Postmarketing Expedited Adverse Experience Reporting for Human Drug and Licensed Biological Products; Increased Frequency Reports

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 310, 314, and 600

[Docket No. 96N-0108]

Postmarketing Expedited Adverse Experience Reporting for Human

Drug and Licensed Biological Products; Increased Frequency Reports

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to

[[Page 55603]]

amend its postmarketing expedited adverse experience reporting

regulations to revoke the requirement for increased frequency reports

for human drug and licensed biological products as expedited reports.

This action, which is part of the President's regulatory reinvention

initiative, is based on FDA's determination that increased frequency

reports, as currently required, have not contributed to timely

identification of safety problems requiring regulatory action and are

no longer necessary for FDA surveillance of postmarketing adverse

experiences. This action would simplify and streamline postmarketing

expedited reporting of adverse experiences for human drug and licensed

biological products.

DATES: Written comments by January 13, 1997. The agency proposes that

any final rule that may issue based on this proposal become effective

30 days after its date of publication in the Federal Register.

ADDRESSES: Submit written comments to the Dockets Management Branch

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

Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: Audrey A. Thomas, Center for Drug

Evaluation and Research (HFD-7), Food and Drug Administration, 7500

Standish Pl., Rockville, MD 20855, 301-594-1049.

SUPPLEMENTARY INFORMATION:

I. Introduction

On March 4, 1995, President Clinton issued a memorandum titled

``Regulatory Reinvention Initiative.'' This memorandum, part of the

reform of the Federal regulatory system, directed heads of departments

and agencies to undertake a page-by-page review of their existing

regulations and to eliminate or modify those that are outdated or

otherwise in need of reform. The President's directive was issued

because private businesses, especially small ones, often face a

profusion of overlapping and sometimes conflicting rules from Federal

regulatory objectives.

As part of their review, agencies were charged to consider the

following issues carefully: Is the regulation obsolete; could its

intended goal be achieved in more efficient, less intrusive ways; are

there private sector alternatives, such as market mechanisms, that can

better achieve the public good envisioned by the regulations; could

private business, setting its own standards and being subject to public

accountability, do the job as well; and could the States or local

governments do the job, making the Federal regulation unnecessary.

In response to the President's regulatory reinvention initiative,

FDA conducted a comprehensive review of its existing regulations and

identified regulations to eliminate or modify. Although this proposal

was not a result of the initial review of regulations, FDA is

continuing its efforts to carry out the President's program. The

current proposal to revoke parts of its regulations in Secs. 310.305,

314.80, and 600.80 (21 CFR 310.305, 314.80, and 600.80) that require

postmarketing expedited increased frequency reports of adverse

experiences for human drug and licensed biological products is part of

the continuing effort.

II. Background

In the Federal Register of February 22, 1985 (50 FR 7452), FDA

published revised regulations governing the approval for marketing of

new drugs for human use, which included revisions to its adverse

experience reporting requirements. Under Sec. 314.80(c)(1)(ii), any

applicant with an approved new drug application (NDA) is required to

submit expedited increased frequency reports for any significant

increase in frequency of an adverse experience that is both serious and

expected. In the Federal Register of July 3, 1986 (51 FR 24476), FDA

published regulations for adverse experience reporting for marketed

prescription drugs without approved NDA's or abbreviated new drug

applications (ANDA's). Under Sec. 310.305(c)(4), any manufacturer,

packer, or distributor of a marketed prescription drug without an

approved NDA or ANDA is required to submit expedited increased

frequency reports for any significant increase in frequency of an

adverse experience that is both serious and expected. In the Federal

Register of April 28, 1992 (57 FR 17950), FDA published regulations for

ANDA's, including requirements for adverse experience reporting for

drugs with approved ANDA's and abbreviated antibiotic drug applications

(AADA's). Under Sec. 314.98 (21 CFR 314.98), any applicant with an

approved ANDA or AADA is required to comply with the requirements of

Sec. 314.80 regarding the reporting and recordkeeping of adverse

experiences. In the Federal Register of October 27, 1994 (59 FR 54034),

FDA finalized regulations for adverse experience reporting for licensed

biological products. Under Sec. 600.80(c)(1)(ii), manufacturers of

licensed biological products are required to submit expedited increased

frequency reports for any significant increase in frequency of an

adverse experience that is both serious and expected.

