Federal Register / Vol. 61, No. 115 / Thursday, June 13, 1996 / Proposed Rules 30001

TABLE 4—Continued

Brake manufacturer Part No. Document/chapter Date/revision (or later revisions)

FOR MODEL A300–600 SERIES AIRPLANES:

Messier-Bugatti C20060–100 Series CMM 32–44–24 December 31, 1991.

ALS (Bendix) 2607932–1 and S.C.* CMM 32–42–05

SB 2607932–32-002

SB 2607932–32–003

Revision 4/February 15,1992.

March 31,1993, and

Revision 1/October 1, 1993.

May 31, 1995.

FOR MODEL A300 B4–600R SERIES AIRPLANES:

Messier-Bugatti C20210000

and

C20210200 Series

CMM 32–44–51

SB 470–32–675

August 31, 1994.

Revision 1/

September 26, 1994.

FOR MODEL A310–200 SERIES AIRPLANES:

Messier-Bugatti C20089000 Series CMM 32–46–23 January 31, 1992.

ALS (Bendix) 2606822–1 and S.C. CMM 32–42–03

SB 2606822–32–002

Revision 5/

January 31, 1991.

March 31, 1993.

FOR MODEL A310–300 SERIES AIRPLANES:

Messier-Bugatti C20194000 and

C20194200 Series

CMM 32–46–37

SB 470–32–675

August 31, 1994.

Revision 1/

September 26, 1994.

ABS 5010995 CMM 32–43–97 February 28, 1991.

FOR MODEL A320 SERIES AIRPLANES:

Messier-Bugatti C20225000 and

C20225200 Series

CMM 32–47–20

SB 580–32–3042

January 31, 1995.

Revision 1/June 30, 1995.

BFGoodrich 2–1526/–2/–5

2–1526–3/–4

2–1572

CMM 32–44–38

CMM 32–44–38

CMM 32–41–63

March 15, 1993.

March 15, 1993.

April 29, 1994.

ABS 5011075 CMM 32–41–18 February 28, 1991.

* S.C. represents ‘‘Service Configured’’ brakes, which are marked according to the instructions provided in the brake manufacturer’s CMM.

NOTE 4: Once an operator has complied with the requirement of paragraph (b) of this AD, that paragraph does not require

that the operator subsequently record accomplishment of those requirements each time a brake is inspected or overhauled in accordance

with that operator’s FAA-approved maintenance inspection program.

(c) Prior to installation of any brake having a part number other than those specified in Table 3 of this AD, revise the FAAapproved maintenance program to include the provisions specified in paragraph (b) of this AD for that part number brake, that

have been approved by the Manager, Standardization Branch, ANM–113, FAA, Transport Airplane Directorate.

(d) An alternative method of compliance or adjustment of the compliance time that provides an acceptable level of safety may

be used if approved by the Manager, Standardization Branch, ANM–113. Operators shall submit their requests through an appropriate

FAA Principal Maintenance Inspector, who may add comments and then send it to the Manager, Standardization Branch, ANM–

113.

Note 5: Information concerning the existence of approved alternative methods of compliance with this AD, if any, may be obtained

from the Standardization Branch, ANM–113.

(e) Special flight permits may be issued in accordance with sections 21.197 and 21.199 of the Federal Aviation Regulations (14

CFR 21.197 and 21.199) to operate the airplane to a location where the requirements of this AD can be accomplished. Issued in

Renton, Washington, on June 6, 1996.

James V. Devany,

Acting Manager, Transport Airplane Directorate, Aircraft Certification Service.

[FR Doc. 96–14988 Filed 6–12–96; 8:45 am]

BILLING CODE 4910–13–U
30002 Federal Register / Vol. 61, No. 115 / Thursday, June 13, 1996 / Proposed Rules

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Part 343

[Docket No. 77N–094A]

RIN 0910–AA01

Internal Analgesic, Antipyretic, and

Antirheumatic Drug Products for Overthe-Counter Human Use; Proposed

Amendment to the Tentative Final

Monograph

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice of proposed rulemaking.

SUMMARY: The Food and Drug

Administration (FDA) is proposing to

amend the tentative final monograph for

over-the-counter (OTC) internal

analgesic, antipyretic, and

antirheumatic drug products to include

the use of aspirin, buffered aspirin, and

aspirin in combination with antacid to

reduce the risk of vascular mortality in

people with a suspected acute

myocardial infarction (MI). This

proposal is in response to two citizen

petitions and is part of the ongoing

review of OTC drug products conducted

by FDA.

DATES: Submit written comments by

September 11, 1996. Written comments

on the agency’s economic impact

determination by September 11, 1996.

The agency is proposing that any final

rule that may issue based on this

proposal be effective 12 months after the

date of its publication in the Federal

Register.

ADDRESSES: 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:

William E. Gilbertson, Center for Drug

Evaluation and Research (HFD–105),

Food and Drug Administration, 5600

Fishers Lane, Rockville, MD 20857,

301–827–2304.

SUPPLEMENTARY INFORMATION:

I. Introduction

In the Federal Register of November

16, 1988 (53 FR 46204), the agency

published a tentative final monograph

(TFM) to establish conditions under

which OTC internal analgesic,

antipyretic, and antirheumatic drug

products are generally recognized as

safe and effective and not misbranded

(hereinafter referred to as the 1988

TFM). The 1988 TFM included

professional labeling for drug products

containing aspirin, buffered aspirin, and

aspirin in combination with an antacid

for certain cardiovascular and

cerebrovascular uses to: (1) Reduce the

risk of death and/or nonfatal MI in

patients with a previous infarction or

unstable angina pectoris, and (2) reduce

the risk of recurrent transient ischemic

attacks (TIA’s) or stroke in men who

have had transient ischemia of the brain

due to fibrin platelet emboli.

The agency has received two citizen

petitions (Refs. 1 and 2), submitted in

accord with § 10.30 (21 CFR 10.30),

requesting that the professional labeling

section of the monograph for OTC

internal analgesic, antipyretic, and

antirheumatic drug products be

amended to include an indication for

the use of aspirin in treating acute MI.

One petition included reports of four

studies to support this indication. The

petitions are on public display in the

Dockets Management Branch (address

above).

FDA has reviewed the information in

the petitions and finds that it supports

the safety and effectiveness of aspirin,

buffered aspirin, or aspirin in

combination with antacid to reduce the

risk of vascular mortality in patients

with a suspected acute MI. Therefore,

the agency is proposing to amend the

professional labeling in § 343.80 of the

1988 TFM for OTC internal analgesic

drug products to include information on

aspirin, buffered aspirin, or aspirin in

combination with antacid for this

indication. Final agency action on this

proposal will occur in a future issue of

the Federal Register.

II. The Citizen Petitions

A. The Agency’s Evaluation of the

Citizen Petitions

One citizen petition (Ref. 1) included

reports of four clinical trials conducted

to evaluate the safety and effectiveness

of aspirin in treating acute MI (Refs. 3

through 6). The petition cited the

results of the Second International

Study of Infarct Survival (ISIS–2) (Ref.

