' or ``15-day Alert report-followup.''

(5) A person identified in paragraph (c)(1)(i) of this section is

not required to resubmit to FDA adverse drug experience reports

forwarded to that person by FDA; however, the person must submit all

followup information on such reports to FDA.

(d) * * * (1) Except as provided in paragraph (d)(3) of this

section, each person identified in paragraph (c)(1)(i) of this section

shall submit each report of a serious and unexpected adverse drug

experience on an FDA Form 3500A (foreign events may be submitted either

on an FDA Form 3500A or, if preferred, on a CIOMS I form).

* * * * *

(3) * * *

(ii) The format is agreed to in advance by MedWatch: The FDA

Medical Products Reporting Program.

(4) Ten copies or fewer of FDA Form 3500A and/or a copy of the

instructions for completing the form may be obtained from the Division

of Pharmacovigilance and Epidemiology (HFD-730), Center for Drug

Evaluation and Research, Food and Drug Administration, 5600 Fishers

Lane, Rockville, MD 20857. More than 10 copies of the form may be

obtained by writing to the Consolidated Forms and Publications

Distribution Center, Washington Commerce Center, 3222 Hubbard Rd.,

Landover, MD 20785.

* * * * *

PART 312--INVESTIGATIONAL NEW DRUG APPLICATION

5. The authority citation for 21 CFR part 312 continues to read as

follows:

Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701 of

the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351,

352, 353, 355, 356, 357, 371); sec. 351 of the Public Health Service

Act (42 U.S.C. 262).

6. Section 312.32 is amended by revising paragraphs (a), (b),

(c)(1)(i), (c)(2), and (d)(3); by adding in the second sentence of

paragraph (c)(3) the words ``new drug review'' before the phrase

``division in the Center for Drug Evaluation and Research'' and the

words ``the director of the product review division in'' before the

phrase ``the Center for Biologics Evaluation and Research''; and by

removing in paragraph (e) the word ``section'' and replacing it with

the word ``part'', to read as follows:

Sec. 312.32 IND safety reports.

(a) Definitions. The following definitions of terms apply to this

section:

Associated with the use of the drug. There is a reasonable

possibility that the experience may have been caused by the drug.

Disability. A substantial disruption of a person's ability to

conduct normal life functions.

Life-threatening adverse drug experience. Any adverse drug

experience that places the patient or subject, in the view of the

investigator, at immediate risk of death from the reaction as it

occurred, i.e., it does not include a reaction that, had it occurred in

a more severe form, might have caused death.

Serious adverse drug experience: Any adverse drug experience

occurring at any dose that results in any of the following outcomes:

Death, a life-threatening adverse drug experience, inpatient

hospitalization or prolongation of existing hospitalization, a

persistent or significant disability/ incapacity, or a congenital

anomaly/birth defect. Important medical events that may not result in

death, be life-threatening, or require hospitalization may be

considered a serious adverse drug experience when, based upon

appropriate medical judgment, they may jeopardize the patient or

subject and may require medical or surgical intervention to prevent one

of the outcomes listed in this definition. Examples of such medical

events include allergic bronchospasm requiring intensive treatment in

an emergency room or at home, blood dyscrasias or convulsions that do

not result in inpatient hospitalization, or the development of drug

dependency or drug abuse.

Unexpected adverse drug experience: Any adverse drug experience,

the specificity or severity of which is not consistent with the current

investigator brochure; or, if an investigator brochure is not required

or available, the specificity or severity of which is not consistent

with the risk information described in the general investigational plan

or elsewhere in the current application, as amended. For example, under

this definition, hepatic necrosis would be unexpected (by virtue of

greater severity) if the investigator brochure only referred to

elevated hepatic enzymes or hepatitis. Similarly, cerebral

thromboembolism and cerebral vasculitis would be unexpected (by virtue

of greater specificity) if the investigator brochure only listed

cerebral vascular accidents. ``Unexpected,'' as used in this

definition, refers to an adverse drug experience that has not been

previously observed (e.g., included in the investigator brochure)

rather than from the perspective of such experience not being

anticipated from the pharmacological properties of the pharmaceutical

product.

