Regulatory History of AspirinRegulatory History of Aspirin Regulatory History of AspirinRegulatory History of Aspirin

Cardiovascular and Renal Drugs Advisory Committee Meeting

Michelle M. Jackson, Ph.D.Division of Over-The-Counter Drug Products

Cardiovascular and Renal Drugs Advisory Committee Meeting

Michelle M. Jackson, Ph.D.Division of Over-The-Counter Drug Products

Cardiovascular and Renal Drugs AC MeetingCardiovascular and Renal Drugs AC MeetingDecember 8, 2003December 8, 2003

2Cardiovascular and Renal Drugs AC MeetingCardiovascular and Renal Drugs AC MeetingDecember 8, 2003December 8, 2003

ContentContentContentContent

• The OTC Drug Monograph Process

• Regulatory History of Aspirin

• 1989 & 1997 Advisory Committee Discussions

• Professional Labeling for Aspirin

• The OTC Drug Monograph Process

• Regulatory History of Aspirin

• 1989 & 1997 Advisory Committee Discussions

• Professional Labeling for Aspirin

3Cardiovascular and Renal Drugs AC MeetingCardiovascular and Renal Drugs AC MeetingDecember 8, 2003December 8, 2003

OTC Drug Monograph ProcessOTC Drug Monograph ProcessOTC Drug Monograph ProcessOTC Drug Monograph Process

1. Advisory Review PanelsPanels submit reports to FDA

2. Advance Notice of Proposed Rulemaking (ANPR)Public comment period

3. Tentative Final Monograph (TFM)Public comment period

4. Final Monograph (FM)

1. Advisory Review PanelsPanels submit reports to FDA

2. Advance Notice of Proposed Rulemaking (ANPR)Public comment period

3. Tentative Final Monograph (TFM)Public comment period

4. Final Monograph (FM)

4Cardiovascular and Renal Drugs AC MeetingCardiovascular and Renal Drugs AC MeetingDecember 8, 2003December 8, 2003

OTC Drug ReviewOTC Drug ReviewOTC Drug ReviewOTC Drug Review

Citizen Petition (21 CFR 10.30)

• Right of citizens to petition the government

• Used to issue, amend, or revoke a regulation

• Used to take or refrain from taking certain actions

Citizen Petition (21 CFR 10.30)

• Right of citizens to petition the government

• Used to issue, amend, or revoke a regulation

• Used to take or refrain from taking certain actions

5Cardiovascular and Renal Drugs AC MeetingCardiovascular and Renal Drugs AC MeetingDecember 8, 2003December 8, 2003

OTC Drug Review OTC Drug Review (con’t)(con’t)OTC Drug Review OTC Drug Review (con’t)(con’t)

• OTC Drug Labeling – - OTC drug labeling provided for consumers

- Consumers are able to safely self medicate

• Professional Drug Labeling – - OTC drug labeling provided for healthcare

professionals (not for the general public) - Advice of a healthcare professional is needed

for the safe and effective use of the drug product

• OTC Drug Labeling – - OTC drug labeling provided for consumers

- Consumers are able to safely self medicate

• Professional Drug Labeling – - OTC drug labeling provided for healthcare

professionals (not for the general public) - Advice of a healthcare professional is needed

for the safe and effective use of the drug product

6Cardiovascular and Renal Drugs AC MeetingCardiovascular and Renal Drugs AC MeetingDecember 8, 2003December 8, 2003

Regulatory History of AspirinRegulatory History of Aspirin

• July 21, 1972 Review of OTC internal analgesic ingredients

Advisory Review Panel

• July 8, 1977 ANPR - Publication of OTC internal analgesic panel report

Public Comment Period

• November 16, 1988 TFM - Public Comment Period

• May 8, 1989 Comment: Sterling Drug Inc.Claim for aspirin for the prevention of primary heart attack

• October 6, 1989 Advisory Committee Meeting

• July 21, 1972 Review of OTC internal analgesic ingredients

Advisory Review Panel

• July 8, 1977 ANPR - Publication of OTC internal analgesic panel report

Public Comment Period

• November 16, 1988 TFM - Public Comment Period

• May 8, 1989 Comment: Sterling Drug Inc.Claim for aspirin for the prevention of primary heart attack

• October 6, 1989 Advisory Committee Meeting

7Cardiovascular and Renal Drugs AC MeetingCardiovascular and Renal Drugs AC MeetingDecember 8, 2003December 8, 2003

Regulatory History of Aspirin (con’t)Regulatory History of Aspirin (con’t)

• October 15, 1992 Aspirin Foundation (CP9): Claim for treating acute MI

• December 21, 1992 Aspirin Strategy Group (CP10): Claim for treating acute MI

• June 6, 1994 Aspirin Strategy Group (CP12): Claim for anyone at risk for MI and stroke

• June 13, 1996 Amendment to the TFM

• January 23, 1997 Advisory Committee Meeting

• October 23, 1998 Final Monograph: Professional Labeling

• October 15, 1992 Aspirin Foundation (CP9): Claim for treating acute MI

• December 21, 1992 Aspirin Strategy Group (CP10): Claim for treating acute MI

• June 6, 1994 Aspirin Strategy Group (CP12): Claim for anyone at risk for MI and stroke

