1. Regulatory History of Pediatric Cough/Cold Products Joint Meeting of the Nonprescription Drugs Advisory Committee (NDAC) and the Pediatric Advisory Committee (PAC) Silver Spring, Maryland October 18 & 19, 2007 Marina Y. Chang, R. Ph. Team Leader, Interdisciplinary Scientist Division of Nonprescription Regulation Development Office of Nonprescription Products Joint Meeting of the Nonprescription Drugs Advisory Committee (NDAC) and the Pediatric Advisory Committee (PAC) Silver Spring, Maryland October 18 & 19, 2007 Marina Y. Chang, R. Ph. Team Leader, Interdisciplinary Scientist Division of Nonprescription Regulation Development Office of Nonprescription Products Center for Drug Evaluation and Research

2. Joint Advisory Committee Meeting (NDAC/PAC) October 18 & 19, 2007 2 ContentContent OTC Monograph Process History of Cough/Cold Monograph –Pediatric Dosing Standardized Pediatric Dosing Schedule OTC Monograph Process History of Cough/Cold Monograph –Pediatric Dosing Standardized Pediatric Dosing Schedule

3. Joint Advisory Committee Meeting (NDAC/PAC) October 18 & 19, 2007 3

4. Joint Advisory Committee Meeting (NDAC/PAC) October 18 & 19, 2007 4 X X X

5. Joint Advisory Committee Meeting (NDAC/PAC) October 18 & 19, 2007 5 Regulation of OTC Drugs New Drug Application (NDA) –Drug product-specific –Confidential Monograph –Active ingredient-specific –Public New Drug Application (NDA) –Drug product-specific –Confidential Monograph –Active ingredient-specific –Public

6. Joint Advisory Committee Meeting (NDAC/PAC) October 18 & 19, 2007 6 OTC Monographs OTC Drug Review initiated in 1972 > 300,000 OTC drug products 800 active ingredients Classified into different therapeutic categories OTC Drug Review initiated in 1972 > 300,000 OTC drug products 800 active ingredients Classified into different therapeutic categories

7. Joint Advisory Committee Meeting (NDAC/PAC) October 18 & 19, 2007 7 OTC Monographs Category I: GRASE (Generally Recognized as Safe and Effective) Category II: not GRASE Category III: cannot determine if safe and effective Category I: GRASE (Generally Recognized as Safe and Effective) Category II: not GRASE Category III: cannot determine if safe and effective Advisory Review Panel

8. Joint Advisory Committee Meeting (NDAC/PAC) October 18 & 19, 2007 OTC Drug Monograph Process Advance Notice of Proposed Rulemaking (ANPR) ► Public comment period Tentative Final Monograph (TFM) ► Public comment period Final Monograph (FM) ► Effective regulation Advance Notice of Proposed Rulemaking (ANPR) ► Public comment period Tentative Final Monograph (TFM) ► Public comment period Final Monograph (FM) ► Effective regulation

9. Joint Advisory Committee Meeting (NDAC/PAC) October 18 & 19, 2007 9 What is in an OTC Drug Monograph? Active ingredients (GRAS/E) –Dosage Forms –Dose or Concentration –Permitted Combinations Required labeling (uses, warnings, directions) Professional labeling (if applicable) Active ingredients (GRAS/E) –Dosage Forms –Dose or Concentration –Permitted Combinations Required labeling (uses, warnings, directions) Professional labeling (if applicable)

10. Joint Advisory Committee Meeting (NDAC/PAC) October 18 & 19, 2007 10 Monograph Permitted Combinations 21 CFR 330.10(a)(4)(iv) May combine two or more GRASE ingredients when: –Each contributes to the claimed effect(s) –None decreases the safety and effectiveness of the other ingredients –Combination is a rational therapy May combine two or more GRASE ingredients when: –Each contributes to the claimed effect(s) –None decreases the safety and effectiveness of the other ingredients –Combination is a rational therapy

11. Joint Advisory Committee Meeting (NDAC/PAC) October 18 & 19, 2007 11 What is in a OTC Drug Monograph? Active ingredients (GRAS/E) –Dosage Forms –Dose or Concentration –Permitted Combinations Required labeling (uses, warnings, directions) Professional labeling (if applicable) Active ingredients (GRAS/E) –Dosage Forms –Dose or Concentration –Permitted Combinations Required labeling (uses, warnings, directions) Professional labeling (if applicable)

12. Joint Advisory Committee Meeting (NDAC/PAC) October 18 & 19, 2007 What is Professional Labeling for an OTC Ingredient? Information for healthcare providers for conditions that consumers can not self-diagnose or safely treat –Aspirin to treat rheumatoid arthritis –Antihistamine for children < 6 years Not on the “Drug Facts” label Information for healthcare providers for conditions that consumers can not self-diagnose or safely treat –Aspirin to treat rheumatoid arthritis –Antihistamine for children < 6 years Not on the “Drug Facts” label 12

13. Joint Advisory Committee Meeting (NDAC/PAC) October 18 & 19, 2007 13 ContentContent OTC Monograph Process History of Cough/Cold Monograph –Pediatric Dosing Standardized Pediatric Dosing Schedule OTC Monograph Process History of Cough/Cold Monograph –Pediatric Dosing Standardized Pediatric Dosing Schedule

