Regulatory History ofRegulatory History ofPediatric Cough/Cold Products Pediatric Cough/Cold Products Regulatory History ofRegulatory History ofPediatric Cough/Cold Products Pediatric Cough/Cold Products
Joint Meeting of the Nonprescription Drugs Advisory Joint Meeting of the Nonprescription Drugs Advisory Committee (NDAC) and the Pediatric Advisory Committee (NDAC) and the Pediatric Advisory Committee (PAC)Committee (PAC)Silver Spring, MarylandSilver Spring, Maryland
October 18 & 19, 2007October 18 & 19, 2007
Marina Y. Chang, R. Ph.Team Leader, Interdisciplinary ScientistDivision of Nonprescription Regulation DevelopmentOffice of Nonprescription Products
Joint Meeting of the Nonprescription Drugs Advisory Joint Meeting of the Nonprescription Drugs Advisory Committee (NDAC) and the Pediatric Advisory Committee (NDAC) and the Pediatric Advisory Committee (PAC)Committee (PAC)Silver Spring, MarylandSilver Spring, Maryland
October 18 & 19, 2007October 18 & 19, 2007
Marina Y. Chang, R. Ph.Team Leader, Interdisciplinary ScientistDivision of Nonprescription Regulation DevelopmentOffice of Nonprescription Products
Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research
Joint Advisory Committee Meeting (NDAC/PAC)Joint Advisory Committee Meeting (NDAC/PAC)October 18 & 19, 2007October 18 & 19, 2007 2
ContentContentContentContent
• 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
Joint Advisory Committee Meeting (NDAC/PAC)Joint Advisory Committee Meeting (NDAC/PAC)October 18 & 19, 2007October 18 & 19, 2007 3
Joint Advisory Committee Meeting (NDAC/PAC)Joint Advisory Committee Meeting (NDAC/PAC)October 18 & 19, 2007October 18 & 19, 2007 4
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Joint Advisory Committee Meeting (NDAC/PAC)Joint Advisory Committee Meeting (NDAC/PAC)October 18 & 19, 2007October 18 & 19, 2007 5
Regulation of OTC DrugsRegulation of OTC DrugsRegulation of OTC DrugsRegulation 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
Joint Advisory Committee Meeting (NDAC/PAC)Joint Advisory Committee Meeting (NDAC/PAC)October 18 & 19, 2007October 18 & 19, 2007 6
OTC MonographsOTC MonographsOTC MonographsOTC 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
Joint Advisory Committee Meeting (NDAC/PAC)Joint Advisory Committee Meeting (NDAC/PAC)October 18 & 19, 2007October 18 & 19, 2007 7
OTC Monographs OTC Monographs
OTC Monographs 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
Joint Advisory Committee Meeting (NDAC/PAC)Joint Advisory Committee Meeting (NDAC/PAC)October 18 & 19, 2007October 18 & 19, 2007
OTC Drug Monograph ProcessOTC 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
Joint Advisory Committee Meeting (NDAC/PAC)Joint Advisory Committee Meeting (NDAC/PAC)October 18 & 19, 2007October 18 & 19, 2007 9
What is in an OTC Drug Monograph?What is in an OTC Drug Monograph?What is in an OTC Drug Monograph?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)
Joint Advisory Committee Meeting (NDAC/PAC)Joint Advisory Committee Meeting (NDAC/PAC)October 18 & 19, 2007October 18 & 19, 2007 10
Monograph Permitted Monograph Permitted CombinationsCombinations
21 CFR 330.10(a)(4)(iv)21 CFR 330.10(a)(4)(iv)
Monograph Permitted Monograph Permitted CombinationsCombinations
21 CFR 330.10(a)(4)(iv)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
Joint Advisory Committee Meeting (NDAC/PAC)Joint Advisory Committee Meeting (NDAC/PAC)October 18 & 19, 2007October 18 & 19, 2007 11
What is in a OTC Drug Monograph?What is in a OTC Drug Monograph?What is in a OTC Drug Monograph?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)
Joint Advisory Committee Meeting (NDAC/PAC)Joint Advisory Committee Meeting (NDAC/PAC)October 18 & 19, 2007October 18 & 19, 2007
What is Professional Labeling What is Professional Labeling for an OTC Ingredient?for an OTC Ingredient?
