[Federal Register Volume 73, Number 165 (Monday, August 25, 2008)]
[Pages 50033-50036]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E8-19657]

[[Page 50033]]



Food and Drug Administration

[Docket No. FDA-2008-N-0466]

Over the Counter Cough and Cold Medications for Pediatric Use; 
Notice of Public Hearing

AGENCY:  Food and Drug Administration, HHS.

ACTION:  Notice of public hearing; request for comments.


SUMMARY: The Food and Drug Administration (FDA) is announcing a public 
hearing to obtain input regarding over-the-counter (OTC) cough and cold 
drugs marketed for pediatric use. Many of these nonprescription cough 
and cold drug products are marketed under the OTC Drug Review, which 
established a monograph describing the conditions under which certain 
OTC ingredients are considered to be generally recognized as safe and 
effective. Recently, safety and efficacy concerns have been raised 
regarding the pediatric dosing and use of certain active ingredients in 
OTC cough and cold drug products. FDA is developing a proposed rule to 
revise the pediatric labeling contained in the Final Monograph for 
Cough, Cold, Allergy, Bronchodilator, and Antiasthmatic Drug Products 
for Over-the-Counter Human Use. At this public hearing, FDA is 
interested in obtaining public comment about certain scientific, 
regulatory, and product use issues as it proceeds with the rulemaking 
and reviews new drug applications (NDAs) for these ingredients.
    Dates and Times: The public hearing will be held on October 2, 
2008, from 8 a.m. to 5 p.m.
    Location: The public hearing will be held at the Sheraton 
Washington North Hotel, 4095 Powder Mill Rd., Beltsville, MD 20705.

ADDRESSES: Submit written registration and written comments to the 
Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Submit electronic 
registration to http://www.regulations.gov.
    Submit electronic comments to http://www.regulations.gov. All 
comments should be identified with the docket number found in brackets 
in the heading of this document.
    Transcripts of the hearing will be available for review at the 
Division of Dockets Management and on the Internet at http://www.regulations.gov approximately 30 days after the hearing.
    For Registration to Attend and/or Participate in the Hearing:
Seating at the hearing is limited. People interested in attending 
should submit written or electronic registration to the Division of 
Docket Management (see ADDRESSES) by close of business on September 15, 
2008. Registration is free and will be on a first-come, first-served 
basis. Written or electronic comments will be accepted until December 
2, 2008.
    If you wish to make an oral presentation at the hearing, you must 
state your intention on your registration submission (see ADDRESSES). 
To speak, submit your name, title, business affiliation, address, 
telephone and fax numbers, and e-mail address. FDA has included 
questions for comment in section II of this document. You should also 
identify by number each question you wish to address in your 
presentation. FDA will do its best to accommodate requests to speak. 
Individuals and organizations with common interests are urged to 
consolidate or coordinate their presentations, and to request time for 
a joint presentation. FDA will determine the amount of time allotted to 
each presenter and the approximate time that each oral presentation is 
scheduled to begin.
    If you need special accommodations because of a disability, please 
inform Faith Dugan, (see For Information on the Hearing Contact).
    For Information on the Hearing Contact: Faith Dugan, Food and Drug 
Administration, 5600 Fishers Lane, rm. 14-101, Rockville, MD 20857, 
301-796-3446, FAX: 301-847-4752, e-mail: Faith.Dugan@fda.hhs.gov.