3) as primary support for the safety and

effectiveness of aspirin in the treatment

of acute MI to reduce the risk of fatal

and nonfatal cardiovascular and

cerebrovascular events.

The ISIS–2 study was undertaken

after a pilot study (Ref. 7) of 619

subjects suggested that aspirin was

effective in reducing the incidence of

nonfatal reinfarction, death, and stroke

in subjects with suspected acute MI.

The ISIS–2 study was a 2 x 2 factorial

study of 17,187 subjects (both men and

women) with suspected acute MI,

randomized so that 8,592 subjects

received a single dose of streptokinase

(1.5 million units (MU)) and 8,595

received an intravenous placebo

(hepatitis-B-antigen-free albumin).

Streptokinase or placebo was

intravenously infused over about 1 hour

in 50 to 200 milliliters of physiological

saline. Of the subjects, 8,587 were also

allocated randomly to receive oral

aspirin (162.5 milligrams (mg), entericcoated) daily for 1 month (the first dose

crushed, sucked, or chewed), and 8,600

received oral placebo (enteric-coated

starch tablets). Thus, within 24 hours of

the onset of symptoms, 4,300 subjects

received streptokinase plus oral

placebo, 4,295 received aspirin plus

placebo infusion, 4,292 received both

active treatments, and 4,300 received

double placebo. Subjects in whom acute

MI was suspected but not confirmed

were eligible for the study if they were

entered within 24 hours of the onset of

symptoms and had no clear indication

for, or contraindication to, streptokinase

or aspirin. Subjects from 417 hospitals

in 16 countries were included in the

study. Information collected and

recorded prior to randomization

included patient identifiers, age,

systolic blood pressure, hours from

onset of pain, aspirin use in the week

prior to admission, and details

concerning the planned treatment.

Ancillary treatment (including

treatment with aspirin) was not

restricted. Electrocardiogram (ECG)

results were not used as a basis for

randomization. Once enrolled, subjects

remained in the assigned treatment

group for an intent-to-treat analysis of

results.

An ECG done prerandomization was

submitted along with information on

compliance with the study treatment,

other drug use, and adverse events.

Observers blind to the treatment

assignment read the ECG’s and reviewed

the deaths. Causes of death were

categorized as ‘‘vascular’’ or

‘‘nonvascular.’’ The protocol defined

vascular deaths as those attributed to

cardiac, cerebral, hemorrhagic, other

vascular, or unknown causes. Further

details of reports of stroke were

collected for blinded review by a

neurologist.

Three primary analyses were

conducted to assess the following

effects: (1) Streptokinase on vascular

mortality during the first 35 days, (2)

streptokinase on vascular mortality

during the entire study period (a median

followup of 15 months), and (3) oral

daily aspirin on vascular mortality

during the first 35 days. The effects of

allocated treatment on clinical events

(reinfarction, cardiac rupture, cardiac

arrest, bleeding, and stroke) and on

nonvascular mortality were also
Federal Register / Vol. 61, No. 115 / Thursday, June 13, 1996 / Proposed Rules 30003

evaluated. Although not specified in the

protocol, subgroup analysis on vascular

mortality in days 0 to 35 was performed

for certain parameters, such as age,

gender, diabetes, and systolic blood

pressure.

Results were presented as absolute

changes and as changes in the odds of

death. The report states: ‘‘* * * a change

from 10 percent dead (odds 10/90) to 8

percent dead (odds 8/92) involves an

odds ratio of 8/92 divided by 10/90, or

0.78, and is therefore described as a 22

percent reduction in the odds of death

(rather than as a 20 percent reduction in

the risk of death).’’ (A change from 10

percent dead (risk 10/100) to 8 percent

dead (risk 8/100) would represent a 20

percent reduction in risk of death.)

During the first 35 days, there were

804 (9.4 percent) vascular deaths in the

8,587 subjects randomized to receive

oral aspirin, and 1,016 (11.8 percent)

vascular deaths in the 8,600 subjects

randomized to placebo. These results

represent an absolute reduction of 2.4

percent in the mean 35-day vascular

mortality attributable to aspirin and a

highly significant (23 percent) reduction

in the odds of vascular death (2p <

0.00001, confidence interval 15 to 30

percent). Although not an endpoint

specified in the protocol, an effect of

aspirin was still present after the

median 15-month followup was

completed, with a total reduction of

early and late vascular mortality of 1.9

percent, highly significant (2p < 0.001).

The number of nonvascular deaths in

subjects allocated to receive aspirin was

not significantly different from subjects

receiving placebo for the 15-month

median followup. One nonvascular

death occurred before 5 weeks, and 24

deaths occurred after 5 weeks in the

aspirin group, compared to 7 and 32,

respectively, in the placebo group. Total

mortality (vascular plus nonvascular)

was reduced at both 35 days (9.4

percent versus 11.9 percent, odds ratio

0.77) and after 15 months median

followup (16.0 percent versus 18.1

percent odds ratio 0.87) for the aspirin

group and placebo group). The

reduction in all-cause mortality was

highly significant (2p < 0.001) at both

times.

The beneficial effects of aspirin on

vascular mortality in days 0 to 35 was

found to be independent of

streptokinase infusion. (See Table 1.)

TABLE 1.—BENEFICIAL EFFECTS OF ASPIRIN ON

VASCULAR MORTALITY IN DAYS 0 TO 35

Treatment1 Tablet/Infusion Vascular Deaths/No. of Subjects Percent

Percent

Absolute

Change

Percent

Reduction in

Odds of Death

A/S+A/P 804/8,5872 9.4

vs

P/S+P/P 1,016/8,6003 11.8 -2.4 23 (2p<0.00001)

A/P 461/4,295 10.7

vs

P/P 568/4,300 13.2 -2.5 21 (2p<0.001)

A/S 343/4,292 8.0

vs

P/S 448/4,300 10.4 -2.4 25 (2p<0.001)

A/S 343/4,292 8.0

vs

P/P 568/4,300 13.2 -5.2 42 (2p<0.00001)

A/S 343/4,292 8.0

vs

A/P 461/4,295 10.7 -2.7 28 (2p<0.0001)

P/S 448/4,300 10.4

vs

P/P 568/4,300 13.2 -2.8 23 (2p<0.0001)

A/S+P/S 791/8,5924 9.2

vs

A/P+P/P 1,029/8,5955 12.0 -2.8 25 (2p<0.00001)

1 A=aspirin, S=streptokinase, and P=placebo. 2 Inludes 4,295 allocated aspirin tablets + placebo infusion and 4,292 allocated aspirin tablets + streptokinase infusion. 3 Includes 4,300 allocated placebo tablets + placebo infusion and 4,300 allocated placebo tablets + streptokinase infusion. 4Includes 4,292 allocated aspirin tablets + placebo infusion and 4,300 allocated streptokinase infusion + placebo tablets.

5Includes 4,295 allocated aspirin tablets + placebo infusion and 4,300 allocated placebo tablets + placebo infusion.

