> Contents of Background Package

Background summary and draft questions

TAB 1 [Bayer HealthCare Citizen\'s Petition]{.underline}

-   Action requested

```{=html}
<!-- -->
```
-   Statement of grounds

-   Physicians Health Study

-   British Doctor Trial

-   Thrombosis Prevention Trial

-   Hypertension Optimal Treatment

-   Primary Prevention trial

-   Evaluation of Aspirin Safety

-   Risk Benefit Evaluation

```{=html}
<!-- -->
```
-   Regulatory Summary of aspirin Indications

-   Aspirin Primary Prevention Indication Worldwide

```{=html}
<!-- -->
```
-   Third Party recommendation

```{=html}
<!-- -->
```
-   Supporting published statements

```{=html}
<!-- -->
```
-   Proposed Labeling

```{=html}
<!-- -->
```
-   References

TAB 6 Federal Register Notice: Establishment of a Monograph for OTC
Internal Analgesic, Antipyretic, and Antirheumatic Drug Products - July
8, 1977

TAB 7 Federal Register Notice: Tentative Final Monograph for OTC
Internal Analgesic, Antipyretic, and Antirheumatic Drug Products -
November 16,1988

TAB 8 Federal Register Notice: Amendment to the Tentative Final
Monograph for OTC Internal Analgesic, Antipyretic, and Antirheumatic
Drug Products - June 13, 1996

TAB 9 Federal Register Notice: Final Rule for Professional Labeling of
Aspirin, Buffered Aspirin, and Aspirin in combination with Antacid Drug
Products - October 23, 1998

TAB 10 Review materials from 1989 reviews of Physician\'s Heath Study

TAB 11 Medical and Statistical Reviews of current Citizen\'s Petition
materials.

Background Information: An Amendment to the Final Rule for Professional
Labeling for Aspirin

A Joint Meeting of the

Cardiovascular and Renal Drugs & Nonprescription Drugs Advisory
Committee December 8, 2003

[Purp]{.underline}ose:

Bayer HealthCare submitted a Citizen\'s Petition (TAB 1) dated February
11, 2003, requesting FDA\'s approval for expanded cardiovascular
indications and labeling for the use of a daily aspirin regimen (75 mg
to 325 mg) in individuals: 1) with a 10 percent or greater risk of
coronary heart disease (CHD) over 10 years or 2) for whom there is a
positive benefit-risk as assessed by their healthcare providers.

> In support of their request, the petition provided results of five
> clinical trials in primary prevention: 1) Physician\'s Health Study
> (PHS) - 1988
>
> 2\) British Doctor\'s Trial (BDT) - 1988
>
> 3\) Thrombosis Prevention Trial (TPT) - 1998
>
> 4\) Hypertensive Optimal Treatment Study (HOT) - 1998
>
> 5\) Primary Prevention Project (PPP) - 2001

[Backgro]{.underline}und:

***Professional Labeling***

The petition is seeking to amend the current regulation, CFR 21 343.80
(TAB 2), \"Professional Labeling of Aspirin, Buffered Aspirin, and
Aspirin in Combination with Antacid Drug Products for OTC Internal
Analgesic, Antipyretic, and Antirheumatic Drug Products.\" TAB 3
contains the enlarged dosage and administration chart for the
professional labeling of aspirin that includes the indications,
recommended daily dose, and duration of therapy.

Professional labeling contains comprehensive prescribing information
(similar to that found on prescription labels) for the use of aspirin
for vascular indications, in patients who have undergone certain
revascularization procedures, and for rheumatologic diseases.

> The regulation constitutes FDA\'s approved labeling for this use of
> aspirin and is the labeling that is required to be provided to
> healthcare professionals by manufacturers if they choose to promote
> aspirin for this use.
>
> • This information may not appear in the OTC label.