• June 13, 1996 Amendment to the TFM

• January 23, 1997 Advisory Committee Meeting

• October 23, 1998 Final Monograph: Professional Labeling

8Cardiovascular and Renal Drugs AC MeetingCardiovascular and Renal Drugs AC MeetingDecember 8, 2003December 8, 2003

ANPR – July 8, 1977ANPR – July 8, 1977 Panel’s Report:Panel’s Report:

ANPR – July 8, 1977ANPR – July 8, 1977 Panel’s Report:Panel’s Report:

• Anti-platelet effects of aspirin

• Increased bleeding time

• Warnings against use in people with GI or bleeding problems, or during pregnancy

• No mention of CV claims

• Anti-platelet effects of aspirin

• Increased bleeding time

• Warnings against use in people with GI or bleeding problems, or during pregnancy

• No mention of CV claims

9Cardiovascular and Renal Drugs AC MeetingCardiovascular and Renal Drugs AC MeetingDecember 8, 2003December 8, 2003

TFM – November 16, 1988TFM – November 16, 1988 TFM – November 16, 1988TFM – November 16, 1988

• Proposed professional labeling for use of aspirin: - reducing the risk of recurrent TIAs or stroke in men

- reducing the risk of death and/or nonfatal MI

- rheumatologic diseases

• Proposed professional labeling for use of aspirin: - reducing the risk of recurrent TIAs or stroke in men

- reducing the risk of death and/or nonfatal MI

- rheumatologic diseases

10Cardiovascular and Renal Drugs AC MeetingCardiovascular and Renal Drugs AC MeetingDecember 8, 2003December 8, 2003

Comments to the TFMComments to the TFMComments to the TFMComments to the TFM

Professional Labeling for Aspirin:

• Use for primary prevention of MI

• Reduce the dose for TIA and stroke from 1,300 mg to 300 mg a day

• Include labeling for both men and women

Professional Labeling for Aspirin:

• Use for primary prevention of MI

• Reduce the dose for TIA and stroke from 1,300 mg to 300 mg a day

• Include labeling for both men and women

11Cardiovascular and Renal Drugs AC MeetingCardiovascular and Renal Drugs AC MeetingDecember 8, 2003December 8, 2003

1989 Advisory Committee Meeting 1989 Advisory Committee Meeting (PHS: Labeling claim for primary prevention of MI)(PHS: Labeling claim for primary prevention of MI)

1989 Advisory Committee Meeting 1989 Advisory Committee Meeting (PHS: Labeling claim for primary prevention of MI)(PHS: Labeling claim for primary prevention of MI)

• No effect on total cardiovascular mortality

• No data on routine use in men w/o risk factors and in women

• Concerns about use in healthy people or inappropriate patient populations

• No effect on total cardiovascular mortality

• No data on routine use in men w/o risk factors and in women

• Concerns about use in healthy people or inappropriate patient populations

12Cardiovascular and Renal Drugs AC MeetingCardiovascular and Renal Drugs AC MeetingDecember 8, 2003December 8, 2003

Amendment to the TFM Amendment to the TFM June 13, 1996 June 13, 1996

Amendment to the TFM Amendment to the TFM June 13, 1996 June 13, 1996

In response to 2 CPs requesting:

• an indication for use of aspirin in treating acute MI: initial dose of 160 mg to 162.5 mg continued daily for at least 30 days

In response to 2 CPs requesting:

• an indication for use of aspirin in treating acute MI: initial dose of 160 mg to 162.5 mg continued daily for at least 30 days

13Cardiovascular and Renal Drugs AC MeetingCardiovascular and Renal Drugs AC MeetingDecember 8, 2003December 8, 2003

1997 Advisory Committee Meeting 1997 Advisory Committee Meeting

CP requested an amendment to the CP requested an amendment to the professional labeling for aspirin in secondary professional labeling for aspirin in secondary

prevention of CV events in patientsprevention of CV events in patients::

1997 Advisory Committee Meeting 1997 Advisory Committee Meeting

CP requested an amendment to the CP requested an amendment to the professional labeling for aspirin in secondary professional labeling for aspirin in secondary

prevention of CV events in patientsprevention of CV events in patients::

• undergoing coronary, cerebral, or peripheral arterial revascularization procedures

• with chronic non-valvular atrial fibrillation

• requiring hemodialysis access with fistula or shunt

• with elevated risk due to some form of vascular disease

• undergoing coronary, cerebral, or peripheral

arterial revascularization procedures

• with chronic non-valvular atrial fibrillation

• requiring hemodialysis access with fistula or shunt

• with elevated risk due to some form of vascular disease

14Cardiovascular and Renal Drugs AC MeetingCardiovascular and Renal Drugs AC MeetingDecember 8, 2003December 8, 2003