Each subject received one tablet and

one infusion (e.g., each subject was

allocated either a single active

ingredient plus placebo, both active

ingredients, or two placebos). Aspirin

reduced the odds of death within 35

days by 25 percent (standard deviation

(SD) 6) in people who were also given

streptokinase infusion, and by 21

percent (SD 6) in people given a placebo

infusion (2p < 0.001). Thus, aspirin was

effective in reducing mortality both in

the presence and absence of

streptokinase.

Similarly, there were significantly

fewer deaths in the streptokinase group

compared to the placebo both in the

presence and absence of aspirin. The

effect of the combined therapy of aspirin

plus streptokinase was approximately

additive. The 35-day vascular mortality

of the group that received aspirin plus

streptokinase was 8 percent compared

to 13.2 percent for the double-placebo

group. These results represent an

absolute reduction of 5.2 percent and a

42-percent reduction in odds of death in
30004 Federal Register / Vol. 61, No. 115 / Thursday, June 13, 1996 / Proposed Rules

the aspirin plus streptokinase group (2p

< 0.00001).

When specific clinical events (fatal

plus nonfatal) that occurred in the

hospital were evaluated separately,

statistically significant absolute

reductions favoring aspirin were found

for reinfarction (1.5 percent absolute

reduction, 45 percent odds reduction,

2p < 0.00001), cardiac arrest (1.2

percent absolute reduction, 14.2 percent

odds reduction, 2p < 0.01), and total

stroke (0.4 percent absolute reduction,

41.5 percent odds reduction, 2p < 0.01).

Moreover, the effect of aspirin over and

above its effect on mortality was

evidenced by small, but significant,

reductions in vascular morbidity in

those subjects who were discharged.

The combination of streptokinase

infusion and daily aspirin was

significantly better than either active

treatment alone for vascular mortality

(See Table 1). The differences in favor

of aspirin plus streptokinase compared

to double placebo for specific clinical

events were 1.1 percent in reinfarction,

2.5 percent in cardiac arrest, and 0.5

percent (2p = 0.02) in total stroke. The

effects of aspirin and aspirin in

combination with streptokinase on

major clinical events that occurred in a

hospital is shown in Table 2.

TABLE 2.—EFFECTS OF ASPIRIN AND ASPIRIN

PLUS STREPTOKINASE ON MAJOR CLINICAL

EVENTS IN HOSPITAL

Aspirin Aspirin plus Streptokinase

Asprin Tablets Placebo

Tablets

Percent

Absolute

Change

Aspirin and

Streptokinase

Placebo

Infusion and

Tablet

Percent

Absolute

Change

Number randomized 8,587 8,600 4,292 4,300

Number discharged alive 8,492 8,489 4,239 4,238

Reinfarction (any) 156 284 1.5 77 123 1.1

(any discharged alive) 83 170 1.0 46 61 0.4

Cardiac rupture (any) 69 81 0.1 31 38 0.2

(any discharged alive) 7 5 0.0 2 1 0.0

Cardiac arrest (any) 690 793 1.2 311 417 2.5

(any discharged alive) 259 289 0.4 133 129 -0.1

Stroke (any) 47 81 0.4 25 45 0.5

(fatal) 20 30 0.1 12 18 0.1

(disabled) 17 23 0.1 9 15 0.1

(not disabled) 10 28 0.2 4 12 0.2

(hemorrhagic) 5 2 0.0 5 0 -0.1

(any discharged alive) 27 51 0.3 13 27 0.3

Major bleeds (transfused) 31 33 0.0 24 11 -0.3

Minor bleeds

(not transfused) 215 163 -0.6 167 33 -3.2

Subgroup analysis was done for 35-

day vascular mortality for 3,945 women

assigned to either aspirin (1,994) or oral

placebo (1,951), and for 13,125 men

assigned to aspirin (6,540) or oral

placebo (6,585). Vascular mortality was

higher in women than men in both the

placebo and the aspirin group, but the

absolute reduction of risk of vascular

death was 2.6 percent for women and

2.4 percent for men, representing a 19

percent (p = 0.018) odds reduction for

women and a 25 percent (p < 0.0001)

odds reduction for men. These data

suggest that beneficial effects of aspirin

may be expected in treating both men

and women for an acute MI.

Subgroup analyses suggest that all age

groups analyzed benefited from aspirin.

There were 1 percent fewer vascular

deaths recorded for 3,870 subjects under

60 years of age who received aspirin

than for 3,850 subjects who received

oral placebo (18 percent relative risk

reduction). In subjects 60 to 69 years

old, 3.1 percent fewer vascular deaths

were recorded for 2,999 subjects who

received aspirin than for 3,057 subjects

who received placebo (22 percent

relative risk reduction). Subjects over 70

years old (1,718 on aspirin versus 1,693

on placebo) appeared to have the

greatest (4.7 percent) absolute reduction

in vascular death. The relative risk

reduction in subjects over 70 years old

was 21 percent for those who received

aspirin.

However, the agency agrees with the

investigators’ conclusion that more

weight should be placed on the overall

results than on any particular subgroup

of people. The agency has determined

that the evidence is insufficient at

present to validate efficacy results in

particular subsets of patients with

suspected acute MI.

The principal entry criterion for

subjects in the ISIS–2 study was that the

responsible physician suspected acute

MI based on clinical presentation. The

protocol did not require that MI be

documented in those entering the study.

The agency notes that the only

preliminary indications of an MI are

chest pain and changes in the ECG. The

report did not indicate how many of the

subjects actually had an acute MI. In a

retrospective analysis, about 98 percent

of the subjects admitted to the study had

some ECG abnormality.

Aspirin produced similar-sized

reductions in vascular mortality among

subjects treated early and treated late

after the onset of symptoms (odds

reductions at 0 to 4, 5 to 12, and 13 to

24 hours were 25 percent, 21 percent,

and 21 percent, respectively). The

effects of streptokinase appeared to be

greatest among those treated earliest.

When comparing subjects who received

both aspirin and streptokinase to

subjects who received double placebo,

the odds of death were more reduced

among those subjects randomized 0 to 4

hours (53 percent odds reduction; 2p <

0.00001) after the onset of pain than

those randomized later: 5 to 12 hours

(32 percent odds reduction; 2p <

0.0001), and 13 to 24 hours (38 percent

odds reduction; 2p < 0.01).

The aspirin regimen was well

tolerated. There was no difference in the

incidence of major bleeding (bleeds

requiring transfusion) between the two

groups (0.4 percent for aspirin; 0.4

percent for placebo). There was a small

but statistically significant 0.6 percent

(SD = 0.2, 2p < 0.01) increase in minor

bleeding in people taking aspirin

compared to placebo (2.5 versus 1.9
Federal Register / Vol. 61, No. 115 / Thursday, June 13, 1996 / Proposed Rules 30005

percent). No other significant adverse

effects were reported. Although there

were five confirmed cerebral

hemorrhages in the aspirin group

compared with two in the placebo

group, this difference was not

statistically significant. As discussed

above, the incidence of stroke of any

cause was lower in subjects taking

aspirin when compared to those on oral

placebo (47 versus 81), a 0.4 percent

absolute reduction and a 41.5 percent

reduction in odds of stroke (2p < 0.01)

in subjects taking aspirin.