What is Professional Labeling What is Professional Labeling for an OTC Ingredient?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
Joint Advisory Committee Meeting (NDAC/PAC)Joint Advisory Committee Meeting (NDAC/PAC)October 18 & 19, 2007October 18 & 19, 2007 13
ContentContentContentContent
• 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
Joint Advisory Committee Meeting (NDAC/PAC)Joint Advisory Committee Meeting (NDAC/PAC)October 18 & 19, 2007October 18 & 19, 2007 14
Cough/ColdCough/Cold Advisory Review Panel (1972) Advisory Review Panel (1972)
Cough/ColdCough/Cold Advisory Review Panel (1972) 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
Joint Advisory Committee Meeting (NDAC/PAC)Joint Advisory Committee Meeting (NDAC/PAC)October 18 & 19, 2007October 18 & 19, 2007 15
How the Panel Classified the How the Panel Classified the Cough/Cold ingredientsCough/Cold ingredients
How the Panel Classified the How the Panel Classified the Cough/Cold ingredientsCough/Cold ingredients
Pharmacological Group
Panel Reviewed
FM(GRASE)
Antihistamine 13 13
Antitussive 22 8
Expectorants 26 1
Nasal Decongestants 31 13
Total 92 35
Joint Advisory Committee Meeting (NDAC/PAC)Joint Advisory Committee Meeting (NDAC/PAC)October 18 & 19, 2007October 18 & 19, 2007 16
What did the Cough/Cold Advisory Review What did the Cough/Cold Advisory Review Panel think about the Dosing for Children? Panel think about the Dosing for Children?
(1972) (1972)
What did the Cough/Cold Advisory Review What did the Cough/Cold Advisory Review Panel think about the Dosing for Children? Panel think about the Dosing for Children?
(1972) (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
Joint Advisory Committee Meeting (NDAC/PAC)Joint Advisory Committee Meeting (NDAC/PAC)October 18 & 19, 2007October 18 & 19, 2007 17
What did the Cough/Cold Advisory Review What did the Cough/Cold Advisory Review Panel recommend about Dosing for Panel recommend about Dosing for
Children?Children? (1972) (1972)
What did the Cough/Cold Advisory Review What did the Cough/Cold Advisory Review Panel recommend about Dosing for Panel recommend about Dosing for
Children?Children? (1972) (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
Joint Advisory Committee Meeting (NDAC/PAC)Joint Advisory Committee Meeting (NDAC/PAC)October 18 & 19, 2007October 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 + Cough/Cold Advisory Review Panel + Special Panel on Pediatric Dosing Special Panel on Pediatric Dosing
RecommendationsRecommendations (1974)(1974)
Cough/Cold Advisory Review Panel + Cough/Cold Advisory Review Panel + Special Panel on Pediatric Dosing Special Panel on Pediatric Dosing
RecommendationsRecommendations (1974)(1974)
Joint Advisory Committee Meeting (NDAC/PAC)Joint Advisory Committee Meeting (NDAC/PAC)October 18 & 19, 2007October 18 & 19, 2007 19
Cough/Cold Final MonographCough/Cold Final MonographPublicationsPublications
Cough/Cold Final MonographCough/Cold Final MonographPublicationsPublications
Therapeutic Category Final Monograph
Antitussive 8/12/87
Expectorant 2/28/89
Antihistamine 12/9/92
Nasal Decongestant 8/23/94
Permitted Combination 12/23/02
Joint Advisory Committee Meeting (NDAC/PAC)Joint Advisory Committee Meeting (NDAC/PAC)October 18 & 19, 2007October 18 & 19, 2007 20
ContentContentContentContent
• 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
Joint Advisory Committee Meeting (NDAC/PAC)Joint Advisory Committee Meeting (NDAC/PAC)October 18 & 19, 2007October 18 & 19, 2007 21
Why did FDA propose a Standardized Why did FDA propose a Standardized Pediatric Dosing Schedule? Pediatric Dosing Schedule?