1997 Advisory Committee Meeting 1997 Advisory Committee Meeting RecommendationsRecommendations

1997 Advisory Committee Meeting 1997 Advisory Committee Meeting RecommendationsRecommendations

• Low-dose aspirin in patients with stable angina

• Low-dose aspirin in patients with arterial revascularization procedures

• Not indicated in patients with peripheral vascular disease

• Low-dose aspirin in patients with stable angina

• Low-dose aspirin in patients with arterial revascularization procedures

• Not indicated in patients with peripheral vascular disease

15Cardiovascular and Renal Drugs AC MeetingCardiovascular and Renal Drugs AC MeetingDecember 8, 2003December 8, 2003

1998 Final Monograph1998 Final Monograph FDA’s Evaluation of the PHSFDA’s Evaluation of the PHS Reasons why the claim for primary preventionReasons why the claim for primary prevention

of MI was not included in the FMof MI was not included in the FM::

1998 Final Monograph1998 Final Monograph FDA’s Evaluation of the PHSFDA’s Evaluation of the PHS Reasons why the claim for primary preventionReasons why the claim for primary prevention

of MI was not included in the FMof MI was not included in the FM::

• Some subjects had prior MI

• 8% who suffered a nonfatal MI also had evidence of a previous MI

• No statistically significant effects of aspirin when fatal / nonfatal MI and stroke were combined

• Some subjects had prior MI

• 8% who suffered a nonfatal MI also had evidence of a previous MI

• No statistically significant effects of aspirin when fatal / nonfatal MI and stroke were combined

16Cardiovascular and Renal Drugs AC MeetingCardiovascular and Renal Drugs AC MeetingDecember 8, 2003December 8, 2003

1998 Final Monograph1998 Final Monograph FDA’s Evaluation of the PHSFDA’s Evaluation of the PHS (con’t)(con’t)

1998 Final Monograph1998 Final Monograph FDA’s Evaluation of the PHSFDA’s Evaluation of the PHS (con’t)(con’t)

• Reduction in the incidence of fatal and non-fatal MI was accompanied by an increase in:

- hemorrhagic stroke - sudden death - other CV deaths

• BDT does not support the use of aspirin to prevent initial MI

• Reduction in the incidence of fatal and non-fatal MI was accompanied by an increase in:

- hemorrhagic stroke - sudden death - other CV deaths

• BDT does not support the use of aspirin to prevent initial MI

17Cardiovascular and Renal Drugs AC MeetingCardiovascular and Renal Drugs AC MeetingDecember 8, 2003December 8, 2003

Professional LabelingProfessional LabelingProfessional LabelingProfessional Labeling

• Information does not appear on the OTC label

• Labeling is provided to healthcare professionals by manufacturers

• Prescribing information for:• vascular indications• revascularization procedures• rheumatologic diseases

• Information does not appear on the OTC label

• Labeling is provided to healthcare professionals by manufacturers

• Prescribing information for:• vascular indications• revascularization procedures• rheumatologic diseases

18Cardiovascular and Renal Drugs AC MeetingCardiovascular and Renal Drugs AC MeetingDecember 8, 2003December 8, 2003

Professional LabelingProfessional Labeling (cont.)(cont.)Professional LabelingProfessional Labeling (cont.)(cont.)

Professional Labeling of Aspirin

Components of Professional Labeling

Warnings Precautions

Adverse Reactions

Overdosage

Dosage & Administration

Contraindications

Indications

19Cardiovascular and Renal Drugs AC MeetingCardiovascular and Renal Drugs AC MeetingDecember 8, 2003December 8, 2003

Professional Labeling (cont.)Professional Labeling (cont.)Professional Labeling (cont.)Professional Labeling (cont.)

Vascular Indications

Indications Recommended Daily Dose(mg)

Ischemic Strokes / TIA 50 - 325

Suspected Acute MI 160 - 162.5

Prevention of Recurrent MI 75 - 325

Unstable Angina Pectoris 75 - 325

Chronic Stable Angina Pectoris 75 - 325

20Cardiovascular and Renal Drugs AC MeetingCardiovascular and Renal Drugs AC MeetingDecember 8, 2003December 8, 2003

Professional Labeling (cont.)Professional Labeling (cont.)Professional Labeling (cont.)Professional Labeling (cont.)

Revascularization Procedures

Indications Recommended Daily Dose(mg)

Coronary Artery 325 Bypass Graft

Percutaneous Transluminal Presurgery: 325 Coronary Artery Postsurgery: 160 - 325

Carotid Endarterectomy 80 - 650

21Cardiovascular and Renal Drugs AC MeetingCardiovascular and Renal Drugs AC MeetingDecember 8, 2003December 8, 2003

Bayer Healthcare’s RequestBayer Healthcare’s RequestBayer Healthcare’s RequestBayer Healthcare’s Request

• Professional labeling for the use of aspirin regimen (75-325 mg) for primary prevention of MI in patients at risk for a CHD

• Professional labeling for the use of aspirin regimen (75-325 mg) for primary prevention of MI in patients at risk for a CHD

22Cardiovascular and Renal Drugs AC MeetingCardiovascular and Renal Drugs AC MeetingDecember 8, 2003December 8, 2003

23Cardiovascular and Renal Drugs AC MeetingCardiovascular and Renal Drugs AC MeetingDecember 8, 2003December 8, 2003