Peter Lurie, M.D., M.P.H., and Elizabeth Barbehenn, Ph.D.
Health Research Group of Public Citizen
Before the Joint Meeting of the Non-Prescription Drugs and
Pediatrics Advisory Committees of the Food and Drug Administration
Public Citizen welcomes the opportunity to present its position on the availability of over-the-counter (OTC) pediatric cough and cold formulations. To summarize, our major comments are as follows: 1. all dosage forms such as droppers or syringes intended for children should be removed from the market; 2. all remaining products should be clearly labeled to say that the products have not been shown to work in children and may be dangerous; and 3. the definition of “children” should be those up to 12 years of age.
In essence, there are two paths to pediatric drug approval: a. direct proof of efficacy in children; and b. proof of efficacy in adults with extrapolation to children. Let us consider these in turn.
A. There is no direct evidence of efficacy for these products in children
In preparing a response to the recent Citizen Petition about these drugs, the Food and Drug Administration (FDA) Medical Officer conducted a literature search and found only 11 clinical trials (some so poorly designed they did not even have placebo arms) involving children treated with cough and cold medications over the last 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 medications when used to treat symptoms of the common cold in this population.”
Similarly, in its comments to the docket, the American Academy of Pediatrics concluded that, “The OTC cough and cold products, therefore, constitute a group of drugs that do not produce any discernable health benefits in this population [children under six] according to the published peer-review literature. As such, any associated risks from these treatments, irrespective of how infrequent or small, are unacceptable given the lack of benefit obtained.”
The American College of Chest Physicians recently published clinical practice guidelines for cough management and concluded that, “In children [under the age of 15] with cough, cough suppressants and other over-the-counter cough medicines should not be used as patients, especially young children, may experience significant morbidity and mortality.”
We were not able to identify a single adequately designed study that compared the efficacy of these products in older and younger children. The efficacy in children 6-12 years of age thus remains as unproven as it does in younger children. (Arguably still older children are more similar to adults.)
It is noteworthy that in the 1970s, the Advisory Panel to the FDA recommended that the terms “baby” and “infant” not appear in the labeling of cough and cold products unless safety and efficacy could be demonstrated in those groups. Somehow, this language did not make it into the final OTC cough and cold monograph.
The industry has made much of the purported difficulties in conducting such studies, but this claim is overblown. The involvement of parents (e.g., cough counts) can improve the quality of the studies and randomization should preclude most biases. Moreover, the argument that these studies 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 (which, of course, is all we have), failed to detect any benefit and assumptions about what might happen with larger sample sizes is mere speculation.
B. Evidence of effectiveness in adults cannot be extrapolated to children
For the effectiveness of a drug in children to be inferred from data in adults, all of the following criteria would have to be met:
1. The product would have to be effective in adults
It is much less than clear that several of the cough and cold ingredients are even effective in adults. In a meta-analysis restricted to adult studies conducted for the Cochrane Collaboration, the authors concluded that, “Over the counter cough medicines cannot be recommended because there is no good evidence for their effectiveness.”
2. There would have to be a reasonable biological basis to assume that the pharmacological responses and disease processes are similar in adults and children
The American Academy of Pediatrics, in its letter to the FDA, emphasized that, “Extrapolation of therapeutic data from adults to children, although common, is fraught with danger.” It noted that changes in all four aspects of pharmacokinetics (drug absorption, distribution, metabolism and elimination) occur during childhood development.
More tellingly, the Academy concluded, “Even if extrapolation of adult data to children were scientifically appropriate, it is unnecessary in the case of most OTC cough and cold products, which have been studied in children and found to be ineffective.”
3. There would have to be adequate pharmacokinetic data in children
The process by which the pediatric dosage recommendations for these medications were reached lays bare their fragile basis. In the OTC cough and cold monographs, the dose for 6-12 year-olds was set at one-half the adult dose and for 2-6 year-olds was set at one-quarter the adult dose. For 0-2 year-olds (under-6 year-olds for anti-histamines), parents were advised to consult with their physicians, even though physicians would have no rational basis for making a recommendation and the drugs are supposed to be acceptable for OTC use. It is revealing that these dosing guidelines were recommended irrespective of the drug to be used, when each drug would likely have a unique pharmacokinetic pattern.