Why did FDA propose a Standardized Why did FDA propose a Standardized Pediatric Dosing Schedule? 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)
• 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)
2 4 6 8 10 12Age (yr):
Cough/Cold:
Internal Analgesic:
Joint Advisory Committee Meeting (NDAC/PAC)Joint Advisory Committee Meeting (NDAC/PAC)October 18 & 19, 2007October 18 & 19, 2007 22
Federal Register PublicationFederal Register Publication (1988) (1988)
Federal Register PublicationFederal Register Publication (1988) (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
Joint Advisory Committee Meeting (NDAC/PAC)Joint Advisory Committee Meeting (NDAC/PAC)October 18 & 19, 2007October 18 & 19, 2007 23
Federal Register PublicationFederal Register Publication (1988) (1988) (cont.)(cont.)
Federal Register PublicationFederal Register Publication (1988) (1988) (cont.)(cont.)
Age (years) Weight (lb) Dosing Units*
Adult Dose
4 months to < 1 12 to 17 1 1/8
1 to < 2 18 to 23 1.5 3/16
2 to < 4 24 to 35 2 1/4
4 to < 6 36 to 47 3 3/8
6 to < 9 48 to 59 4 1/2
9 to < 11 60 to 71 5 5/8
11 to < 12 72 to 95 6 3/4
12 and over 96 and over 8 1* 1 dosing unit equals one-eighth adult dose
Joint Advisory Committee Meeting (NDAC/PAC)Joint Advisory Committee Meeting (NDAC/PAC)October 18 & 19, 2007October 18 & 19, 2007
Federal Register PublicationFederal Register Publication (1988) (1988) (cont.)(cont.)
Federal Register PublicationFederal Register Publication (1988) (1988) (cont.)(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?
Joint Advisory Committee Meeting (NDAC/PAC)Joint Advisory Committee Meeting (NDAC/PAC)October 18 & 19, 2007October 18 & 19, 2007 25
Comments Received After the Comments Received After the 1988 FR Publication Varied1988 FR Publication Varied
Comments Received After the Comments Received After the 1988 FR Publication Varied1988 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
Joint Advisory Committee Meeting (NDAC/PAC)Joint Advisory Committee Meeting (NDAC/PAC)October 18 & 19, 2007October 18 & 19, 2007 26
NDAC Meeting on Pediatric NDAC Meeting on Pediatric Dosing and Labeling (1995)Dosing and Labeling (1995)NDAC Meeting on Pediatric NDAC Meeting on Pediatric Dosing and Labeling (1995)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
Joint Advisory Committee Meeting (NDAC/PAC)Joint Advisory Committee Meeting (NDAC/PAC)October 18 & 19, 2007October 18 & 19, 2007 27
NDAC Meeting on Pediatric NDAC Meeting on Pediatric Dosing and Labeling (1995) Dosing and Labeling (1995) (cont.)(cont.)
NDAC Meeting on Pediatric NDAC Meeting on Pediatric Dosing and Labeling (1995) Dosing and Labeling (1995) (cont.)(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
Joint Advisory Committee Meeting (NDAC/PAC)Joint Advisory Committee Meeting (NDAC/PAC)October 18 & 19, 2007October 18 & 19, 2007
AntihistamineAntihistamine
• 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)
Joint Advisory Committee Meeting (NDAC/PAC)Joint Advisory Committee Meeting (NDAC/PAC)October 18 & 19, 2007October 18 & 19, 2007
AntitussiveAntitussive
RequiredTemporarily reduces cough due to minor throat and bronchial irritation associated with a cold or inhaled irritants
orTemporarily 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
RequiredTemporarily reduces cough due to minor throat and bronchial irritation associated with a cold or inhaled irritants
orTemporarily 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
Joint Advisory Committee Meeting (NDAC/PAC)Joint Advisory Committee Meeting (NDAC/PAC)October 18 & 19, 2007October 18 & 19, 2007
ExpectorantExpectorant
• Helps loosen phlegm (mucus) and thin bronchial secretions to rid the bronchial passage of bothersome mucus and make coughs more productive
• Helps loosen phlegm (mucus) and thin bronchial secretions to rid the bronchial passage of bothersome mucus and make coughs more productive
Joint Advisory Committee Meeting (NDAC/PAC)Joint Advisory Committee Meeting (NDAC/PAC)October 18 & 19, 2007October 18 & 19, 2007
Nasal DecongestantNasal DecongestantRequired
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