The second study (Ref. 4) was a study

of low dose aspirin (75 mg daily) and

intravenous heparin in 945 men with

unstable coronary artery disease,

defined as non-Q-wave MI or increasing

angina within the previous 4 weeks

associated with ischemia (deficiency of

oxygen supply to the heart muscle, due

to the constriction or obstruction of a

blood vessel) in a resting ECG or during

a predischarge exercise test. The

subjects were randomized within 72

hours after admission to coronary care

units to receive bolus intravenous

injections of heparin (10,000 units 4

times a day for 1 day and 7,500 units 4

times a day for 4 additional days) or

placebo (saline) for 5 days, and oral

aspirin (75 mg daily) or placebo for 1

year. The study was stopped early after

publication of the ISIS–2 study. As a

result, the minimum period of

randomized treatment was reduced to 3

months. A detailed report of this study

has not been submitted to the agency for

review.

One hundred and forty-nine subjects

were excluded from the study (115 with

no evidence of myocardial ischemia

after an exercise test, and 34 with an

anterior Q-wave MI before recruitment).

The remaining 796 subjects were

randomized to either double placebo

(199), heparin and aspirin (210), aspirin

and placebo (189), or heparin and

placebo (198).

The combined rate of MI or death in

subjects on aspirin (aspirin with placebo

and aspirin with heparin) was 9.1

percent and 10.6 percent lower at 1 and

3 months, respectively, than the

combined rate for subjects receiving

placebo (double placebo or placebo with

heparin), a risk reduction of 68 percent

at 1 month (p = 0.0001) and 62 percent

at 3 months (p = 0.0001). Heparin alone

did not appear to affect the rate of death

or MI. However, the combination of

heparin and aspirin was the only

regimen that significantly reduced the

risk of MI during the first 5 days in the

hospital. Thus, the authors suggested

that reduction of events in the aspirin

treated group may have been influenced

by initial simultaneous treatment with

heparin.

A few side effects were reported with

the daily aspirin dose used in this

study, although details were not

provided. Hematological side effects

were reported to be rare and minor.

Gastrointestinal side effects were similar

in the aspirin and placebo groups at 1

month, but were more frequent with

aspirin (5.2 percent to 6.5 percent) than

with placebo (0.7 percent to 1.9 percent)

at 3 months.

This study primarily involved the use

of aspirin in subjects with unstable

angina. The agency has already accepted

the benefits of aspirin in unstable

angina and has included that indication

in § 343.80(c).

The third study (Ref. 5) compared the

effect of aspirin (100 mg daily) to

placebo for 3 months on infarct size,

death, reinfarction, unstable angina, and

revascularization in 100 subjects with

early symptoms of first anterior wall

acute MI. All subjects also received

subcutaneous heparin until they were

mobilized. In addition, those subjects

who were less than 70 years of age and

had symptoms for less than 4 hours

when recruited (24 subjects on aspirin

and 26 subjects on placebo) also

received thrombolysis therapy

(intravenous streptokinase). The study

was randomized for aspirin but not for

thrombolysis.

The primary endpoint was infarct size

in the first 72 hours. The size of the

infarct was determined by the

cumulative release of serum lactate

dehydrogenase (LDH) in the first 72

hours. Secondary endpoints were death,

reinfarction, unstable angina, and

revascularization. The results showed a

10 percent difference in infarct size

(1,431 ± 782 versus 1,592 ± 1,082 LDH

units per liter) for the aspirin versus

placebo group. This difference was not

statistically significant (p = 0.35). Of the

secondary endpoints evaluated, only

reinfarction was significantly lower in

the aspirin than the placebo group (4

percent versus 18 percent, p < 0.03) at

3 months. Mortality rate was 20 percent

in subjects given aspirin compared to 24

percent in those given placebo. This

difference was not statistically

significant (p = 0.65).

The significant reduction in incidence

of reinfarction in this study is surprising

because of the small size of the study

and may depend on an atypical

incidence of reinfarction in the control

group (18 percent at 3 months). This

was much higher than in the control

group of the ISIS–2 study

(approximately 3 percent at 35 days).

Followup for this third study was longer

than for the ISIS–2 study (3 months

versus 35 days). Only subjects with

early signs of first anterior wall

infarction were eligible for entry in the

third study, while in the ISIS–2 study

subjects with only ‘‘suspected acute MI’’

were eligible. The more stringent entry

criteria and the longer followup period

may account for the higher incidence of

reinfarction in the control group and the

significant effect of aspirin on

reinfarction in the third study. A

detailed report of this study was not

submitted to the agency. Based on the

information provided, this study

provides little additional evidence of

the effectiveness of aspirin in treating

acute MI.

The fourth study (Ref. 6) was an

uncontrolled study to evaluate infarct

vessel patency in subjects started on

both aspirin (325 mg/day) and

dipyridamole (75 mg/day) after

thrombolytic therapy with

streptokinase. In the absence of a

control group, the study cannot provide

any information on the effectiveness of

aspirin in treating acute MI.

The second petition (Ref. 2) also

requested the agency to approve

professional labeling for aspirin for

prevention of fatal and nonfatal

cardiovascular events in patients with

suspected acute MI. The petition

requested approval of an initial dose of

‘‘at least 162 mg aspirin’’ during the 24

hours following acute MI, with

continued treatment for at least the

subsequent 30-day followup period at

the minimum dose of 162 mg/day. The

petition relied primarily on the results

of ISIS–2 (Ref. 3) to support the labeling

claim. Data from that study are

summarized above.

In addition to ISIS–2, the petition

included results of four published

efficacy studies of aspirin in acute MI

(Refs. 5, 7, 8, and 9). The study by

Verheugt et al. (Ref. 5) was also

submitted in the first petition and is

discussed above.

In the ISIS–2 pilot study (Ref. 7), there

was a nonsignificant reduction in

nonfatal reinfarction in 313 subjects

who received 325 mg aspirin on

alternate days compared with 306

subjects who received placebo. Inhospital death (all causes) was reported

to be significantly lower in the aspirintreated group. Postdischarge death was

reported at a similar rate in both the

aspirin and placebo subjects.

Elwood and Williams (Ref. 8) found

no evidence of reduced mortality in

males or females evaluated up to 28

days after a single 300 mg dose of

aspirin. Aspirin or placebo was

administered to 2,530 subjects, upon

first suspicion of acute MI. Analysis was
30006 Federal Register / Vol. 61, No. 115 / Thursday, June 13, 1996 / Proposed Rules

confined to 1,705 subjects in whom

acute MI was subsequently confirmed.