(b) Review of safety information. The sponsor shall promptly review

all information relevant to the safety of the drug obtained or

otherwise received by the sponsor from any source, foreign or domestic,

including information derived from any clinical or epidemiological

investigations, animal investigations, commercial marketing experience,

reports in the scientific literature, and unpublished scientific

papers, as well as reports from foreign regulatory authorities that

have not already been previously reported to the agency by the sponsor.

(c) IND safety reports. (1) Written reports--(i) The sponsor shall

notify FDA and all participating investigators in a written IND safety

report of:

(A) Any adverse experience associated with the use of the drug that

is both serious and unexpected; or

(B) Any finding from tests in laboratory animals that suggests a

significant risk for human subjects including reports of mutagenicity,

teratogenicity, or carcinogenicity. Each notification shall be made as

soon as possible and in no event later than 15 calendar days after the

sponsor's initial receipt of the information. Each written notification

may be submitted on FDA

[[Page 52251]]

Form 3500A or in a narrative format (foreign events may be submitted

either on an FDA Form 3500A or, if preferred, on a CIOMS I form;

reports from animal or epidemiological studies shall be submitted in a

narrative format) and shall bear prominent identification of its

contents, i.e., ``IND Safety Report.'' Each written notification to FDA

shall be transmitted to the FDA new drug review division in the Center

for Drug Evaluation and Research or the product review division in the

Center for Biologics Evaluation and Research that has responsibility

for review of the IND. If FDA determines that additional data are

needed, the agency may require further data to be submitted.

* * * * *

(2) Telephone and facsimile transmission safety reports. The

sponsor shall also notify FDA by telephone or by facsimile transmission

of any unexpected fatal or life-threatening experience associated with

the use of the drug as soon as possible but in no event later than 7

calendar days after the sponsor's initial receipt of the information.

Each telephone call or facsimile transmission to FDA shall be

transmitted to the FDA new drug review division in the Center for Drug

Evaluation and Research or the product review division in the Center

for Biologics Evaluation and Research that has responsibility for

review of the IND.

* * * * *

(d) * * *

(3) If the results of a sponsor's investigation show that an

adverse drug experience not initially determined to be reportable under

paragraph (c) of this section is so reportable, the sponsor shall

report such experience in a written safety report as soon as possible,

but in no event later than 15 calendar days after the determination is

made.

* * * * *

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG OR AN

ANTIBIOTIC DRUG

7. The authority citation for 21 CFR part 314 continues to read as

follows:

Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701,

704, 721 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321,

331, 351, 352, 353, 355, 356, 357, 371, 374, 379e).

8. Section 314.80 is amended by revising paragraphs (a), (c)(1),

(f)(1), (f)(3)(ii), and (f)(4) and the introductory text of paragraph

(c); by adding two new sentences at the end of paragraph (b); by

removing in paragraph (d)(2) the words ``Epidemiology and

Surveillance'' and adding in their place the words ``Pharmacovigilance

and Epidemiology''; by removing in paragraphs (c)(2)(ii)(b), (d)(2),

(f)(2), and (f)(3) and in the heading for paragraph (f) the words

``Form FDA-1639'' or ``FDA-1639'' and adding in their place the words

``FDA Form 3500A''; and by removing paragraph (j) and redesignating

paragraphs (k) and (l) as paragraphs (j) and (k), respectively, to read

as follows:

Sec. 314.80 Postmarketing reporting of adverse drug experiences.

(a) Definitions. The following definitions of terms apply to this

section:

Adverse drug experience. Any adverse event associated with the use

of a drug in humans, whether or not considered drug related, including

the following: An adverse event occurring in the course of the use of a

drug product in professional practice; an adverse event occurring from

drug overdose whether accidental or intentional; an adverse event

occurring from drug abuse; an adverse event occurring from drug

withdrawal; and any failure of expected pharmacological action.