14. Joint Advisory Committee Meeting (NDAC/PAC) October 18 & 19, 2007 14 Cough/Cold Advisory Review Panel (1972) Applied the standards for safety and effectiveness (21 CFR 330.10 (a)(4)) –Clinical Studies –Extensive marketing experience For active ingredients in these categories: –Antihistamine –Antitussive –Expectorant –Nasal Decongestant Applied the standards for safety and effectiveness (21 CFR 330.10 (a)(4)) –Clinical Studies –Extensive marketing experience For active ingredients in these categories: –Antihistamine –Antitussive –Expectorant –Nasal Decongestant

15. Joint Advisory Committee Meeting (NDAC/PAC) October 18 & 19, 2007 15 How the Panel Classified the Cough/Cold ingredients Pharmacological Group Panel Reviewed FM (GRASE) Antihistamine13 Antitussive228 Expectorants261 Nasal Decongestants3113 Total9235

16. Joint Advisory Committee Meeting (NDAC/PAC) October 18 & 19, 2007 16 What did the Cough/Cold Advisory Review Panel think about the Dosing for Children? (1972) Traditionally, dosing for infants and children has been based on weight, body surface area or age of the child as a proportion of the “usual adult dose” However the panel noted: –Data on use in children for most drugs is negligible or nonexistent –Dosing in a particular individual dependent on many factors –Definitive data should be derived from clinical trials with children, but these are extremely difficult to conduct –Need to make recommendation for pediatric dosage pending data Traditionally, dosing for infants and children has been based on weight, body surface area or age of the child as a proportion of the “usual adult dose” However the panel noted: –Data on use in children for most drugs is negligible or nonexistent –Dosing in a particular individual dependent on many factors –Definitive data should be derived from clinical trials with children, but these are extremely difficult to conduct –Need to make recommendation for pediatric dosage pending data

17. Joint Advisory Committee Meeting (NDAC/PAC) October 18 & 19, 2007 17 What did the Cough/Cold Advisory Review Panel recommend about Dosing for Children? (1972) Dosing calculated based on age is –Most convenient and easily understood –May be least reliable (weight variation) –History of wide margin of safety From adverse events reported Time and extent of use Dosing calculated based on age is –Most convenient and easily understood –May be least reliable (weight variation) –History of wide margin of safety From adverse events reported Time and extent of use

18. Joint Advisory Committee Meeting (NDAC/PAC) October 18 & 19, 2007 18 Children 6 to under 12 years of age: ½ the adult dose Children 2 to under 6 years of age: ¼ the adult dose Under 2 years of age: – Advice and supervision of a physician Except under the supervision of a doctor Consult a physician or Ask a doctor ANPR with the panel’s recommendation published in 1976 Children 6 to under 12 years of age: ½ the adult dose Children 2 to under 6 years of age: ¼ the adult dose Under 2 years of age: – Advice and supervision of a physician Except under the supervision of a doctor Consult a physician or Ask a doctor ANPR with the panel’s recommendation published in 1976 Cough/Cold Advisory Review Panel + Special Panel on Pediatric Dosing Recommendations (1974)

19. Joint Advisory Committee Meeting (NDAC/PAC) October 18 & 19, 2007 19 Cough/Cold Final Monograph Publications Therapeutic CategoryFinal Monograph Antitussive8/12/87 Expectorant2/28/89 Antihistamine12/9/92 Nasal Decongestant8/23/94 Permitted Combination12/23/02

20. Joint Advisory Committee Meeting (NDAC/PAC) October 18 & 19, 2007 20 ContentContent OTC Monograph Process History of Cough/Cold Monograph –Pediatric Dosing Standardized Pediatric Dosing Schedule OTC Monograph Process History of Cough/Cold Monograph –Pediatric Dosing Standardized Pediatric Dosing Schedule

21. Joint Advisory Committee Meeting (NDAC/PAC) October 18 & 19, 2007 21 Why did FDA propose a Standardized Pediatric Dosing Schedule? Different Advisory Review Panels recommended different pediatric dosing schedules based on age Different dosing schedules made it very difficult to make a combination product (e.g. internal analgesic + cough/cold ingredients) 24681012Age (yr): Cough/Cold: Internal Analgesic:

22. Joint Advisory Committee Meeting (NDAC/PAC) October 18 & 19, 2007 22 Federal Register Publication (1988) FDA considering proposing a rule about dosing information for children < 12 years FDA published a suggested dosing scheme based on age and weight and fraction of adult dose –Based on public comments FDA considering proposing a rule about dosing information for children < 12 years FDA published a suggested dosing scheme based on age and weight and fraction of adult dose –Based on public comments

23. Joint Advisory Committee Meeting (NDAC/PAC) October 18 & 19, 2007 23 Federal Register Publication (1988) (cont.) Federal Register Publication (1988) (cont.) Age (years)Weight (lb)Dosing Units* Adult Dose 4 months to < 112 to 1711/8 1 to < 218 to 231.53/16 2 to < 424 to 3521/4 4 to < 636 to 4733/8 6 to < 948 to 5941/2 9 to < 1160 to 7155/8 11 to < 1272 to 9563/4 12 and over96 and over81 * 1 dosing unit equals one-eighth adult dose

24. Joint Advisory Committee Meeting (NDAC/PAC) October 18 & 19, 2007 Federal Register Publication (1988) (cont.) Solicit comments on how pediatric dosing information should be presented in labeling: –Age and weight-based dosing schedule –Greater subdivisions of age ranges –Another approach? Solicit comments on how pediatric dosing information should be presented in labeling: –Age and weight-based dosing schedule –Greater subdivisions of age ranges –Another approach?