***OTC Drug Review***

The professional labeling regulation was developed as part of the OTC
drug review. The review is a four­step notice and public comment
rulemaking process:

+----------------------------------+-----------------------------------+
| > OTC Drug Review                | > Description of the Process      |
+----------------------------------+-----------------------------------+
| > Advisory Review Panel          | > Evaluation of data submitted in |
|                                  | > response to FDA\'s              |
+----------------------------------+-----------------------------------+
|                                  | > call for data on an OTC drug    |
|                                  | > Product category,               |
+----------------------------------+-----------------------------------+
|                                  | > e.g., analgesic/antipyretic     |
|                                  | > drug products.                  |
+----------------------------------+-----------------------------------+
| > Advance Notice of Proposed     | > Publication of the Panel\'s     |
| > Rulemaking (ANPR)              | > recommendations along           |
+----------------------------------+-----------------------------------+
|                                  | > with FDA\'s proposed regulation |
|                                  | > based on these                  |
+----------------------------------+-----------------------------------+
|                                  | > recommendations with an         |
|                                  | > opportunity for                 |
+----------------------------------+-----------------------------------+
|                                  | > comment and submission of new   |
|                                  | > data.                           |
+----------------------------------+-----------------------------------+

+----------------------------------+-----------------------------------+
| > Tentative Final Monograph      | > FDA\'s proposed regulation      |
| > (TFM)                          | > based on FDA\'s                 |
+----------------------------------+-----------------------------------+
|                                  | > consideration of the Panel\'s   |
|                                  | > recommendations and             |
+----------------------------------+-----------------------------------+
|                                  | > comments and new data received  |
|                                  | > with an                         |
+----------------------------------+-----------------------------------+
|                                  | > opportunity for comment and     |
|                                  | > submission of new               |
+----------------------------------+-----------------------------------+
|                                  | > data.                           |
+----------------------------------+-----------------------------------+
| > Final Rule (FR)                | > FDA\'s regulation.              |
+----------------------------------+-----------------------------------+

[October 6, 1989 - FDA\'s Cardiovascular and Renal Drugs Advisory
Committee]{.underline} (TAB 4)

The Committee met to consider a claim for aspirin for the prevention of
primary (first) heart attack based on the findings of the U.S.
Physicians\' Health Study. The Committee was aware of the findings of
the BDT study, but only the findings from the PHS were presented in
detail.

***Advisory Committee Meetings***

> • The Committee did not have confidence in efficacy for prevention of
> fatal MI alone, although combined fatal and not-fatal MI appeared to
> be reduced. Aspirin had no effect on total cardiovascular mortality.
> The number of fatal strokes was too small to reach a conclusion. The
> Committee was divided 4-no, 3-yes whether there was a significant
> effect for increased hemorrhagic stroke in the aspirin group. The
> committee was also divided on the weight of the BDT. They voted 4-no,
> 3-yes that this outcome influenced their evaluation of the PHS.
>
> • The Committee recommended (by a 6 to 2 vote) that, although some
> claim should be considered for some high-risk group of patients,
> aspirin should not be used routinely in patients without risk factors
> or in women, until such patients had been studied. The Committee
> minority was concerned about the toxicity of aspirin and the number of
> normal individuals at low risk of having a heart attack who would be
> treated long-term.
>
> • The Committee recommended (by a 6 to 2 vote) that some type of
> primary claim for some group of patients could be developed. The
> committee was concerned that aspirin would be used in healthy people
> or inappropriate patient populations and would be promoted for such
> use.
>
> • The Committee unanimously agreed that patients should ask their
> doctor before beginning prophylactic therapy.

[January 23, 1997 - Cardiovascular and Renal Drugs Advisory Committee
and Nonprescription Drugs Advisory Committee]{.underline} (TAB 5)

The Committee met to discuss a Citizen\'s Petition from the Aspirin
Strategy Group, seeking broadened indications for professional labeling
for aspirin to include anyone at risk for heart attack and stroke.

> The Committee unanimously recommended that results from the Swedish
> Angina Pectoris Antiplatelet Trial supported the benefits for low-dose
> aspirin in patients with stable angina pectoris.
>
> • The Committee unanimously recommended that low-dose aspirin be
> extended to patients with arterial revascularization procedures, i.e.,
> CABG or PTCA.
>
> • The Committee recommended (by an 11 to 2 vote) that professional
> labeling should not include an indication for use in peripheral
> vascular disease because the evidence did not meet usual standards for
> approval.