Under Secs. 310.305(c)(4), 314.80(c)(1)(ii) and (c)(1)(iii), and

600.80(c)(1)(ii) and (c)(1)(iii), applicants and manufacturers,

packers, and distributors, including licensed manufacturers, are

required to review periodically (at least as often as the periodic

reporting cycle) the frequency of reports of adverse experiences that

are both serious and expected and reports of therapeutic failure (lack

of effect), regardless of source, and report any significant increase

in frequency as soon as possible but in any case within 15 working days

of determining that a significant increase in frequency exists. For

drugs with an approved NDA or ANDA, or licensed biological products,

the reporting interval is quarterly in the first 3 years of marketing

and annually thereafter (Secs. 314.80(c)(2) and 600.80(c)(2)), while

for marketed prescription drugs without an approved NDA or ANDA, the

reporting interval is annually (Sec. 310.305(c)(4)). Operationally, an

increased frequency exists if the adjusted reporting for the reporting

interval is at least two times greater than the adjusted reporting for

the comparison interval (previous reporting interval). Reporting is

adjusted by the ratio of estimated drug use for the reporting interval

to that of the comparison interval. If the number of reports received

during the reporting interval is less than four, an increased frequency

report is not required (see CDER's ``Guideline for Postmarketing

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

``Guideline for Adverse Experience Reporting for Licensed Biological

Products,'' October 1993).

These regulations are intended to ensure that applicants and

manufacturers, packers, and distributors, including licensed

manufacturers, identify increases in the incidence of serious, labeled

adverse experiences that occur with changes in medical practice, such

as using a drug or biological product in higher risk populations, at

higher dosages, or concomitantly with other drugs or biological

products causing interactions. FDA intended for these reports to detect

increasing incidences of serious, labeled adverse experiences that were

not anticipated from premarketing clinical trials and that would

necessitate labeling changes or other regulatory actions.

FDA is proposing to amend its postmarketing expedited adverse

experience reporting regulations by revoking the requirement for

expedited increased frequency reports in Secs. 310.305(c)(4),

314.80(c)(1)(ii), and 600.80(c)(1)(ii). This action would not

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affect the requirement for expedited reporting of all serious,

unexpected adverse experiences. Applicants and manufacturers, packers,

and distributors, including licensed manufacturers, must continue to

submit 15-day alert reports and followup reports for serious,

unexpected events, as required under Secs. 310.305(c), 314.80(c),

314.98, and 600.80(c). FDA is also proposing to revoke the definition

of ``increased frequency'' in Secs. 310.305(b)(5), 314.80(a), and

600.80(a). This term is defined as an increase in the rate of

occurrence of a particular adverse drug (or biological product)

experience, e.g., an increased number of reports of a particular

adverse drug (or biological product) experience after appropriate

adjustment for drug (or biological product) exposure.

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

proposed to amend, among other things, its regulations for periodic

postmarketing reporting of adverse experiences for human drug and

licensed biological products in Secs. 314.80(c)(2) and 600.80(c)(2).

FDA proposed to amend the requirements for the content of periodic

adverse experience reports by adding a section for overall safety

evaluation. This section would contain a critical analysis and full

discussion of the safety information provided in the periodic report as

it pertains to a number of matters, including increased frequencies of

known toxicity. FDA based this proposed revision on recommendations

developed by the World Health Organization's Council for International

Organizations of Medical Sciences (CIOMS) Working Group II. Recently,

the International Conference on Harmonisation of Technical Requirements

for Registration of Pharmaceuticals for Human Use (ICH) developed,

based on the CIOMS II proposals, a draft guideline for periodic

reporting entitled ``Clinical Safety Data Management: Periodic Safety

Update Reports for Marketed Drugs'' (the ICH E2C guideline). The ICH

E2C draft guideline, published in the Federal Register of April 5, 1996

(61 FR 15352), recommends that the overall safety evaluation section of

periodic safety update reports highlight any new information on

increased frequencies of known adverse drug reactions, including

comments on whether it is believed that these data reflect a meaningful

change in adverse drug reaction occurrences. Thus, under this

guideline, regulatory authorities would be able to obtain reports of

increased frequencies from periodic reports. FDA plans to finalize its

proposed amendments to the periodic postmarketing safety reporting

regulations after consensus is reached by ICH on a final guideline on

postmarketing periodic safety update reports.

III. FDA's Experience With Increased Frequency Reports

FDA has found that increased frequency reports have rarely prompted

regulatory action during the time that the agency has been receiving

such reports. These reports have been of little value in identifying

increased incidences of serious, labeled experiences.

