1. Joint NDAC/PAC meeting October 18, 2007 OTC Cold and Cough Products: Use in Children Advisory Committee Meeting October 18, 2007 Joel Schiffenbauer, MD Deputy Division Director/DNCE Office of Nonprescription Products Joel Schiffenbauer, MD Deputy Division Director/DNCE Office of Nonprescription Products

2. Joint NDAC/PAC meeting October 18, 2007 2 AgendaAgenda Introduction Monograph Petitioners Industry representatives FDA representatives Discussion Open public session Discussion and Questions Introduction Monograph Petitioners Industry representatives FDA representatives Discussion Open public session Discussion and Questions

3. Joint NDAC/PAC meeting October 18, 2007 3 What is the issue? Are cough/cold products safe and effective in children?

4. Joint NDAC/PAC meeting October 18, 2007 4 Citizen Petition Children are frequently afflicted by the common cold A growing body of evidence demonstrates that these products are not effective in young children Although typically considered safe by parents and pediatricians misuse has led to significant adverse effects in children under 6 Children are frequently afflicted by the common cold A growing body of evidence demonstrates that these products are not effective in young children Although typically considered safe by parents and pediatricians misuse has led to significant adverse effects in children under 6

5. Joint NDAC/PAC meeting October 18, 2007 5 Citizen Petition: Actions Requested Provide a statement to the public explaining that OTC antitussive, expectorant, nasal decongestant, antihistamine and combination cough and cold products have not been shown to be safe and effective for the treatment of cough and cold in children under six years of age

6. Joint NDAC/PAC meeting October 18, 2007 6 Citizen Petition: Actions Requested Notify manufacturers of these products whose labeling uses such terms as “infant” or “baby” or display images of children under the age of 6 that: –such marketing is not supported by scientific evidence and –manufacturers will be subject to enforcement action at any time Notify manufacturers of these products whose labeling uses such terms as “infant” or “baby” or display images of children under the age of 6 that: –such marketing is not supported by scientific evidence and –manufacturers will be subject to enforcement action at any time

7. Joint NDAC/PAC meeting October 18, 2007 7 Citizen Petition: Actions Requested Amend 21CFR 341 to require that labeling for OTC antitussive, expectorant, nasal decongestant, antihistamine and combination cough and cold products state: –these products have not been found to be safe or effective in children under 6 years of age for treatment of cough and cold and –these products should not be used for treatment of cough and cold in children under 6 years of age Amend 21CFR 341 to require that labeling for OTC antitussive, expectorant, nasal decongestant, antihistamine and combination cough and cold products state: –these products have not been found to be safe or effective in children under 6 years of age for treatment of cough and cold and –these products should not be used for treatment of cough and cold in children under 6 years of age

8. Joint NDAC/PAC meeting October 18, 2007 8 OTC Monographs OTC Drug Review –Safety/Efficacy review of OTC drugs marketed in US prior to 1975 >300,000 OTC drug products 800 active ingredients in multiple therapeutic categories OTC Drug Review –Safety/Efficacy review of OTC drugs marketed in US prior to 1975 >300,000 OTC drug products 800 active ingredients in multiple therapeutic categories

9. Joint NDAC/PAC meeting October 18, 2007 9 Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug Products for Over-the-Counter Human Use 21 CFR 341 Therapeutic Categories –Antihistamine (21 CFR 341.12) –Antitussive (21 CFR 341.14) –Bronchodilator (21 CFR 341.16) –Expectorant (21 CFR 341.18) –Nasal Decongestant (21 CFR 341.20) Therapeutic Categories –Antihistamine (21 CFR 341.12) –Antitussive (21 CFR 341.14) –Bronchodilator (21 CFR 341.16) –Expectorant (21 CFR 341.18) –Nasal Decongestant (21 CFR 341.20)

10. Joint NDAC/PAC meeting October 18, 2007 10 Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug Products for Over-the-Counter Human Use 21 CFR 341 Provides the following information: –Permitted active ingredients –Permitted combinations –Labeling Statement of identity Indications Directions for use Warnings –Professional labeling Provides the following information: –Permitted active ingredients –Permitted combinations –Labeling Statement of identity Indications Directions for use Warnings –Professional labeling

11. Joint NDAC/PAC meeting October 18, 2007 11 Examples of Combination Products Permitted in Monograph Decongestant and antihistamine Decongestant and expectorant Decongestant and analgesic Antitussive and expectorant Decongestant, antihistamine and antitussive Decongestant, antihistamine, antitussive and analgesic