Disability. A substantial disruption of a person's ability to

conduct normal life functions.

Life-threatening adverse drug experience. Any adverse drug

experience that places the patient, in the view of the initial

reporter, at immediate risk of death from the adverse drug experience

as it occurred, i.e., it does not include an adverse drug experience

that, had it occurred in a more severe form, might have caused death.

Serious adverse drug experience. Any adverse drug experience

occurring at any dose that results in any of the following outcomes:

Death, a life-threatening adverse drug experience, inpatient

hospitalization or prolongation of existing hospitalization, a

persistent or significant disability/ incapacity, or a congenital

anomaly/birth defect. Important medical events that may not result in

death, be life-threatening, or require hospitalization may be

considered a serious adverse drug experience when, based upon

appropriate medical judgment, they may jeopardize the patient or

subject and may require medical or surgical intervention to prevent one

of the outcomes listed in this definition. Examples of such medical

events include allergic bronchospasm requiring intensive treatment in

an emergency room or at home, blood dyscrasias or convulsions that do

not result in inpatient hospitalization, or the development of drug

dependency or drug abuse.

Unexpected adverse drug experience. Any adverse drug experience

that is not listed in the current labeling for the drug product. This

includes events that may be symptomatically and pathophysiologically

related to an event listed in the labeling, but differ from the event

because of greater severity or specificity. For example, under this

definition, hepatic necrosis would be unexpected (by virtue of greater

severity) if the labeling only referred to elevated hepatic enzymes or

hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis

would be unexpected (by virtue of greater specificity) if the labeling

only listed cerebral vascular accidents. ``Unexpected,'' as used in

this definition, refers to an adverse drug experience that has not been

previously observed (i.e., included in the labeling) rather than from

the perspective of such experience not being anticipated from the

pharmacological properties of the pharmaceutical product.

(b) * * * Applicants are not required to resubmit to FDA adverse

drug experience reports forwarded to the applicant by FDA; however,

applicants must submit all followup information on such reports to FDA.

Any person subject to the reporting requirements under paragraph (c) of

this section shall also develop written procedures for the

surveillance, receipt, evaluation, and reporting of postmarketing

adverse drug experiences to FDA.

(c) Reporting requirements. The applicant shall report to FDA

adverse drug experience information, as described in this section. The

applicant shall submit two copies of each report described in this

section to the Central Document Room, 12229 Wilkins Ave., Rockville, MD

20852. FDA may waive the requirement for the second copy in appropriate

instances.

(1)(i) Postmarketing 15-day ``Alert reports''. The applicant shall

report each adverse drug experience that is both serious and

unexpected, whether foreign or domestic, as soon as possible but in no

case later than 15 calendar days of initial receipt of the information

by the applicant.

(ii) Postmarketing 15-day ``Alert reports''--followup. The

applicant shall promptly investigate all adverse drug experiences that

are the subject of these postmarketing 15-day Alert reports and shall

submit followup reports within 15 calendar days of receipt of new

information or as requested by FDA. If additional information is not

obtainable, records should be maintained of the unsuccessful steps

taken to seek additional information. Postmarketing 15-day Alert

reports and followups to

[[Page 52252]]

them shall be submitted under separate cover.

(iii) Submission of reports. The requirements of paragraphs

(c)(1)(i) and (c)(1)(ii) of this section, concerning the submission of

postmarketing 15-day Alert reports, shall also apply to any person

other than the applicant (nonapplicant) whose name appears on the label

of an approved drug product as a manufacturer, packer, or distributor.

To avoid unnecessary duplication in the submission to FDA of reports

required by paragraphs (c)(1)(i) and (c)(1)(ii) of this section,

obligations of a nonapplicant may be met by submission of all reports

of serious adverse drug experiences to the applicant. If a nonapplicant

elects to submit adverse drug experience reports to the applicant

rather than to FDA, the nonapplicant shall submit each report to the

applicant within 5 calendar days of receipt of the report by the

nonapplicant, and the applicant shall then comply with the requirements

of this section. Under this circumstance, the nonapplicant shall

maintain a record of this action which shall include:

(A) A copy of each adverse drug experience report;

(B) The date the report was received by the nonapplicant;

(C) The date the report was submitted to the applicant; and

(D) The name and address of the applicant.