From January 1, 1987, to May 31, 1995, FDA received approximately

1,800 increased frequency reports. Over this period, FDA identified

only a small number of drug/biological product safety problems where

increased frequency reports played a role in risk assessment that

resulted in regulatory action, three examples of which are given below.

For each of the examples, the safety problems may have been detected in

other safety reports required by FDA such as periodic adverse

experience reports, field alert reports, or annual reports.

One safety problem involved buprenorphine, a narcotic agonist-

antagonist analgesic approved in 1985 and labeled at that time as

causing less respiratory depression than morphine. In 1986, FDA

received an increased frequency report for respiratory depression with

buprenorphine, prompting careful monitoring. This resulted in labeling

changes and warnings that buprenorphine may depress respiration in a

manner equivalent to an equianalgesic dose of morphine.

A second safety problem involved an increased frequency report of

neurotoxicity caused by a medication administration error when

vincristine, an antineoplastic, was mistaken for methotrexate, another

antineoplastic, and administered intrathecally. This resulted in the

repackaging of vincristine to avoid confusion with methotrexate.

A third safety problem involved Orthoclone OKT3, a monoclonal

antibody used as an immunosuppressant for treatment of acute allograft

rejection in renal, cardiac, and hepatic transplant patients. In 1990,

FDA received an increased frequency report for anaphylaxis and serum

sickness associated with Orthoclone OKT3. Two of three anaphylaxis

patients were undergoing second courses of therapy. This report

resulted in labeling amendments including the addition of a boxed

warning on the risk of anaphylaxis after any dose and a boldface

paragraph providing further details.

FDA has also received increased frequency reports for adverse

experiences that were previously identified as potential problems in

premarketing clinical trials. For example, based on FDA's review of NDA

data on ketorolac, an analgesic, the agency was aware of its potential

for causing upper gastrointestinal bleeding (UGIB) and renal failure

when given at higher doses. Following approval in 1989, the sponsor was

asked to conduct a postmarketing safety study. Meanwhile, in 1992, FDA

received increased frequency reports for UGIB and renal failure.

However, a causal relationship between these adverse experiences and

ketorolac could not be established from the increased frequency reports

because of uncertainties caused by the underlying illness, concomitant

drug administration, and the indication (postsurgical analgesia) for

which ketorolac was being used. Following a review of the postmarketing

safety study, FDA required labeling changes to address the safety

problems associated with ketorolac. Thus, the increased frequency

reports did not contribute to the risk assessment that resulted in this

regulatory action.

FDA has found that expedited postmarketing adverse experience

reporting systems are best used to identify rare, unexpected adverse

drug reactions such as aplastic anemia, hepatic necrosis, renal

failure, or anaphylaxis that were not detected in preclinical studies

or clinical trials during drug development. For such unexpected

reactions, warnings can be added to the labeling without quantifying

the incidence of the reaction. Warnings for expected adverse reactions

(such as those obtained in increased frequency reports) are already in

the labeling. In addition, risk information regarding incidence cannot

generally be ascertained from an increased frequency report but

requires controlled studies.

IV. Limitations of Increased Frequency Reports

Increased frequency information is derived from incidence rates. An

incidence rate is estimated by dividing the number of adverse

experiences (numerator) by the number of persons exposed to a drug or

biological product (denominator). For increased frequency reports,

applicants and manufacturers, including licensed manufacturers,

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compare incidence rates estimated for the reporting interval with rates

estimated for the previous reporting interval.

FDA is aware of several factors that affect the accuracy of

incidence rates. First, health care providers do not report all adverse

experiences. The percentage of adverse experiences reported is unknown

and varies unpredictably over time. Hence, the numerator cannot be

reliably estimated. Second, the number of persons exposed to a drug or

biological product during a reporting period is not precisely known; it

is estimated from sales or production data. The lag time between

production or sales by the manufacturer and consumption by patients can

vary, thus adding further distortion to comparisons between reporting

periods. Hence, the denominator is not always reliably estimated.

Third, adverse experience reports may be used for calculating increased

frequencies even though the suspect drug or biological product did not

necessarily cause the adverse experience. Assessment of causality is

frequently limited by incomplete data and uncertainty caused by the

underlying illness, indication, or other drug exposures. Fourth,

increased frequency calculations are based on the dates when adverse

experience reports are received by the sponsor. If health care

providers hold adverse experience reports and submit them all at one

time, there can be a cluster of adverse experiences that fall into one

reporting period creating a false-positive signal.