Husted et al. (Ref. 9) compared aspirin

100 mg/day, aspirin 1,000 mg/day, and

placebo in 293 subjects with suspected

acute MI. An intent-to-treat analysis

showed no significant difference

between groups. A significant benefit of

100 mg/day (but not 1,000 mg/day) on

the combined incidence of cardiac death

and nonfatal MI was found when

subjects who withdrew from the study

were excluded from the analysis. No

conclusions were drawn as to the

reasons for the difference in effect

between a 100 mg and 1,000 mg daily

dose.

The agency received additional

comments that raised other issues

related to professional labeling of

aspirin for cardiovascular use. Those

issues will be addressed in a future

issue of the Federal Register.

B. Summary of the Agency’s Evaluation

The agency has determined that the

ISIS–2 study (Ref. 3) supports the use of

aspirin at a dose of 162.5 mg/day,

started as soon as possible after an

infarction and continued for at least 30

days to reduce the risk of fatal and

nonfatal cardiovascular and

cerebrovascular events in subjects with

a suspected acute MI. The study also

shows that the effect of aspirin is not

diminished with concomitant early

treatment with a thrombolytic (i.e., an

immediate 1-hour, single-dose, infusion

of 1.5 million units of streptokinase).

Aspirin treatment should be started as

soon as the physician suspects an MI,

rather than delaying treatment until

definitive testing can be done. A

significant benefit of aspirin in reducing

the risk of vascular death was seen in

ISIS–2 for aspirin alone compared to

placebo as well as for aspirin plus

streptokinase compared to streptokinase

alone, representing, in effect, two

separate studies showing a benefit of

aspirin. This internal replication

supports the indication for treatment of

acute MI. The large number of

investigators involved in the study and

the consistency of results among

countries lend further credibility to the

results of this single study.

The benefit of aspirin is evident for

both all-cause mortality and vascular

mortality for aspirin alone and for

aspirin in addition to early thrombolytic

treatment. Although the most important

effect of aspirin in acute MI is the

reduction in mortality, small, but

statistically significant, decreases in

nonfatal reinfarction and stroke were

also found. Overall, the other studies

included in the petitions are consistent

with a favorable effect of aspirin in the

acute and subacute MI setting, but do

not provide substantial support for

ISIS–2. While the dosage in the ISIS–2

study was 162.5 mg enteric-coated

aspirin daily, the agency believes onehalf of a conventional 325-mg tablet or

two 80- or 81-mg tablets are also

reasonable doses (i.e., a range of 160 to

162.5 mg).

In the 1988 TFM (53 FR 46204 at

46229 and 46231), the agency proposed

(in § 343.20(b)(3)) that aspirin, buffered

aspirin, and aspirin in combination with

antacids are effective to treat patients

with TIA, a previous MI, or unstable

angina pectoris. That proposal was

based on recommendations of the

Peripheral and Central Nervous System

Drugs Advisory Committee, the agency’s

review of data submitted to show that

buffered aspirin would be expected to

have similar effects, and on the data

from an unstable angina trial that used

a highly buffered aspirin solution. Based

on those data, the agency is proposing

that aspirin, buffered aspirin, or aspirin

in combination with an antacid may be

used to treat patients with a suspected

acute MI. After the 30-day

recommended treatment with aspirin for

acute MI, physicians should consider

further therapy based on the labeling for

dosage and administration of aspirin for

prevention of recurrent MI

(reinfarction).

Based on the above discussion, the

agency is now proposing several

changes in the professional labeling

proposed in § 343.80(c) for OTC drug

products containing aspirin proposed in

§ 343.10(b) or permitted combinations

proposed in § 343.20(b)(3) as follows: (1)

Add information for treatment of a

suspected acute MI, and (2) revise some

of the previously proposed text based on

additional information from the ISIS–2

study (Ref. 8).

III. Summary of Agency Changes

In summary, the agency is proposing

to add the following to the professional

labeling in § 343.80(c): An indication for

aspirin to reduce the risk of vascular

mortality in patients with a suspected

acute MI; the findings of the ISIS–2

study under ‘‘Clinical Trials;’’ a dosage

of 160 to 162.5 mg for a suspected acute

MI taken as soon as the infarct is

suspected and then daily for at least 30

days; and a statement that this use of

aspirin applies to both solid, oral dosage

forms and buffered aspirin in solution.

To add the findings of the ISIS–2

study and to improve readability, the

agency is also proposing the following:

Change the heading from ‘‘Indication’’

to ‘‘Indications;’’ add the subheadings,

‘‘Recurrent MI (Reinfarction) or

Unstable Angina Pectoris’’ and

‘‘Suspected Acute MI,’’ under the

headings ‘‘Indications,’’ ‘‘Clinical

Trials,’’ and ‘‘Dosage and

Administration;’’ revise the text under

‘‘Gastrointestinal Reactions’’ and change

from 300 mg aspirin to 160 mg aspirin

daily the dosage level at which subjects

should have biochemical measurements

assessed; add a subheading, ‘‘Bleeding,’’

under the heading ‘‘Adverse Reactions’’

(after ‘‘Gastrointestinal Reactions’’);

renumber existing reference (8) as

reference (9); and add a new reference

(8).

IV. References

The following references are on

display in 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) Comment No. CP9, Docket No. 77N–

0094, Dockets Management Branch.

(2) Comment No. CP10, Docket No 77N–

0094, Dockets Management Branch.

(3) ISIS–2 (Second International Study of

Infarct Survival) Collaborative Group,

‘‘Randomized Trial of Intravenous

Streptokinase, Oral Aspirin, Both, or Neither

Among 17,187 Cases of Suspected Acute

Myocardial Infarction: ISIS–-2,’’ Lancet,

2:349–360, 1988.

(4) RISC Group, ‘‘Risk of Myocardial

Infarction and Death During Treatment with

Low Dose Aspirin and Intravenous Heparin

in Men with Unstable Coronary Artery

Disease,’’ Lancet, 336:827–830, 1990.

(5) Verheugt, F. W. et al., ‘‘Effects of Early

Intervention with Low-dose Aspirin (100 mg)

on Infarct Size, Reinfarction and Mortality in

Anterior Wall Acute Myocardial Infarction,’’

American Journal of Cardiology, 66:267–270,

1990.

(6) Hays, L. J. et al., ‘‘Short-term Infarct

Vessel Patency with Aspirin and

Dipyridamole Started 24 to 36 Hours After

Intravenous Streptokinase,’’ American Heart

Journal, 115:717–721, 1988.

(7) ISIS Pilot Study Investigators,

‘‘Randomized Factorial Trial of High-Dose

Intravenous Streptokinase, of Oral Aspirin

and of Intravenous Heparin in Acute

Myocardial Infarction,’’ European Heart

Journal, 8:634–642, 1987.

(8) Elwood, P. C., and W. O. Williams, ‘‘A

Randomized Controlled Trial of Aspirin in

the Prevention of Early Mortality in

Myocardial Infarction,’’ Journal of the Royal

College of General Practitioners, 29:413–416,

1979.

