Testimony of Alejandro Necochea, M.D., M.P.H., and Peter Lurie, M.D., M.P.H.
Health Research Group at Public Citizen
at Food and Drug Administration Part 15 Public Hearing
on Pediatric Use of Cough and Cold Products
Public Citizen welcomes the opportunity to present its position on the availability of over-the-counter (OTC) pediatric cough and cold formulations. But our most fundamental question is this: Why is this meeting taking place at all? The Food and Drug Administration (FDA) has all the legal authority it needs to propose changes to the existing cough and cold monograph, review the comments submitted and remove these products from the market should no data supporting their availability be generated. This hearing may generate some useful information, but mostly it represents an unnecessary delay in efforts to protect children from these ineffective and hence needlessly dangerous products.
Over a year ago, a joint meeting of the Nonprescription Drugs and the Pediatric Advisory Committees concluded that OTC cough and cold medications should not be given to children under 6 years of age. At the time, the Committees cited safety concerns and mounting evidence that these drugs are not effective in children. On January 17, 2008, the FDA announced that these products should not be used in children under 2, but that they could continue to be available for children over 2 while the agency reviewed the data for children 2 to 11. In fact, the leading manufacturers of pediatric cough and cold medications had already claimed prior to the advisory committee meeting that products for the under-2 market would no longer be sold.
Despite the manufacturers’ assurances, these products are still readily available. We visited two pharmacies (one in Washington, DC and one in Baltimore) last week and found that only 8 out of 34 (24%) cough and cold medications intended for pediatric use warn parents not to give these formulations to children under 2 years of age. Some of these medications were manufactured after the voluntary withdrawal. Asking parents to “consult [their] doctor” (74% of products) for infant dosages does not amount to an effective withdrawal, especially when many of the adverse events with these medications are seen among people who do not have a regular doctor.Among the brand names suggesting doctor consultation for under-2s are Pediacare, Robitussin, and Triaminic-three of the brands that voluntarily withdrew their under-2 products in 2007. Furthermore, we found 2 products (Toddler’s Dimetapp and Pediatric Robitussin) that included droppers or an “oral syringe” for easier administration of medication to very young children. We also found 3 products with pictures of young children on the box. It appears that the much-touted voluntary withdrawal was more successful in gaining the companies favorable PR and putting off more definitive FDA action than it was in protecting the health of children.
The needless delay by the FDA and the continued sale of these products might be acceptable if new scientific data undermining the advisory committees’ conclusions had been generated. But, in fact, the few new studies published in the past year support the committee’s general conclusions concerning lack of efficacy and safety problems. The sole efficacy study was published last December and showed that dextromethorphan (DM) was no better than no treatment in ameliorating cough in children. In this study, 105 children ages 2 to 18 with upper respiratory infection-related cough were randomized to receive no treatment honey-flavored DM or honey. Honey, but not DM, was found to be significantly superior to no treatment in relieving the primary outcome of cough frequency. Honey and DM were not statistically different from one another on this measure.
In the absence of direct evidence that a product is effective, no amount of toxicity is acceptable.
In addition, during the past year, more studies have highlighted the safety concerns related to OTC cough-and-cold medications. Based on a sampling of emergency rooms (ERs), Schaefer estimated that ER visits for cough-and-cold medication adverse events accounted for 6% of medication-related ER visits for children under 12. Sixty-four percent of the visits were for children 2 to 5 years old. Pitetti showed that 5% of infants with apparently life-threatening events presenting to an ER had positive toxicology results for OTC cough-and-cold medications.Remsza showed that 10 out of 90 unexplained infant deaths in Arizona in 2006 were associated with cough-and-cold medications.
In fact, there is evidence that OTC cough-and-cold products are more widely used than previously thought. Between 1999 and 2006, 1 in 10 US children younger than 18 used one of these medications in any given week. Although most use occurs in children under 6 years of age, 2-6% of children 6 to 11 used these medications in any given week.
We would like to draw particular attention to the lack of evidence that these medications are effective in the 6-11 age group, as the FDA’s focus seems to be in the under-6 population. In preparing a response to last year’s Citizen’s Petition about these drugs, the FDA Medical Officer found only 11 clinical trials involving children treated with cough-and-cold medications over the past 50 years. The Medical Officer concluded that, “Based on the review of published clinical trials in children (1½ months to 18 years old), there is no convincing evidence of efficacy of cough and cold medication when used to treat symptoms of the common cold in this population.”(The newest efficacy study does not provide an age breakdown on the overall finding of inefficacy.) If the dictates of science (and the law) are to be followed, these products should not be labeled for use in anyone under 12 unless new data undermine the Medical Officer’s conclusion.
The FDA seems concerned that the public might start using adult formulations of the drugs, with consequent “greater risk of misuse or overdose.” A parallel situation occurred in the 1980s, when the link between Reye’s syndrome and aspirin use was discovered. The CDC and the Surgeon General issued warnings in 1980 and 1982 advising against the use of aspirin in children. In 1985, some aspirin manufacturers agreed to a voluntary label warning against the use of aspirin in children with influenza-like illnesses or varicella, and a mandatory warning label was required on all aspirin-containing medications starting in 1986. Cases of Reye’s syndrome dropped sharply and in a stepwise manner after each of these warnings, with no evidence of increased incidence from the use of adult formulations of aspirin. Even if there was some substitution of adult for pediatric formulations, it is clear that the net effect of these warnings and labels was beneficial to the public health.