25. Joint Advisory Committee Meeting (NDAC/PAC) October 18 & 19, 2007 25 Comments Received After the 1988 FR Publication Varied No changes should be made –Monograph dosing is safe and effective Age ranges with corresponding weight ranges do not agree with the 1979 National Center for Health Statistics data Require pharmacokinetic (pK) studies Addition to dosing by weight/age: –length/height-based –surface area No changes should be made –Monograph dosing is safe and effective Age ranges with corresponding weight ranges do not agree with the 1979 National Center for Health Statistics data Require pharmacokinetic (pK) studies Addition to dosing by weight/age: –length/height-based –surface area

26. Joint Advisory Committee Meeting (NDAC/PAC) October 18 & 19, 2007 26 NDAC Meeting on Pediatric Dosing and Labeling (1995) Provide advice on pediatric dosing and labeling –Age, weight, height or length, body surface area or combination Answer: Weight, then age Is the current dosing approach adequate? Answer: 2-dose division is not adequate, but multi-dose divisions cannot be used for all products Provide advice on pediatric dosing and labeling –Age, weight, height or length, body surface area or combination Answer: Weight, then age Is the current dosing approach adequate? Answer: 2-dose division is not adequate, but multi-dose divisions cannot be used for all products

27. Joint Advisory Committee Meeting (NDAC/PAC) October 18 & 19, 2007 27 NDAC Meeting on Pediatric Dosing and Labeling (1995) (cont.) Should dosing ranges for specific ingredients/classes of drug products be the same? Answer: Case by case basis Should calibrated dosage devices be required? Answer: Not required, but nice to have What is the minimum age/weight to appear in labeling and should this be different for certain classes of drug? Answer: Depending on the drug Should dosing ranges for specific ingredients/classes of drug products be the same? Answer: Case by case basis Should calibrated dosage devices be required? Answer: Not required, but nice to have What is the minimum age/weight to appear in labeling and should this be different for certain classes of drug? Answer: Depending on the drug

28. Joint Advisory Committee Meeting (NDAC/PAC) October 18 & 19, 2007 Antihistamine Temporarily relieves runny nose, sneezing, itching of the nose or throat and itchy, watery eyes due to hay fever or other upper respiratory allergies. Temporarily relieves runny nose and sneezing associated with the common cold. ( currently allowed under the TFM ) Temporarily relieves runny nose, sneezing, itching of the nose or throat and itchy, watery eyes due to hay fever or other upper respiratory allergies. Temporarily relieves runny nose and sneezing associated with the common cold. ( currently allowed under the TFM )

29. Joint Advisory Committee Meeting (NDAC/PAC) October 18 & 19, 2007 Antitussive Required Temporarily reduces cough due to minor throat and bronchial irritation associated with a cold or inhaled irritants or Temporarily reduces cough associated with a cold or inhaled irritants May also state Cough suppressant which temporarily reduces the impulse to cough Temporarily helps you cough less Temporarily helps to reduce the cough reflex that causes coughing Temporarily reduces the intensity of coughing Reduces cough to help you sleep Required Temporarily reduces cough due to minor throat and bronchial irritation associated with a cold or inhaled irritants or Temporarily reduces cough associated with a cold or inhaled irritants May also state Cough suppressant which temporarily reduces the impulse to cough Temporarily helps you cough less Temporarily helps to reduce the cough reflex that causes coughing Temporarily reduces the intensity of coughing Reduces cough to help you sleep

30. Joint Advisory Committee Meeting (NDAC/PAC) October 18 & 19, 2007 Expectorant Helps loosen phlegm (mucus) and thin bronchial secretions to rid the bronchial passage of bothersome mucus and make coughs more productive

31. Joint Advisory Committee Meeting (NDAC/PAC) October 18 & 19, 2007 Nasal Decongestant Required Temporarily relieves nasal congestion due to (may state either or both) a cold hay fever or other upper respiratory allergies May Also State Temporarily relieves stuffy nose Reduces swelling of nasal passages Temporarily restores freer breathing through the nose Temporarily relieves sinus congestion and pressure Promotes nasal and/or sinus drainage Required Temporarily relieves nasal congestion due to (may state either or both) a cold hay fever or other upper respiratory allergies May Also State Temporarily relieves stuffy nose Reduces swelling of nasal passages Temporarily restores freer breathing through the nose Temporarily relieves sinus congestion and pressure Promotes nasal and/or sinus drainage