(9) Husted, S. E. et al., ‘‘Acetylsalicylic

Acid 100 mg and 1,000 mg Daily in Acute

Myocardial Infarction Suspects: A PlaceboControlled Trial,’’ Journal of Internal

Medicine, 226:303–310, 1989.

V. Enforcement Policy

The agency is allowing the proposed

professional labeling to be used prior to

the completion of a final rule for OTC

internal analgesic, antipyretic, and

antirheumatic drug products. This

decision is based on the substantial data
Federal Register / Vol. 61, No. 115 / Thursday, June 13, 1996 / Proposed Rules 30007

supporting the safety and effectiveness

of aspirin for suspected acute MI and on

the importance of early dissemination of

this information to health professionals.

Manufacturers who disseminate this

information must use the exact

professional labeling set forth in this

proposal. Such labeling may be

disseminated pending issuance of a

final rule, subject to the risk that the

agency may, in the final rule, adopt a

different position that could require

relabeling, recall, or other regulatory

action. Those manufacturers who do not

wish to revise the professional labeling

in accordance with this proposal may

continue to disseminate the labeling

proposed in the 1988 TFM (53 FR 46204

at 46258 through 46260) until a final

rule becomes effective. Dissemination of

professional labeling that is not in

accord with the labeling in the 1988

TFM or with this proposed amendment

to the 1988 TFM may result in

regulatory action against the product,

the marketer, or both.

VI. 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,

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. If this proposed rule becomes a

final rule, direct one-time costs

associated with changing professional

labeling will be imposed. That cost is

estimated to be less than $1 million.

Also, there appears to be a limited

number of aspirin products involved

because many manufacturers of these

products do not distribute professional

labeling for their products.

Manufacturers who do distribute such

professional labeling will have an

additional claim to make for their

product(s) and will have 1 year after

publication of the final rule to

implement this relabeling. Accordingly,

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.

The agency invites public comment

regarding any substantial or significant

economic impact that this rulemaking

would have on the professional labeling

of OTC internal analgesic, antipyretic,

and antirheumatic drug products that

contain aspirin, buffered aspirin, or

aspirin in combination with antacid.

Types of impact may include, but are

not limited to, costs associated with

relabeling. Comments regarding the

impact of this rulemaking on these OTC

drug products should be accompanied

by appropriate documentation. The

agency will evaluate any comments and

supporting data that are received and

will reassess the economic impact of

this rulemaking in the preamble to the

final rule.

VII. Paperwork Reduction Act of 1995

FDA tentatively concludes that the

labeling requirements proposed in this

document are not subject to review by

the Office of Management and Budget

because they do not constitute a

‘‘collection of information’’ under the

Paperwork Reduction Act of 1995 (44

U.S.C. 3501 et seq.). Rather, the

proposed labeling statements are a

‘‘public disclosure of information

originally supplied by the Federal

Government to the recipient for the

purpose of disclosure to the public’’ (5

CFR 1320.3(c)(2)).

VIII. Environmental Impact

The agency has determined under 21

CFR 25.24(c)(6) 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.

IX. Request for Comments

Interested persons may, on or before

September 11, 1996, submit to the

Dockets Management Branch (address

above) written comments regarding this

proposal. Written comments on the

agency’s economic impact

determination may be submitted on or

before September 11, 1996. Three copies

of all 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 and may be accompanied by

a supporting memorandum or brief.

Received comments may be seen in the

office above between 9 a.m. and 4 p.m.,

Monday through Friday.

List of Subjects in 21 CFR Part 343

Labeling, Over-the-counter drugs.

Therefore, under the Federal Food,

Drug, and Cosmetic Act and under

authority delegated to the Commissioner

of Food and Drugs, it is proposed that

21 CFR part 343 (proposed in the

Federal Register of November 16, 1988,

53 FR 46204) be amended as follows:

PART 343—INTERNAL ANALGESIC,

ANTIPYRETIC, AND ANTIRHEUMATIC

DRUG PRODUCTS FOR OVER–THE–

COUNTER HUMAN USE

1. The authority citation for 21 CFR

part 343 continues to read as follows:

Authority: Secs. 201, 501, 502, 503, 505,

510, 701 of the Federal Food, Drug, and

Cosmetic Act (21 U.S.C. 321, 351, 352, 353,

355, 360, 371).

2. Section 343.80 is amended by

revising paragraph (c) to read as follows:

§ 343.80 Professional labeling.

* * * * *

(c) For products containing aspirin

identified in § 343.10(b) or permitted

combinations identified in

§ 343.20(b)(3). The labeling states, under

the heading ‘‘ASPIRIN FOR

MYOCARDIAL INFARCTION,’’ the

following:

Indications:

Recurrent Myocardial Infarction (MI)

(Reinfarction) or Unstable Angina Pectoris

Aspirin is indicated to reduce the risk of

death and/or nonfatal MI in patients with a

previous MI or unstable angina pectoris.

Suspected Acute MI

Aspirin is indicated to reduce the risk of

vascular mortality in patients with a

suspected acute MI.

Clinical Trials:

Recurrent MI (Reinfarction) and Unstable

Angina Pectoris

The indication is supported by the results

of six large, randomized multicenter,

placebo-controlled studies involving 10,816,

predominantly male, post-MI subjects and

one randomized placebo-controlled study of

1,266 men with unstable angina (1–7).

Therapy with aspirin was begun at intervals

after the onset of acute MI varying from less

than 3 days to more than 5 years and

continued for periods of from less than 1 year

to 4 years. In the unstable angina study,

treatment was started within 1 month after

the onset of unstable angina and continued

for 12 weeks, and patients with complicating

conditions such as congestive heart failure

were not included in the study.

Aspirin therapy in MI subjects was

associated with about a 20-percent reduction

in the risk of subsequent death and/or

nonfatal reinfarction, a median absolute

decrease of 3 percent from the 12- to 22-

percent event rates in the placebo groups. In

aspirin-treated unstable angina patients the

reduction in risk was about 50 percent, a
30008 Federal Register / Vol. 61, No. 115 / Thursday, June 13, 1996 / Proposed Rules

reduction in the event rate of 5-percent from

the 10-percent rate in the placebo group over

the 12-weeks of the study.

Daily dosage of aspirin in the post-MI

studies was 300 milligrams in one study and

900 to 1,500 milligrams in five studies. A

dose of 325 milligrams was used in the study

of unstable angina.

Suspected Acute MI

The use of aspirin in patients with a

suspected acute MI is supported by the

results of a large, multicenter 2 x 2 factorial

study of 17,187 subjects with suspected acute

MI (8). Subjects were randomized within 24

hours of the onset of symptoms so that 8,587

subjects received oral aspirin (162.5

milligrams, enteric-coated) daily for 1 month

(the first dose crushed, sucked, or chewed)

and 8,600 received oral placebo. Of the

subjects, 8,592 were also randomized to

receive a single dose of streptokinase (1.5

million units) infused intravenously for

about 1 hour, and 8,595 received a placebo

infusion. Thus, 4,295 subjects received

aspirin plus placebo, 4,300 received

streptokinase plus placebo, 4,292 received

aspirin plus streptokinase, and 4,300

received double placebo.