Thus, the reliability of increased frequency reports is limited

because of the difficulty in accurately estimating incidence rates. FDA

has concluded that these concerns make it difficult to rely on

increased frequency reports as a tool for identifying important safety

problems requiring labeling changes or other regulatory action.

V. Public Comments on Increased Frequency Report Requirements

In the October 27, 1994, proposed rule, FDA proposed to amend its

regulations for expedited and periodic premarketing and postmarketing

safety reporting of adverse experiences for human drug and biological

products. The proposal included revisions to the postmarketing

increased frequency report requirements under Secs. 310.305, 314.80,

and 600.80. FDA proposed to amend these requirements by altering the

time period for submitting increased frequency reports from 15 working

days to 15 calendar days, and by revising the reporting interval. Under

proposed Sec. 310.305, this interval would be increased from at least

once a year to at least twice a year, and, under proposed Secs. 314.80

and 600.80, this interval would be revised from at least quarterly for

the first 3 years of marketing and annually thereafter to at least

twice a year. FDA did not receive any comments on these proposed

increased frequency reporting revisions.

However, FDA received comments from 12 pharmaceutical companies and

1 individual regarding other aspects of the current increased frequency

reporting requirements that were not within the scope of the October

27, 1994, proposal. FDA considered these comments in developing the

current proposal.

Nine comments opposed the requirement for increased frequency

reports. One comment stated that there is ``common agreement'' that

increased frequency assessments have not provided information on

significant safety risks to patients. Another comment stated that it

was not aware of any important safety signal that had been identified

by an increased frequency report. One comment stated that there is no

benefit to be gained from increased frequency assessments, especially

for drugs that are not the subject of an approved application. Another

comment noted that applicants have available other mechanisms to

identify and characterize changes in the nature and frequency of

adverse experiences reported to them. Another comment noted that no

provision exists for increased frequency calculations in the

recommendations of either ICH or CIOMS. Three comments recommended that

FDA revoke the requirement unless the agency can show that these

reports have produced safety information not otherwise obtainable (for

example, important labeling revisions or the initiation of other

communication to enhance the safe and effective use of drugs).

One comment opposed increased frequency reports of therapeutic

failure for over-the-counter (OTC) drugs subject to an approved

application. The comment contended that such reports are generally not

unexpected from consumers of OTC drugs and are unlikely to involve

serious outcomes. The comment requested that FDA limit these reports to

prescription drugs and to cases involving serious consequences. Another

comment requested that FDA limit increased frequency reports of

therapeutic failure to U.S. reports.

One comment requested clarification of the methodology for

estimating increased frequency rates because the FDA guideline

describing these methods is vague. The comment noted that the

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

refers to the use of either an arithmetical or statistical method of

analysis without specifying either method. The comment said that use of

the arithmetic method can produce an increased frequency calculation

that would not be replicated by the statistical method (and conversely

for the statistical method), thus leading to conflicting

interpretations of increased frequency. Another comment requested

clarification of the sources of data to be used for increased frequency

analyses because of confusion caused by Secs. 314.80(d)(1) and

600.80(d)(1), which state that increased frequency reports required

under Secs. 314.80(c)(1)(ii) and 600.80(c)(1)(ii) apply only to reports

found in scientific and medical journals, either as the result of a

formal clinical trial or from epidemiological studies or analyses of

experience in a monitored series of patients.

VI. Request for Comments

Interested persons may, on or before January 13, 1997, submit to

the Dockets Management Branch (address above) written comments

regarding this proposal. Two copies of any comments are to be

submitted, except that individuals may submit one copy. Comments are to

be identified with the docket number found in brackets in the heading

of this document. Received comments may be seen in the office above

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

VII. Environmental Impact

The agency has determined under 21 CFR 25.24(a)(8) 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.

VIII. Paperwork Reduction Act of 1995

This proposed rule does not require information collections and,

thus, is not subject to review by the Office of Management and Budget

(OMB) under the Paperwork Reduction Act of 1995 (Pub. L. 104-13).

IX. Analysis of Impacts

FDA has examined the impacts of the proposed rule under Executive

Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354).

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,

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environmental, public health and safety, and other advantages;

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

proposed rule is consistent with the regulatory philosophy and

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

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

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

The Regulatory Flexibility Act requires agencies to analyze

regulatory options that would minimize any significant impact of a rule

on small entities. Because this proposed rule would simplify and

streamline current requirements, the agency certifies that the proposed

rule will not have a significant economic impact on a substantial

number of small entities. Therefore, under the Regulatory Flexibility

Act, no further analysis is required.