The statute provides no leeway: products without evidence of safety and effectiveness need to be removed from the market. However, any ban on pediatric OTC cough and cold medications should be accompanied by a comprehensive national educational campaign that would address the potential substitution issue.
Before concluding, we would like to comment on the FDA’s request for suggestions on how to conduct safety and effectiveness trials on OTC pediatric cough-and-cold medications. Certainly, the current gold standard is a randomized, controlled trial, using a placebo or no-treatment arm as the control. Pre-specified age-group ranges up to 12 but including several age groups under 2 years of age should be used to determine appropriate pediatric doses and effectiveness. To monitor safety, we recommend the establishment of a database comprised of patients in the RCTs and patients prospectively followed in uncontrolled trials, because efficacy studies alone will likely be too small to exclude any but the most frequent (and already well-known) adverse events. We also suggest that participants include individuals from populations shown to be at disproportionately higher risk of adverse events from these medications: the poor, underinsured, and those with low English literacy.
The industry has made much of the purported difficulties in conducting studies in the pediatric population, but this claim is overblown. The involvement of parents (e.g., cough counts) can improve the quality of the studies by yielding more objective outcome measures and randomization should preclude most biases. Moreover, the argument that the studies that have been conducted to date may have been too small to detect the effectiveness of these products is purely theoretical. The fact is that the studies, as designed and conducted, failed to detect any benefit and assumptions about what might happen with larger sample sizes are mere speculation.
Modern scientific understanding precludes the simple extrapolation of adult data to the pediatric population. The embarrassingly outdated practice of formulating pediatric doses by dividing by 2 or 4 must also be abandoned.
In conclusion, we would like to make two over-arching points and four more detailed ones: The FDA should 1) proceed with the amendment of the OTC cough-and-cold monograph through a more expedited process than it appears to contemplate, and 2) ensure that OTC cough-and-cold medications for children under 12 are removed from the market as soon as possible unless new data prove them safe and effective.
Our more detailed points are as follows:
1) Delivery devices that clearly are intended only for children, such and droppers and syringes should be removed from the market. It is a mixed message to recommend against newborn and toddler use and then have formulations specifically designed for newborns and toddler available for purchase, as our little survey showed is still the case.
2) Because there is no evidence from the studies available that there is demonstrable efficacy for children at all, the label’s exhortation against pediatric use should extend to children 12 years and under.
3) Any photographs or other representations on the box of children appearing to be 12 or under should be prohibited.
4) Because many of the overdoses have resulted from confusion over the contents of these multi-ingredient formulations, we recommend that the FDA allow only single-ingredient formulations to be sold. This would likely lead to more rational use of these ingredients, replacing the shotgun approach to therapy that currently predominates.
We again urge the FDA to take a firm, more determined stance regarding this issue. With each passing month we see more unnecessary cases of child poisoning from these products and millions more parents squandering their earnings on these ineffective medications. The FDA should set and adhere to a strict time table for its actions. If the manufacturers fail to comply with the time table, the FDA should simply proceed with a rulemaking and, in the absence of evidence to the contrary, exclude the non-complying products from the amended monograph.
 Food and Drug Administration. Public Health Advisory: Nonprescription Cough and Cold Medicine Use in Children. Jan 17, 2008. Accessed on September 30, 2008, at: http://www.fda.gov/cder/drug/advisory/cough_cold_2008.htm. Now available at: http://www.fda.gov/Drugs/DrugSafety/PublicHealthAdvisories/ucm051137.html.
 Rimsza M, Newberry S. Unexpected deaths associated with use of cough and cold medications. Pediatrics. August 2008;122(2):e318-22.
 Paul I, Beiler J, McMonagle A, Shaffer M, Duda L, Berlin C. Effect of honey, dextromethorphan, and no treatment on nocturnal cough and sleep quality for coughing children and their parents. Archives of Pediatrics & Adolescent Medicine. December 2007;161(12):1140-1146.
 Schaefer M, Shehab N, Cohen A, Bunditz D. Adverse events from cough and cold medications in children. Pediatrics. April 2008;121(4):783-87.
 Pitetti R, Whitman E, Zaylor A. Accidental and nonaccidental poisonings as a cause of apparent life-threatening events in infants. Pediatrics. August 2008;122(2):e359-62.
 Vernacchio L, Kelly J, Kaufman D, Mitchell A. Cough and cold medication use by US children, 1999-2006: Results from the Slone Survey. Pediatrics. August 2008;122(2):e323-29.
 Lopez L. Medical Officer’s Review. Division of Nonprescription Clinical Evaluation, Center for Drug Evaluation and Research. July 24, 2007, p. 200. Accessed on September 30, 2008, at http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4323b1-02-FDA.pdf.
 Food and Drug Administration. Over the Counter Cough and Cold Medications for Pediatric Use; Notice of Public Hearing. August 25, 2008. Accessed on September 28, 2008 at https://www.fda.gov/ohrms/dockets/98fr/e8-19657.htm.
 Belay E, Bressee J, Holman R, Khan A, Shahriari A, Schonberger L. Reye’s syndrome in the United States from 1981 through 1997. New EnglandJournal of Medicine. 1999;340(18):1377-82.
 Bennett D. Aspirin and Reye’s: industry responds. Science News. January 19, 1985. Accessed on September 30, 2008, at http://findarticles.com/p/articles/mi_m1200/is_v127/ai_3607046/pg_1?tag=artBody;col1.