Contents of Background Package

Background summary and draft questions

TAB 1           Bayer HealthCare Citizen's Petition

¨      Action requested

¨      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

¨      Regulatory Summary of aspirin Indications

¨      Aspirin Primary Prevention Indication Worldwide

¨      Third Party recommendation

¨      Supporting published statements

¨      Proposed Labeling

¨      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

Purpose:

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

Background:

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 Rulemaking (ANPR)	Publication of the Panel's recommendations along
	with FDA's proposed regulation based on these
	recommendations with an opportunity for
	comment and submission of new data.

 

Tentative Final Monograph (TFM)	FDA's proposed regulation 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 (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 (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 Register Notice	Information in Notice	Section
Jul 8, 1977 42 FR 35346	FDA published the recommendations of the Advisory Review Panel on OTC	TAB 6
Establishment of a Monograph	Internal Analgesic and Antirheumatic Drug Products (Internal Analgesic
for OTC Internal Analgesic,	Panel).
Antipyretic, and Antirheumatic	• Pages 35384-35386 contain the Panel's extensive discussion on the
Drug Products	effects of aspirin on platelet aggregation and increased bleeding time.
November 16, 1988 (53 FR	In the TFM (pages 46258-46260), the Agency proposed professional	TAB']
46204)	labeling in § 343.80 for the use of aspirin for rheumatologic diseases, for
TFM for OTC Internal	reducing the risk of recurrent transient ischemic attacks (TIA's) or stroke
Analgesic, Antipyretic, and	in men who have had transient ischemia of the brain due to fibrin platelet
Antirheumatic Drug Products	emboli, and for reducing the risk of 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 61 FR 30002)	Amendment to the TFM to include an indication for the use of aspirin in	TAB 8
Amendment to the TFM for	treating acute MI: an initial dose of 160 to 162.5 mg to be continued daily
OTC Internal Analgesic,	for at least 30 days.
Antipyretic, and Antirheumatic
Drug Products
October 23, 1998 63 FR	In the final rule (pages 56803-56804), the Agency concluded that the	TAB 9
56802)	available data did not support the professional labeling of aspirin for the
FR for Professional Labeling of	prevention of first MI; some of the reasons included the following:
Aspirin, Buffered Aspirin, and
Aspirin in Combination with	• The PHS showed that some of the study patients had a prior MI and
Antacid Drug Products for	aspirin is already known to reduce the risk of recurrent MI in such
OTC Internal Analgesic,	patients.
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: ischemic strokes and TIA, suspected acute MI, prevention of
	recurrent MI, unstable angina pectoris, chronic stable angina pectoris.
	• Revascularization Procedures in Selected Individuals: CABG, PTCA,
	carotid endarterectomy.
	• Rheumatologic Disease: rheumatoid arthritis, juvenile rheumatoid
	arthritis, spondyloarthropathies, osteoarthritis, arthritis and pleurisy of
	SLE.

	BDT	PHS	TPT	PPP
All-cause mortality
Cardiovascular mortality
CV death + MI + stroke
Fatal MI + fatal stroke
Fatal or non-fatal MI
Fatal or non-fatal stroke
Non-fatal MI
Non-fatal stroke
Silent MI			,/