*FEDERAL REGISTER Notices*

The active ingredient aspirin and its use for professional indications
has been extensively evaluated in the review. We have included Federal
Register documents related to the development of the rulemaking for
internal analgesic, antipyretic, and antirheumatic drug products for OTC
human use. This provides a frame of reference for the information
available in the public record and the rationale behind past decisions.

+------------------+-------------------------------------------+------+
| > **Federal      | > **Information in Notice**               | >    |
| > Register       |                                           |  **S |
| > Notice**       |                                           | ecti |
|                  |                                           | on** |
+------------------+-------------------------------------------+------+
| > Jul 8, 1977 42 | > FDA published the recommendations of    | >    |
| > FR 35346       | > the Advisory Review Panel on OTC        |  TAB |
|                  |                                           | > 6  |
+------------------+-------------------------------------------+------+
| > Establishment  | > Internal Analgesic and Antirheumatic    |      |
| > of a Monograph | > Drug Products (Internal Analgesic       |      |
+------------------+-------------------------------------------+------+
| > for OTC        | > Panel).                                 |      |
| > Internal       |                                           |      |
| > Analgesic,     |                                           |      |
+------------------+-------------------------------------------+------+
| > Antipyretic,   | > • Pages 35384-35386 contain the         |      |
| > and            | > Panel\'s extensive discussion on the    |      |
| > Antirheumatic  |                                           |      |
+------------------+-------------------------------------------+------+
| > Drug Products  | > effects of aspirin on platelet          |      |
|                  | > aggregation and increased bleeding      |      |
|                  | > time.                                   |      |
+------------------+-------------------------------------------+------+
| > November 16,   | > In the TFM (pages 46258-46260), the     | >    |
| > 1988 (53 FR    | > Agency proposed professional            |  TAB |
|                  |                                           | \'\] |
+------------------+-------------------------------------------+------+
| > 46204\)        | > labeling in § 343.80 for the use of     |      |
|                  | > aspirin for rheumatologic diseases, for |      |
+------------------+-------------------------------------------+------+
| > TFM for OTC    | > reducing the risk of recurrent          |      |
| > Internal       | > transient ischemic attacks (TIA\'s) or  |      |
|                  | > stroke                                  |      |
+------------------+-------------------------------------------+------+
| > Analgesic,     | > in men who have had transient ischemia  |      |
| > Antipyretic,   | > of the brain due to fibrin platelet     |      |
| > and            |                                           |      |
+------------------+-------------------------------------------+------+
| > Antirheumatic  | > emboli, and for reducing the risk of    |      |
| > Drug Products  | > death or nonfatal myocardial            |      |
+------------------+-------------------------------------------+------+
|                  | > infarction (MI) in patients with a      |      |
|                  | > previous infarction or unstable angina  |      |
+------------------+-------------------------------------------+------+
|                  | > pectoris.                               |      |
+------------------+-------------------------------------------+------+
|                  | > • The Agency also proposed professional |      |
|                  | > labeling for the use of carbaspirin     |      |
+------------------+-------------------------------------------+------+
|                  | > calcium, choline salicylate, magnesium  |      |
|                  | > salicylate, or sodium salicylate        |      |
+------------------+-------------------------------------------+------+
|                  | > for rheumatologic diseases.             |      |
+------------------+-------------------------------------------+------+
| > June 13, 1996  | > Amendment to the TFM to include an      | >    |
| > 61 FR 30002)   | > indication for the use of aspirin in    |  TAB |
|                  |                                           | > 8  |
+------------------+-------------------------------------------+------+
| > Amendment to   | > treating acute MI: an initial dose of   |      |
| > the TFM for    | > 160 to 162.5 mg to be continued daily   |      |
+------------------+-------------------------------------------+------+
| > OTC Internal   | > for at least 30 days.                   |      |
| > Analgesic,     |                                           |      |
+------------------+-------------------------------------------+------+
| > Antipyretic,   |                                           |      |
| > and            |                                           |      |
| > Antirheumatic  |                                           |      |
+------------------+-------------------------------------------+------+
| > Drug Products  |                                           |      |
+------------------+-------------------------------------------+------+