(iv) Report identification. Each report submitted under this

paragraph shall bear prominent identification as to its contents, i.e.,

``15-day Alert report,'' or ``15-day Alert report-followup.''

* * * * *

(f) * * * (1) Except as provided in paragraph (f)(3) of this

section, the applicant shall complete FDA Form 3500A for each report of

an adverse drug experience (foreign events may be submitted either on

an FDA Form 3500A or, if preferred, on a CIOMS I form).

* * * * *

(3) * * * (ii) the format is agreed to in advance by MedWatch: The

FDA Medical Products Reporting Program.

(4) Ten copies or fewer of FDA Form 3500A and/or a copy of the

instructions for completing the form may be obtained from the Division

of Pharmacovigilance and Epidemiology (HFD-730), Center for Drug

Evaluation and Research, Food and Drug Administration, 5600 Fishers

Lane, Rockville, MD 20857. More than 10 copies of the form may be

obtained by writing to the Consolidated Forms and Publications

Distribution Center, Washington Commerce Center, 3222 Hubbard Rd.,

Landover, MD 20785.

* * * * *

PART 600--BIOLOGICAL PRODUCTS: GENERAL

9. The authority citation for 21 CFR part 600 continues to read as

follows:

Authority: Secs. 201, 501, 502, 503, 505, 510, 519, 701, 704 of

the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352,

353, 355, 360, 360i, 371, 374); secs. 215, 351, 352, 353, 361, 2125

of the Public Health Service Act (42 U.S.C. 216, 262, 263, 263a,

264, 300aa-25).

10. Section 600.80 is amended by revising paragraphs (a), (c)(1),

(f)(1), and the first sentence of paragraph (g); by adding two new

sentences at the end of paragraph (b); and by removing paragraph (j)

and redesignating paragraphs (k), (l), and (m) as paragraphs (j), (k),

and (l), respectively, to read as follows:

Sec. 600.80 Postmarketing reporting of adverse experiences.

(a) Definitions. The following definitions of terms apply to this

section:

Adverse experience. Any adverse event associated with the use of a

biological product in humans, whether or not considered product

related, including the following: An adverse event occurring in the

course of the use of a biological product in professional practice; an

adverse event occurring from overdose of the product whether accidental

or intentional; an adverse event occurring from abuse of the product;

an adverse event occurring from withdrawal of the product; and any

failure of expected pharmacological action.

Blood Component. As defined in Sec. 606.3(c) of this chapter.

Disability. A substantial disruption of a person's ability to

conduct normal life functions.

Life-threatening adverse experience. Any adverse experience that

places the patient, in the view of the initial reporter, at immediate

risk of death from the adverse experience as it occurred, i.e., it does

not include an adverse experience that, had it occurred in a more

severe form, might have caused death.

Serious adverse experience. Any adverse experience occurring at any

dose that results in any of the following outcomes: Death, a life-

threatening adverse experience, inpatient hospitalization or

prolongation of existing hospitalization, a persistent or significant

disability/incapacity, or a congenital anomaly/birth defect. Important

medical events that may not result in death, be life-threatening, or

require hospitalization may be considered a serious adverse experience

when, based upon appropriate medical judgment, they may jeopardize the

patient or subject and may require medical or surgical intervention to

prevent one of the outcomes listed in this definition. Examples of such

medical events include allergic bronchospasm requiring intensive

treatment in an emergency room or at home, blood dyscrasias or

convulsions that do not result in inpatient hospitalization, or the

development of drug dependency or drug abuse.