Vascular mortality (attributed to cardiac,

cerebral, hemorrhagic, other vascular, or

unknown causes) occurred in 9.4 percent of

the subjects in the aspirin group and in 11.8

percent of the subjects in the oral placebo

group in the 35-day followup. This

represents an absolute reduction of 2.4

percent in the mean 35-day vascular

mortality attributable to aspirin and a 23-

percent reduction in the odds of vascular

death (2p < 0.00001).

Significant absolute reductions in mortality

and corresponding reductions in specific

clinical events favoring aspirin were found

for reinfarction (1.5 percent absolute

reduction, 45 percent odds reduction, 2p <

0.00001), cardiac arrest (1.2 percent absolute

reduction, 14.2 percent odds reduction, 2p <

0.01), and total stroke (0.4 percent absolute

reduction, 41.5 percent odds reduction, 2p <

0.01). The effect of aspirin over and above its

effect on mortality was evidenced by small,

but significant, reductions in vascular

morbidity in those subjects who were

discharged.

The beneficial effects of aspirin on

mortality were present with or without

streptokinase infusion. Aspirin reduced

vascular mortality from 10.4 to 8.0 percent

for days 0 to 35 in subjects given

streptokinase and reduced vascular mortality

from 13.2 to 10.7 percent in subjects given no

streptokinase.

The effects of aspirin and thrombolytic

therapy with streptokinase in this study were

approximately additive. Subjects who

received the combination of streptokinase

infusion and daily aspirin had significantly

lower vascular mortality at 35 days than

those who received either active treatment

alone (combination 8.0 percent, aspirin 10.7

percent, streptokinase 10.4 percent, and no

treatment 13.2 percent). While this study

demonstrated that aspirin has an additive

benefit in patients given streptokinase, there

is no reason to restrict its use to that specific

thrombolytic.

Adverse Reactions:

Gastrointestinal Reactions

Doses of 1,000 milligrams per day of

aspirin caused gastrointestinal symptoms and

bleeding that in some cases were clinically

significant. In the Aspirin Myocardial

Infarction Study (AMIS) (4) with 4,500 postinfarction subjects, the percentage incidences

of gastrointestinal symptoms for the aspirin

(1,000 milligrams of a standard, solid-tablet

formulation) and placebo-treated subjects,

respectively, were: Stomach pain (14.5

percent, 4.4 percent); heartburn (11.9

percent, 4.8 percent); nausea and/or vomiting

(7.6 percent, 2.1 percent); hospitalization for

gastrointestinal disorder (4.8 percent, 3.5

percent). Symptoms and signs of

gastrointestinal irritation were not

significantly increased in subjects treated for

unstable angina with 325 milligrams buffered

aspirin in solution.

Bleeding

In the AMIS and other trials, aspirintreated subjects had increased rates of gross

gastrointestinal bleeding. In the ISIS–2 study

(8), there was no significant difference in the

incidence of major bleeding (bleeds requiring

transfusion) between 8,587 subjects taking

162.5 milligrams aspirin daily and 8,600

subjects taking placebo (31 versus 33

subjects). There were five confirmed cerebral

hemorrhages in the aspirin group compared

with two in the placebo group, but the

incidence of stroke of all causes was

significantly reduced from 81 to 47 for the

placebo versus aspirin group (0.4 percent

absolute change). There was a small and

statistically significant excess (0.6 percent) of

minor bleeding in people taking aspirin (2.5

percent for aspirin, 1.9 percent for placebo).

No other significant adverse effects were

reported.

(Other applicable warnings related to the

use of aspirin as described in § 343.50(c) may

also be included here.)

Cardiovascular and Biochemical

In the AMIS trial (4), the dosage of 1,000

milligrams per day of aspirin was associated

with small increases in systolic blood

pressure (BP) (average 1.5 to 2.1 millimeters

Hg) and diastolic BP (0.5 to 0.6 millimeters

Hg), depending upon whether maximal or

last available readings were used. Blood urea

nitrogen and uric acid levels were also

increased, but by less than 1.0 milligram

percent.

Subjects with marked hypertension or

renal insufficiency had been excluded from

the trial so that the clinical importance of

these observations for such subjects or for

any subjects treated over more prolonged

periods is not known. It is recommended that

patients placed on long-term aspirin

treatment, even at doses of 160 milligrams

per day, be seen at regular intervals to assess

changes in these measurements.

Sodium in Buffered Aspirin for Solution

Formulations:

One tablet daily of buffered aspirin in

solution adds 553 milligrams of sodium to

that in the diet and may not be tolerated by

patients with active sodium-retaining states

such as congestive heart or renal failure. This

amount of sodium adds about 30 percent to

the 70- to 90-milliequivalent intake suggested

as appropriate for dietary treatment of

essential hypertension in the ‘‘1984 Report of

the Joint National Committee on Detection,

Evaluation, and Treatment of High Blood

Pressure’’ (9).

Dosage and Administration:

Recurrent MI (Reinfarction) and Unstable

Angina Pectoris

Although most of the studies used dosages

exceeding 300 milligrams, two trials used

only 300 milligrams, and pharmacologic data

indicate that this dose inhibits platelet

function fully. Therefore, 300 milligrams or

a conventional 325 milligram aspirin dose is

a reasonable, routine dose that would

minimize gastrointestinal adverse reactions.

This use of aspirin applies to both solid, oral

dosage forms (buffered and plain aspirin) and

buffered aspirin in solution.

Suspected Acute MI

The recommended dose of aspirin to treat

suspected acute MI is 160 to 162.5 milligrams

taken as soon as the infarct is suspected and

then daily for at least 30 days. (One-half of

a conventional 325-milligram aspirin tablet

or two 80- or 81-milligram aspirin tablets

may be taken.) This use of aspirin applies to

both solid, oral dosage forms (buffered, plain,

and enteric-coated aspirin) and buffered

aspirin in solution. If using a solid dosage

form, the first dose should be crushed,

sucked, or chewed. After the 30-day

treatment, physicians should consider further

therapy based on the labeling for dosage and

administration of aspirin for prevention of

recurrent MI (reinfarction).

(1) Elwood, P. C. et al., ‘‘A Randomized

Controlled Trial of Acetylsalicylic Acid in

the Secondary Prevention of Mortality from

Myocardial Infarction,’’ British Medical

Journal, 1:436–440, 1974.

(2) The Coronary Drug Project Research

Group, ‘‘Aspirin in Coronary Heart Disease,’’

Journal of Chronic Diseases, 29:625–642,

1976.

(3) Breddin, K. et al., ‘‘Secondary

Prevention of Myocardial Infarction: A

Comparison of Acetylsalicylic Acid,

Phenprocoumon or Placebo,’’ Homeostasis,

470:263–268, 1979.

(4) Aspirin Myocardial Infarction Study

Research Group, ‘‘A Randomized, Controlled

Trial of Aspirin in Persons Recovered from

Myocardial Infarction,’’ Journal of the

American Medical Association, 243:661–669,

1980.

