regulatory history of pediatric cough/cold products joint meeting of the nonprescription drugs...

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



–Pediatric Dosing



X

X

X


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


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


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


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)





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


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?








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





–Pediatric Dosing




–Pediatric Dosing



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


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


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


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


• 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)


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





–Pediatric Dosing




–Pediatric Dosing



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:


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


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




• 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?


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


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


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


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)


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


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


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

regulatory history of pediatric cough/cold products joint meeting of the nonprescription drugs...

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