+ Legislative Advocacy: Why OTCs Go Over Parents’ Heads Allison Baxterbeck Elizabeth Chang Amy DiPilato

+ Case The mother of your 5 year old clinic patient brings her daughter in for a walk-in appointment. The child has had 3 days of URI symptoms. On exam, she is afebrile with normal vital signs for age. She is well appearing and in no distress, but does have nasal congestion and a mild cough. Her mother asks you, “What cough medicine is safe to give her?”

+ Background Historically, lack of pediatric drug testing Smaller market Ethical considerations Logistical issues Prior to 1990s, adult data was often extrapolated to children Trial and error approach to dosing drugs in children Occasionally disastrous results

+ Background Pure Food and Drug Act of 1906 Created the Food and Drug Administration (FDA) First set of consumer protection laws Federal Food, Drug, and Cosmetic Act of 1938 Passed in response to 107 deaths (many children) after ingestion of legally marketed Elixir of Sulfanilamide, which contained diethylene glycol Authorized FDA to demand evidence of drug safety

Pediatric Rule Allowed labeling of drugs for pediatric use based on extrapolation of adult safety data assuming: Disease course similar in adults and children Response to drug similar in adults and children Only a small number of drug studies resulted from this rule

+ Food and Drug Administration Modernization Act of 1997 (FDAMA) Financial incentives for pharmaceutical companies to conduct studies on children Voluntary Pediatric Exclusivity Provision Additional 6 months marketing exclusivity if the drug is voluntarily studied in children Applies to all formulations, dosages, and indications of drug

+ Best Pharmaceuticals for Children Act (2002) Main components Identify and prioritize drugs needing study Develop study requests in collaboration with experts from NIH, FDA, etc Conduct studies on priority drugs if manufacturers do not Extended provisions from FDAMA Pediatric Trials Network

Pediatric Research Equity Act (PREA) Allows FDA to require pediatric studies Required manufacturers of new drugs and biologic agents to conduct pediatric studies

+ FDA Amendments Act of 2007 BPCA reauthorized Extended provision of offering additional patent exclusivity of on- patent drugs tested in children Expanded NIH research program in drug testing in children NIH priority list Proposed pediatric study requests allow trials that need improved labeling to be tested by NIH if manufacturer refuses to do so

+ National Institute of Child Health and Human Development Division of NIH Responsible for providing 25% BPCA funding annually Primarily responsible for studies to develop Investigational New Drugs, label modifications for specific ages and indications Started Pediatric Pharmacology Research Network ( ) Specialized Centers in Research and Pediatric Developmental Pharmacology Program (2010-present)

+ Food and Drug Administration Safety and Innovation Act of 2012 Permanently reauthorized BPCA and PREA Encourages earlier pediatric study planning to ensure expedited pediatric drug information to patients and parents Gives FDA authority to ensure PREA requirements met on time Improves transparency of study data Increases focus on neonates

+ AAP: Committee on Drugs One of 27 national Committees that develop AAP policies and programs Reviews aspects of pediatric pharmacology [drug indications, contraindications, absorption rates, routes of administration, dosing, use precautions and mode of action as they apply to children] Advises the Board of Directors in matters related to drug labeling, safety and efficacy for Rx and OTC drugs Monitors federal legislation related to the drug approval process Promotes the need for expanded pediatric drug trials

+ Over-the-Counter (OTC) Monograph Established in 1972 by the FDA to evaluate safety and effectiveness of OTC products Drugs go through a 3 phase process: Advisory panel looks at active ingredients; reviews claims, recommends labeling: therapeutic indications, dosages, warnings FDA reviews ingredients based on based on panel’s reviews Publication of final regulations as drug monograph

+ Over-the-Counter (OTC) Monograph Essentially serves as a “cook book,” or list of recipes, that include acceptable ingredients, formulations, dosages and labeling for each category of drugs Products containing active ingredients or indications not in the monograph require an approved “New Drug Application” According to the FDA, OTC monographs are continually updated as needed

+ “The monograph process is no longer consistent with current best practices in pediatric pharmacology …While many monograph drugs are safe and effective for use in children… others continue to be labeled for children and heavily marketed to parents despite safety concerns and newer data showing a lack of efficacy in children.”

+ AAP’s Position The OTC monograph system needs reform The New Drug Application (NDA) is the gold standard for the review and approval of drugs based on robust clinical trials and modern standards of evidence Only drugs submitted under the NDA process are subject to the full scope of the pediatric drug laws, BPCA and PREA.

+ AAP’s Position The FDA should have the authority to quickly require the transition of a product from an OTC monograph  NDA when significant concerns about safety and/or efficacy arise The FDA should remove a product from the monograph or allow manufacturers a finite period to develop new data and submit an NDA before ultimate removal of the drug from the monograph Without new efficacy data, revision of monograph drugs should include a de novo review of the appropriateness of extrapolating adult efficacy to pediatric subpopulations.

+ In Short… The need for more research looking at the unique physiology of children: how drugs are absorbed, metabolized, and eliminated Data on age-specific therapeutic data using modern standards for safety and efficacy that are applicable to children not just adults. Recommending pediatric dosing based on peds-specific pharmacokinetic data AND efficacy data

+ OTC Cough/Cold Medications 1. Current recommendations/regulations 2. Timeline leading to current state of OTC cough/cold medications 3. Future directions and improvements

+ Current Recommendations and Regulations for Cough/Cold Meds Regulated under the Cough, Cold, Allergy, Bronchodilator, and Anti-asthmatic Drug Products monograph committee declared that “data on the use in children of most drugs in [cough and cold preparations] are negligible or nonexistent”

+ Current Recommendations AAP: Cough and cold medicines should not be prescribed or recommended for children under 4 years of age. FDA: Strongly recommends that OTC cough and cold products should not be used for infants and children under 2 years of age because serious and potentially life-threatening side effects could occur.