(5) Elwood, P. C., and P. M. Sweetnam,

‘‘Aspirin and Secondary Mortality After

Myocardial Infarction,’’ Lancet, II:1313–1315,

December 22–29, 1979.

(6) The Persantine-Aspirin Reinfarction

Study Research Group, ‘‘Persantine and

Aspirin in Coronary Heart Disease,’’

Circulation, 62:449–461, 1980.

(7) Lewis, H. D. et al., ‘‘Protective Effects

of Aspirin Against Acute Myocardial

Infarction and Death in Men with Unstable

Angina, Results of a Veterans Administration

Cooperative Study,’’ New England Journal of

Medicine, 309:396–403, 1983.

(8) ISIS–2 (Second International Study of

Infarct Survival) Collaborative Group,

‘‘Randomized Trial of Intravenous

Streptokinase, Oral Aspirin, Both, or Neither

Among 17,187 Cases of Suspected Acute

Myocardial Infarction: ISIS–2,’’ Lancet,

2:349–360, August 13, 1988.
Federal Register / Vol. 61, No. 115 / Thursday, June 13, 1996 / Proposed Rules 30009

(9) ‘‘1984 Report of the Joint National

Committee on Detection, Evaluation, and

Treatment of High Blood Pressure,’’ United

States Department of Health and Human

Services and United States Public Health

Service, National Institutes of Health,

Publication No. NIH 84–1088, 1984.

Dated: June 5, 1996.

William K. Hubbard,

Associate Commissioner for Policy

Coordination.

[FR Doc. 96–14894 Filed 6–12–96; 8:45 am]

BILLING CODE 4160–01–F

ARMS CONTROL AND DISARMAMENT

AGENCY

22 CFR Part 603

Privacy Act Policy and Procedures

AGENCY: Arms Control and Disarmament

Agency.

ACTION: Notice of proposed rulemaking.

SUMMARY: The United States Arms

Control and Disarmament Agency

(ACDA) proposes to revise and restate in

their entirety its rules that govern the

means by which individuals can

examine and request correction of

ACDA records containing personal

information. By clarifying these rules,

this proposal will help the public

interact better with ACDA and is part of

ACDA’s effort to update and streamline

its regulations. ACDA invites comments

from interested groups and members of

the public on the proposed regulations.

DATES: To be considered, comments

must be delivered by mail or in person

to the address, or faxed to the telephone

number, listed below by 5 p.m. on

Friday, July 19, 1996.

ADDRESSES: Comments should be

directed to the Office of the General

Counsel, United States Arms Control

and Disarmament Agency, Room 5635,

320 21st Street, NW., Washington, DC

20451; FAX (202) 647–0024. Comments

will be available for inspection between

8:15 a.m. and 5 p.m. at the same

address.

FOR FURTHER INFORMATION CONTACT:

Frederick Smith, Jr., United States Arms

Control and Disarmament Agency,

Room 5635, 320 21st Street, NW.,

Washington, DC 20451, telephone (202)

647–3596.

SUPPLEMENTARY INFORMATION: ACDA

proposes to update, clarify, reorganize,

and streamline its rules implementing

the Privacy Act, as amended. In

addition to containing internal policies

and procedures, these regulations set

forth procedures whereby an individual

can determine if a system of records

maintained by ACDA contains records

pertaining to the individual and can

request disclosure and amendment of

such records. These regulations also set

forth the bases for denying amendment

requests and the procedures for

appealing such denials. ACDA does not

intend the proposed rules to materially

affect current ACDA standards, policies,

or practices.

Regulatory Flexibility Act Certification

It is hereby certified that the proposed

rule will not have a significant

economic impact on a substantial

number of small entities. Accordingly, a

regulatory flexibility analysis is not

required.

Executive Order 12866 Determination

ACDA has determined that the

proposed rule is not a significant

regulatory action within the meaning of

section 3(f) of that Executive Order.

Paperwork Reduction Act Statement

The proposed rule is not subject to the

provisions of the Paperwork Reduction

Act because it does not contain any

information collection requirements

within the meaning of that Act.

Unfunded Mandates Act Determination

ACDA has determined that the

proposed rule will not result in

expenditures by state, local, and tribal

governments, or by the private sector, of

more than $100 million in any one year.

Accordingly, a budgetary impact

statement is not required under section

202 of the Unfunded Mandates Reform

Act of 1995, 2 U.S.C. 1532.

List of Subjects in 22 CFR Part 603

Privacy Act.

The Proposed Regulations

ACDA proposes to revise 22 CFR part

603 to read as follows:

PART 603—PRIVACY ACT POLICY

AND PROCEDURES

Sec.

603.1 Purpose and scope.

603.2 Definitions.

603.3 Policy.

603.4 Requests for determination of

existence of records.

603.5 Requests for disclosure to an

individual of records pertaining to the

individual.

603.6 Requests for amendment of records.

603.7 Appeals from denials of requests.

603.8 Exemptions.

603.9 New and amended systems of

records.

603.10 Fees.

Authority: 5 U.S.C. 552a; 22 U.S.C. 2581;

and 31 U.S.C. 9701.

§ 603.1 Purpose and scope.

This part 603 contains the regulations

of the U.S. Arms Control and

Disarmament Agency implementing the

provisions of the Privacy Act of 1974, 5

U.S.C. 552a. In addition to containing

internal policies and procedures, these

regulations set forth procedures

whereby an individual can determine if

a system of records maintained by the

Agency contains records pertaining to

the individual and can request

disclosure and amendment of such

records. These regulations also set forth

the bases for denying amendment

requests and the procedures for

appealing such denials.

§ 603.2 Definitions.

As used in this part:

(a) Act means the Privacy Act of 1974,

5 U.S.C. 552a.

(b) ACDA and Agency mean the U.S.

Arms Control and Disarmament Agency.

(c) Privacy Act Officer means the

Agency official who receives and acts

upon inquiries, requests for access and

requests for amendment.

(d) Deputy Director means the Deputy

Director of the Agency.

(e) Individual means a citizen of the

United States or an alien lawfully

admitted for permanent residence;

(f) Maintain includes maintain,

collect, use, or disseminate;

(g) Record means any item, collection,

or grouping of information about an

individual that is maintained by an

agency, including, but not limited to,

education, financial transactions,

medical history, and criminal or

employment history and that contains

the name of, or the identifying number,

symbol, or other identification

particularly assigned to, the individual,

such as a finger or voice print or a

photograph;

(h) System of records means a group

of any records under the control of any

agency from which information is

retrieved by the name of the individual

or by some identifying number, symbol,

or other identification particularly

assigned to the individual;

(i) Statistical record means a record in

a system of records maintained for

statistical research or reporting purposes

only and not used in whole or in part

in making any determination about an

identifiable individual, except as

provided by section 8 of title 13 U.S.C.;

and

(j) Routine use means, with respect to

the disclosure of a record, the use of

such record for a purpose which is

compatible with the purpose for which

it was collected.