In advance of this hearing, the FDA conducted a pharmacology review of these products in children and concluded that, “Robust and well-designed clinical pharmacokinetic studies … are currently lacking for cough and cold medications [in children].”
In fact, according to the FDA’s pharmacology review, there appear to be pediatric pharmacokinetic data available for only pseudoephedrine and chlorpheniramine. These limited data reveal that the monograph-based pediatric doses may be too low. In the pseudoephedrine studies, the area under the curve (AUC; a measure of total exposure to the drug) for 2-5 year-old rhinitis patients was 52% of that for healthy adults; for 6-11 year-old healthy children, it was 72% of that for healthy adults. For chlorpheniramine, the AUC for 6-11 year-old rhinitis patients was only 68% of that for healthy adults. Moreover, these studies typically either had few patients of the various ages or did not provide detailed age breakdowns.
We now have considerably more experience with pediatric pharmacokinetic studies than we did when these OTC monographs were under review. Under the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act, many such studies in a wide variety of drugs have been undertaken. According to FDA testimony before the Congress, since 1997, under BPCA alone, there have been labeling changes for 128 products in various therapeutic areas. These include 25 products with dosing adjustments for children and 28 for which the pediatric study demonstrated that the product, while effective in adults, was not effective in children. Through these studies, we have learned that it is not reliable to simply use weight or surface area based on adult doses to determine dosing in children and that drug clearance is highly variable in the pediatric population.
4. The drugs would have to be reasonably safe for use in children
While pediatric use of these drugs is generally well tolerated, the lack of demonstrated efficacy of these products should make any toxicity unacceptable. In fact, 123 fatal cases (54 for decongestants; 69 for antihistamines) were reported to the FDA between 1969 and 2006. The FDA’s safety review concluded that, “both the [Adverse Event Reporting System] and [Toxic Exposure Surveillance System]data suggest thatthe use of prescription and OTC cough and cold medication in children younger than 6 years of age have been associated with serious adverse events, including death.” These are obviously huge underestimates of the actual numbers of associated deaths as there was not even a requirement for sponsors to report adverse events to the FDA.
Moreover, despite the sponsors’ desire to shift the blame to the victims and their parents by ascribing the serious toxicities observed to misuse of the drugs, the safety review noted that, “serious cardiac and respiratory events were reported in cases where the dosage [of various cough and cold ingredients] did not exceed the labeled dose for the lowest age group.”
5. Parents would have to be able to use the drug in accordance with adequate labeling
The FDA’s Division of Medication Errors and Technical Support (DMETS) has assessed the safety of these products in the context of labeling, parent comprehension and the various marketed formulations. It identified multiple contributing factors to medication errors: concurrent use of therapies containing the same active ingredients or therapies in the same therapeutic class; misinterpretation of directions; misuse of measuring devices; formulation changes; and the sheer number of OTC cough and cold products available (there are over 800 in the U.S.). The Division recommended considering discontinuing the more concentrated infant formulations as well as the “elimination of multi-symptom pediatric cough and cold products.”
To reach the conclusion that these products are effective through this “indirect” route (extrapolation from adults) at least these five conditions would have to be met. None has.
In sum, whether one examines studies directly assessing the efficacy of pediatric cough and cold medications or one tries to build an efficacy bridge from adults to children, one reaches the same conclusion: there is no reasonable evidence that these products are effective. In the absence of evidence that a product is effective, no amount of toxicity is acceptable. Given the mounting evidence of the toxicity of pediatric cough and cold medications, there is a still stronger case that these products should be removed from the market.
Accepting for the moment that the adult formulations will remain on the market, how can this restriction best be enforced?
- First, 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.
- Second, since 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.
- Third, the label should clearly state that there is no evidence of efficacy and the products can be dangerous in this 12 and under age group.
- Fourth, any photographs or other representations on the box of children appearing to be 12 or under should be prohibited.
- Fifth, 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 that currently predominates.
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