X. Effective Date

FDA proposes that any final rule that may issue based on this

proposal become effective 30 days after its date of publication in the

Federal Register.

List of Subjects

21 CFR Part 310

Administrative practice and procedure, Drugs, Labeling, Medical

devices, Reporting and recordkeeping requirements.

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, it is proposed that 21 CFR parts 310,

314, and 600 be amended as follows:

PART 310--NEW DRUGS

1. 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).

2. Section 310.305 is amended by revising paragraph (a), by

removing paragraph (b)(5), by removing paragraph (c)(4), by

redesignating paragraphs (c)(5) and (c)(6) as paragraphs (c)(4) and

(c)(5), respectively, by revising the first sentence of newly

redesignated paragraph (c)(4), and by revising paragraph (f)(1) 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) Scope. FDA is requiring manufacturers, packers, and

distributors of marketed prescription drug products that are not the

subject of an approved new drug or abbreviated new drug application to

establish and maintain records and make reports to FDA of all serious,

unexpected adverse drug experiences associated with the use of their

drug products.

* * * * *

(c) * * *

(4) In order 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. * * *

* * * * *

(f) Recordkeeping. (1) Each manufacturer, packer, and distributor

shall maintain for a period of 10 years records of all adverse drug

experiences required under this section to be reported, including raw

data and any correspondence relating to the adverse drug experiences,

and the records required to be maintained under paragraph (c)(4) of

this section.

* * * * *

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG OR AN

ANTIBIOTIC DRUG

3. 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).

4. Section 314.80 is amended by removing the definition for

Increased frequency in paragraph (a), by removing paragraph (c)(1)(ii),

by redesignating paragraphs (c)(1)(iii) and (c)(1)(iv) as paragraphs

(c)(1)(ii) and (c)(1)(iii), respectively, by revising the first two

sentences in the introductory text of newly redesignated paragraph

(c)(1)(ii), by removing the last sentence in paragraph (d)(1), by

revising paragraph (f)(1), and by revising the last sentence in

paragraph (l) to read as follows:

Sec. 314.80 Postmarketing reporting of adverse drug experiences.

* * * * *

(c) * * *

(1) * * *

(ii) The requirements of paragraph (c)(1)(i) of this section,

concerning the submission of 15-day alert reports, shall also apply to

any person (other than the applicant) whose name appears on the label

of an approved drug product as a manufacturer, packer, or distributor.

However, in order to avoid unnecessary duplication in the submission to

FDA, and followup to, reports required by paragraph (c)(1)(i) of this

section, obligations of a nonapplicant may be met by submission of all

reports of serious adverse drug experiences to the applicant.* * *

* * * *

(f) Reporting Form FDA-1639. (1) Except as provided in paragraph

(f)(3) of this section, the applicant shall complete a Form FDA-1639

(Adverse Reaction Report) for each report of an adverse drug

experience.

* * * * *

(l) * * * For purposes of this provision, the term

``applicant'' also includes any person reporting under paragraph

(c)(1)(ii) of this section.

* * * * *

PART 600--BIOLOGICAL PRODUCTS: GENERAL

5. 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).

6. Section 600.80 is amended by removing the definition for

Increased frequency in paragraph (a), by removing paragraph (c)(1)(ii),

by redesignating paragraphs (c)(1)(iii) and (c)(1)(iv) as paragraphs

(c)(1)(ii) and (c)(1)(iii), respectively, by revising the first

sentence in the introductory text of newly redesignated paragraph

(c)(1)(ii), by removing the last sentence in paragraph (d)(1), by

revising paragraph (f)(1), and by revising the last sentence in

paragraph (m) to read as follows:

Sec. 600.80 Postmarketing reporting of adverse experiences.

* * * * *

(c) * * *

(1) * * *

(ii) The requirements of paragraph (c)(1)(i) of this section,

concerning the submission of 15-day Alert reports, shall also apply to

any person other than the licensed manufacturer of the final

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product whose name appears on the label of a licensed biological

product as a manufacturer, packer, distributer, shared manufacturer,

joint manufacturer, or any other participant involved in divided

manufacturing.

* * * * *

(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 (FDA-3500A, or, for vaccines, a VAERS form) for

each report of an adverse experience.

* * * * *

(m) * * * For purposes of this provision, this paragraph also

includes any person reporting under paragraph (c)(1)(ii) of this

section.

Dated: October 17, 1996.

William B. Schultz,

Deputy Commissioner for Policy.

[FR Doc. 96-27593 10-25-96; 8:45 am]

BILLING CODE 4160-01-F