Regulatory History of Pediatric Cough/Cold Products

Regulatory History ofPediatric 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 Center for Drug Evaluation and Research

Content • OTC Monograph Process • History of Cough/Cold Monograph • Pediatric Dosing • Standardized Pediatric Dosing Schedule

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New Drug Application (NDA) Drug product-specific Confidential Monograph Active ingredient-specific Public Regulation of OTC Drugs

OTC Monographs • OTC Drug Review initiated in 1972 • > 300,000 OTC drug products • 800 active ingredients • Classified into different therapeutic categories

Advisory Review Panel OTC Monographs • Category I: GRASE (Generally Recognized as Safe and Effective) • Category II: not GRASE • Category III: cannot determine if safe and effective

OTC Drug Monograph Process Advance Notice ofProposed Rulemaking (ANPR) ► Public comment period Tentative Final Monograph (TFM) ►Public comment period Final Monograph (FM) ► Effective regulation

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 Combinations21 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

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)

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

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

How the Panel Classified the Cough/Cold ingredients

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 childas 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 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

Cough/Cold Advisory Review Panel + Special Panel on Pediatric Dosing Recommendations (1974) • 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 Final MonographPublications

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) Age (yr): 2 4 6 8 10 12 Cough/Cold: Internal Analgesic: 21

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

Federal Register Publication (1988) (cont.) * 1 dosing unit equals one-eighth adult dose

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?

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

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

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

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)

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

Expectorant • Helps loosen phlegm (mucus) and thin bronchial secretions to rid the bronchial passage of bothersome mucus and make coughs more productive

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

Regulatory History of Pediatric Cough/Cold Products