Unexpected adverse experience: Any adverse experience that is not

listed in the current labeling for the biological product. This

includes events that may be symptomatically and pathophysiologically

related to an event listed in the labeling, but differ from the event

because of greater severity or specificity. For example, under this

definition, hepatic necrosis would be unexpected (by virtue of greater

severity) if the labeling only referred to elevated hepatic enzymes or

hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis

would be unexpected (by virtue of greater specificity) if the labeling

only listed cerebral vascular accidents. ``Unexpected,'' as used in

this definition, refers to an adverse experience that has not been

previously observed (i.e., included in the labeling) rather than from

the perspective of such experience not being anticipated from the

pharmacological properties of the pharmaceutical product.

(b) * * * Licensed manufacturers are not required to resubmit to

FDA adverse product experience reports forwarded to the licensed

manufacturer by FDA; licensed manufacturers, however, must submit all

followup information on such reports to FDA. Any person subject to the

reporting requirements under paragraph (c) of this section shall also

develop written procedures for the surveillance, receipt, evaluation,

and reporting of postmarketing adverse experiences to FDA.

(c) * * *

(1)(i) Postmarketing 15-day ``Alert reports''. The licensed

manufacturer shall report each adverse experience that is both serious

and unexpected, whether foreign or domestic, as soon as possible but in

no case later than 15 calendar days of initial receipt of the

information by the licensed manufacturer.

(ii) Postmarketing 15-day ``Alert reports''--followup. The licensed

manufacturer shall promptly investigate

[[Page 52253]]

all adverse experiences that are the subject of these postmarketing 15-

day Alert reports and shall submit followup reports within 15 calendar

days of receipt of new information or as requested by FDA. If

additional information is not obtainable, records should be maintained

of the unsuccessful steps taken to seek additional information.

Postmarketing 15-day Alert reports and followups to them shall be

submitted under separate cover.

(iii) Submission of reports. The requirements of paragraphs

(c)(1)(i) and (c)(1)(ii) of this section, concerning the submission of

postmarketing 15-day Alert reports, shall also apply to any person

whose name appears on the label of a licensed biological product as a

manufacturer, packer, distributor, shared manufacturer, joint

manufacturer, or any other participant involved in divided

manufacturing. To avoid unnecessary duplication in the submission to

FDA of reports required by paragraphs (c)(1)(i) and (c)(1)(ii) of this

section, obligations of persons other than the licensed manufacturer of

the final biological product may be met by submission of all reports of

serious adverse experiences to the licensed manufacturer of the final

product. If a person elects to submit adverse experience reports to the

licensed manufacturer of the final product rather than to FDA, the

person shall submit each report to the licensed manufacturer of the

final product within 5 calendar days of receipt of the report by the

person, and the licensed manufacturer of the final product shall then

comply with the requirements of this section. Under this circumstance,

a person who elects to submit reports to the licensed manufacturer of

the final product shall maintain a record of this action which shall

include:

(A) A copy of all adverse biological product experience reports

submitted to the licensed manufacturer of the final product;

(B) The date the report was received by the person;

(C) The date the report was submitted to the licensed manufacturer

of the final product; and

(D) The name and address of the licensed manufacturer of the final

product.

(iv) Report identification. Each report submitted under this

paragraph shall bear prominent identification as to its contents, i.e.,

``15-day Alert report,'' or ``15-day Alert report-followup.''

* * * * *

(f) Reporting forms. (1) Except as provided in paragraph (f)(3) of

this section, the licensed manufacturer shall complete the reporting

form designated by FDA for each report of an adverse experience (FDA

Form 3500A, or, for vaccines, a VAERS form; foreign events including

those associated with the use of vaccines, may be submitted either on

an FDA Form 3500A or, if preferred, on a CIOMS I form).

* * * * *

(g) Multiple reports. A licensed manufacturer should not include in

reports under this section any adverse experience that occurred in

clinical trials if they were previously submitted as part of the

license application. * * *

* * * * *

Dated: September 25, 1997.

William K. Hubbard,

Associate Commissioner for Policy Coordination.

[FR Doc. 97-26255 Filed 10-6-97; 8:45 am]

BILLING CODE 4160-01-F