+ Lack of Evidence for Efficacy

+ Timeline of Changes: Early 2007: FDA review of – 54 reported child deaths decongestants and 69 from antihistamines March 2007: Citizen petition for Relabeling of Cough/Cold meds to advise against use in children <6yo August 2007: Federal health officials recommended “consult your physician”  Warning: Do not use in children under 2 yr unless directed by your doctor October 2007: Manufacturers voluntarily recall meds for children <2 and change labels

+ Timeline of Changes October 2007: FDA joint mtg - Pediatric Advisory Committee & Nonprescription Drug Advisory Committee: Unanimously vote: adult data should not be used Vote: 13 to 9 to Recommend FDA immediately take meds off market for kids < 6yo January 2008: FDA official statement against use of cough/cold meds in kids <2yr Began working on revising OTC Monograph

+ Timeline of Changes Fall 2008: Manufacturers voluntarily change labels to say: “Do not use” kids <4yr Warning on antihistamines: Do not use to sedate or make child sleepy October 2008: FDA Part 15 Hearing AAP recommended re-labeling against use <6yo, more studies on pharmacokinetics and efficacy in children

+ Effect of Changes: 2013 Study by Hampton et al: <2yo: ED visits for Adverse drug events decreased by 41% after market withdrawal 2-3yo: ED visits for ADE decreased by 32% with labeling revision No significant change in ED visits for ADEs for patients 4-5yo or 6- 11yo FDA has not published a proposal to amend OTC monograph despite recommendations from AAP and FDA’s own advisory committee

+ Future Directions Considering whether to regulate as New Drug Application rather than via OTC Monographs. Modify the OTC Monograph for children New labeling: Against use in children <6yo Making label changes a requirement and not voluntary Education for families about OTC medications

+ Case The mother of your 5 year old clinic patient brings her daughter in for a walk-in appointment. The child has had 3 days of URI symptoms. On exam, she is afebrile with normal vital signs for age. She is well appearing and in no distress, but does have nasal congestion and a mild cough. Her mother asks you, “What cough medicine is safe to give her?”

+ References National Committee Annual Report Committee on Drugs. N.d. MS. American Academy of Pediatrics. Web. 27 Jan "Background." Pediatric Trials Network. Eunice Kennedy Shriver National Institute of Child Health and Human Development, 31 Oct Web. 03 Feb "Best Pharmaceuticals for Children Act." About the BPCA. Eunice Kennedy Shriver National Institute of Child Health and Human Development, 13 May Web. 03 Feb "Drug Research and Children." Drug Research and Children. U.S. Department of Health and Human Services, 24 Aug Web. 03 Feb Hampton LM, Nguyen DB, Edwards JR, Budnitz DS. Cough and cold medication adverse events after market withdrawal and labeling revision. Pediatrics Dec;132(6): Legislation." Regulatory Information. U.S. Food and Drug Administration, 9 July Web. 03 Feb Neville, Katherine, MD. "Regulation of the Over the Counter Drug Products." US FDA Public Hearing. 24 Mar Presentation. "Safe & Effective Drugs for Children." Federal Advocacy. American Academy of Pediatrics, n.d. Web. 03 Feb "U.S. Food and Drug Administration." Over-the-Counter (OTC) Drug Monograph Process. N.p., 7 Jan Web. 27 Jan

+ References Pappas, Diane et al. The common cold in children: Treatment and prevention. UpToDate. January 20, Pappas DE, Hendley JO. The common cold and decongestant therapy. Pediatr Rev 2011; 32:47. Paul IM, Yoder KE, Crowell KR, et al. Effect of dextromethorphan, diphenhydramine, and placebo on nocturnal cough and sleep quality for coughing children and their parents. Pediatrics 2004; 114:e85. Schroeder K, Fahey T. Should we advise parents to administer over the counter cough medicines for acute cough? Systematic review of randomised controlled trials. Arch Dis Child 2002; 86:170. Taverner D, Latte J. Nasal decongestants for the common cold. Cochrane Database Syst Rev 2007; :CD Hutton N, Wilson MH, Mellits ED, et al. Effectiveness of an antihistamine-decongestant combination for young children with the common cold: a randomized, controlled clinical trial. J Pediatr 1991; 118:125. Clemens CJ, Taylor JA, Almquist JR, et al. Is an antihistamine-decongestant combination effective in temporarily relieving symptoms of the common cold in preschool children? J Pediatr 1997; 130:463. Taylor JA, Novack AH, Almquist JR, Rogers JE. Efficacy of cough suppressants in children. J Pediatr 1993; 122:799. Paul IM, Beiler J, McMonagle A, et al. Effect of honey, dextromethorphan, and no treatment on nocturnal cough and sleep quality for coughing children and their parents. Arch Pediatr Adolesc Med 2007; 161:1140. Smith SM, Schroeder K, Fahey T. Over-the-counter (OTC) medications for acute cough in children and adults in community settings. Cochrane Database Syst Rev 2014; 11:CD