12. Joint NDAC/PAC meeting October 18, 2007 12 Sales Data: IMS Health, IMS National Sales Perspectives™, Retail and Non-Retail –Provides in units the amount of drug products purchased by retail and non-retail settings of care –Possible surrogate for use, assuming that facilities purchase drugs in quantities reflective of actual patient use –Provides in units the amount of drug products purchased by retail and non-retail settings of care –Possible surrogate for use, assuming that facilities purchase drugs in quantities reflective of actual patient use

13. Joint NDAC/PAC meeting October 18, 2007 13 IMS Health, IMS National Sales Perspectives™, Years 2002 – 2006

14. Joint NDAC/PAC meeting October 18, 2007 14 IMS Health, IMS National Sales Perspectives™, Years 2002 – 2006

15. Joint NDAC/PAC meeting October 18, 2007 15 What is the issue? Are cough/cold products safe and effective in children? –Citizen petition What is the evidence for efficacy of these products in children? What is the safety profile of these products in children? Are cough/cold products safe and effective in children? –Citizen petition What is the evidence for efficacy of these products in children? What is the safety profile of these products in children?

16. Joint NDAC/PAC meeting October 18, 2007 16 EfficacyEfficacy Studies in children (limitations of study design) Extrapolation of PK data – E11 Guidance Document: Clinical investigations of medicinal products in the pediatric population (December 2000) –Examples: chlorpheniramine, pseudoephedrine Example of development and dosing determinations for drugs for treatment of allergic rhinitis Studies in children (limitations of study design) Extrapolation of PK data – E11 Guidance Document: Clinical investigations of medicinal products in the pediatric population (December 2000) –Examples: chlorpheniramine, pseudoephedrine Example of development and dosing determinations for drugs for treatment of allergic rhinitis

17. Joint NDAC/PAC meeting October 18, 2007 17 SafetySafety Medication errors Reports –Case reports/series in literature –AERS reports/TESS –Maryland Poison Control 2004 - children under 5 Approximately 1100 calls related to cold and cough products Approximately 1400 calls related to topical preparations products For cold and cough products: 5 cases were coded as having symptoms consistent with an outcome of “moderate effect” all had complete resolution with supportive care All 5 cases, except one, were acute accidental overdose (children inadvertently took medication) Medication errors Reports –Case reports/series in literature –AERS reports/TESS –Maryland Poison Control 2004 - children under 5 Approximately 1100 calls related to cold and cough products Approximately 1400 calls related to topical preparations products For cold and cough products: 5 cases were coded as having symptoms consistent with an outcome of “moderate effect” all had complete resolution with supportive care All 5 cases, except one, were acute accidental overdose (children inadvertently took medication)

18. Joint NDAC/PAC meeting October 18, 2007 18 Points to consider Is the disease process (common cold) similar in adults and children? –If so, is extrapolation of efficacy data appropriate for these indications? What additional PK data is needed? –If not, are clinical studies needed? consider difficulties with conducting studies in children What do the published studies contribute to our understanding of the efficacy of these products? Do they demonstrate that these products are not effective in children? Is the disease process (common cold) similar in adults and children? –If so, is extrapolation of efficacy data appropriate for these indications? What additional PK data is needed? –If not, are clinical studies needed? consider difficulties with conducting studies in children What do the published studies contribute to our understanding of the efficacy of these products? Do they demonstrate that these products are not effective in children?

19. Joint NDAC/PAC meeting October 18, 2007 19 Points to consider Are there safety issues that can be identified even when these drugs are used at the correct doses? What contribution does unintentional overdosing make to the overall safety profile of these drugs? –What factors might contribute to unintentional overdosing and are these cases preventable (dosing devices, varying concentrations, overlapping ingredients)? Are there safety issues that can be identified even when these drugs are used at the correct doses? What contribution does unintentional overdosing make to the overall safety profile of these drugs? –What factors might contribute to unintentional overdosing and are these cases preventable (dosing devices, varying concentrations, overlapping ingredients)?

20. Joint NDAC/PAC meeting October 18, 2007 20 Points to consider Are there ages for which these products should not be used (consider less than 2, 2 to less than 6, and 6-12)? If products are labeled “do not use” should this apply to consumers as well as to health care providers such that no one will use these products? How should we address the use of combination products and the potential for medication errors when products contain multiple ingredients? Are there ages for which these products should not be used (consider less than 2, 2 to less than 6, and 6-12)? If products are labeled “do not use” should this apply to consumers as well as to health care providers such that no one will use these products? How should we address the use of combination products and the potential for medication errors when products contain multiple ingredients?

21. Joint NDAC/PAC meeting October 18, 2007 21 DisclaimerDisclaimer The Agency has not reached any final decisions as to actions to be taken in response to the Citizen Petition. Any recommendations expressed by individual reviewers should not be considered final decisions by the Agency.