| > October 23,    | > In the final rule (pages 56803-56804),  | >    |
| > 1998 63 FR     | > the Agency concluded that the           |  TAB |
|                  |                                           | > 9  |
+------------------+-------------------------------------------+------+
| > 56802\)        | > available data did not support the      |      |
|                  | > professional labeling of aspirin for    |      |
|                  | > the                                     |      |
+------------------+-------------------------------------------+------+
| > FR for         | > prevention of first MI; some of the     |      |
| > Professional   | > reasons included the following:         |      |
| > Labeling of    |                                           |      |
+------------------+-------------------------------------------+------+
| > Aspirin,       |                                           |      |
| > Buffered       |                                           |      |
| > Aspirin, and   |                                           |      |
+------------------+-------------------------------------------+------+
| > Aspirin in     | • The PHS showed that some of the study   |      |
| > Combination    | patients had a prior MI and               |      |
| > with           |                                           |      |
+------------------+-------------------------------------------+------+
| > Antacid Drug   | aspirin is already known to reduce the    |      |
| > Products for   | risk of recurrent MI in such              |      |
+------------------+-------------------------------------------+------+
| > OTC Internal   | > patients.                               |      |
| > Analgesic,     |                                           |      |
+------------------+-------------------------------------------+------+
| > Antipyretic,   |                                           |      |
| > and            |                                           |      |
| > Antirheumatic  |                                           |      |
+------------------+-------------------------------------------+------+
| > Drug Products  | > • According to the PHS study protocol,  |      |
|                  | > subjects should not have had an         |      |
+------------------+-------------------------------------------+------+
|                  | > MI before randomization, but the        |      |
|                  | > Agency\'s evaluation showed 8% of the   |      |
+------------------+-------------------------------------------+------+
|                  | > subjects who suffered a nonfatal MI     |      |
|                  | > during the study also had evidence      |      |
+------------------+-------------------------------------------+------+
|                  | > of an old MI.                           |      |
+------------------+-------------------------------------------+------+
|                  | • The PHS, in particular, did not show a  |      |
|                  | statistically significant effect          |      |
+------------------+-------------------------------------------+------+
|                  | > when all deaths as well as nonfatal MI  |      |
|                  | > and stroke were combined.               |      |
+------------------+-------------------------------------------+------+
|                  | > • The BDT, despite its similarity to    |      |
|                  | > the PHS, does not support the use of    |      |
+------------------+-------------------------------------------+------+
|                  | > aspirin to prevent an initial MI.       |      |
+------------------+-------------------------------------------+------+
|                  | > • Currently approved indications:       |      |
+------------------+-------------------------------------------+------+
|                  | > • [Vascular]{.underline}: ischemic      |      |
|                  | > strokes and TIA, suspected acute MI,    |      |
|                  | > prevention of                           |      |
+------------------+-------------------------------------------+------+
|                  | > recurrent MI, unstable angina pectoris, |      |
|                  | > chronic stable angina pectoris.         |      |
+------------------+-------------------------------------------+------+
|                  | > • [Revascularization Procedures in      |      |
|                  | > Selected Individuals]{.underline}:      |      |
|                  | > CABG, PTCA,                             |      |
+------------------+-------------------------------------------+------+
|                  | > carotid endarterectomy.                 |      |
+------------------+-------------------------------------------+------+
|                  | • [Rheumatologic Disease]{.underline}:    |      |
|                  | rheumatoid arthritis, juvenile rheumatoid |      |
+------------------+-------------------------------------------+------+
|                  | > arthritis, spondyloarthropathies,       |      |
|                  | > osteoarthritis, arthritis and pleurisy  |      |
|                  | > of                                      |      |
+------------------+-------------------------------------------+------+
|                  | > SLE.                                    |      |
+------------------+-------------------------------------------+------+

![](media/image1.png){width="2.0631944444444446in"
height="0.65in"}![](media/image2.png){width="0.9930555555555556in"
height="0.2in"}![](media/image3.png){width="0.8833333333333333in"
height="0.85625in"}