I. Background

    On March 1, 2007, FDA received a citizen petition submitted by a 
number of pediatric health care practitioners that raised concerns 
about the safety and efficacy of OTC cough and cold products in 
children less than 6 years old. The petition requested that FDA, among 
other actions, amend the OTC drug monograph for Cold, Cough, Allergy, 
Bronchodilator, and Antiasthmatic Drug Products (CCABADP) in 21 CFR 
part 341 to revise the labeling for OTC antitussive, expectorant, nasal 
decongestant, antihistamine, and combination cough and cold products. 
The petition requested that revised labeling state that these products 
should not be used in children under 6 years of age for the treatment 
of cough and cold because the products have not been found to be safe 
or effective. In addition, the petition requested that the agency 
notify manufacturers of products whose labeling either uses such terms 
as ``infant'' or ``baby,'' or displays images of children under the age 
of 6, that such marketing is not supported by scientific evidence and 
that manufacturers will be subject to enforcement action at any time. 
The petition and additional information can be found at the following 
Web site: http://www.fda.gov/ohrms/dockets/dockets/07p0074/07p0074.htm.
    Many of today's OTC cough and cold medicines are marketed under 
monographs established through the OTC Drug Review and published in the 
Code of Federal Regulations. FDA initiated the OTC Drug Review in 1972, 
after amendments to the Federal Food, Drug, and Cosmetic Act in 1962 
required that drugs be shown to be effective as well as safe. Using 
expert advisory panels to review data, the OTC Drug Review examined 
drug ingredients marketed OTC in the United States to verify which of 
these ingredients can be generally recognized among qualified experts 
as safe and effective for their intended uses (GRAS/E). After review by 
the panel, FDA published advance notices of proposed rulemaking for 
active ingredients in various therapeutic categories to establish 
monographs describing the conditions under which the products could be 
considered GRAS/E and marketed under the monograph without an approved 
new drug application. Based on the recommendations in the panel reports 
and additional public comments and data, FDA published a proposed rule, 
also known as a tentative final monograph (TFM), which set forth the 
FDA's views on the conditions of use for the monograph. Finally, based 
on additional comments and information submitted in response to the 
TFM, FDA published final monographs. The final monographs, codified in 
the Code of Federal Regulations, specify the active ingredients that 
are GRAS/E for each indication, and for each such active ingredient, 
the permitted dosages, claims, and warnings. Products that comply with 
all specified monograph conditions may be marketed without prior FDA 
    Through the OTC Drug Review, FDA has established numerous 
monographs for classes of OTC drug ingredients. Each completed OTC drug 
monograph considers a particular therapeutic class of drugs (e.g., 
antacids, topical antifungal drugs, nighttime sleep aids) and describes 
the active ingredients that have been determined to be GRAS/E through 
the OTC Drug Review process,

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with specifications for the amount of drug per dose, labeling, and 
other general requirements. As long as a manufacturer uses ingredients 
(or combinations of ingredients) that are included in the monograph, 
and follows the monograph specifications in manufacturing and 
marketing, these ``OTC Monograph'' products may be sold over the 
counter without FDA pre-clearance. Drugs that are not covered under the 
OTC Drug Review may be marketed OTC under the terms of an approved NDA.
    In the Federal Register of September 9, 1976 (41 FR 38312), FDA 
published an advance notice of proposed rulemaking (ANPRM) to establish 
a monograph under Sec.  330.10(a)(6) (21 CFR 330.10(a)(6)), for OTC 
cold, cough, allergy, bronchodilator, and antiasthmatic drug products. 
At the same time, FDA published the recommendations of the Advisory 
Review Panel on OTC Cold, Cough, Allergy, Bronchodilator, and 
Antiasthmatic Drug Products (the Panel), which was the advisory review 
panel that evaluated these products.
    The final CCABADP monograph includes GRAS/E active ingredients in 
five separate categories: Antihistamines (13 active ingredients), 
decongestants (13 active ingredients), antitussives (10 active 
ingredients), bronchodilator (7 active ingredients), and expectorants 
(1 active ingredient).\1\

    \1\ The FDA issued the tentative final monograph for single 
ingredient OTC cold, cough, allergy, bronchodilator, and 
antiasthmatic drug products in segments, over a 3-year period. The 
first segment, on anticholinergic drug product and expectorant drug 
products, was published in the Federal Register of July 9, 1982 (47 
FR 30002). The second segment, on bronchodilator drug products, was 
published in the Federal Register of October 26, 1982 (47 FR 47520). 
The third segment, on antitussive drug products, was published in 
the Federal Register of October 19, 1983 (48 FR 48576). The fourth 
and fifth segments, on nasal decongestant drug products and 
antihistamine drug products, were published in the Federal Register 
of January 15, 1985 (50 FR 2200 and 50 FR 2220). The agency's 
tentative final monograph for OTC cough-cold combination drug 
products was published in the Federal Register of August 12, 1988 
(53 FR 30522). Final monographs for these OTC drug products also 
were published in segments between 1985 and 1994: Anticholinergic 
(50 FR 46582, November 8, 1985); bronchodilator (51 FR 35326, 
October 2, 1986); antitussive (52 FR 30042, August 12, 1987); 
expectorant (54 FR 8494, February 28, 1989); antihistamine (57 FR 
58356, December 9, 1992); nasal decongestant (59 FR 43386, August 
23, 1994); and combination products (67 FR 78158, December 23, 

    Dosing for each active ingredient was largely based on the advisory 
panel recommendations, made in consultation with the Special Panel on 
Pediatric Dosage. The following statements appear in the ANPRM:
    The dosage that will produce optimum therapeutic effects in a 
particular patient, adult or child, is dependent upon factors such 
as the drug itself, individual patient variables such as special 
sensitivity or tolerance to the specific agent, age, weight and 
metabolic, pathological, or psychological conditions. Children's 
dosage calculated by any method that does not take all of these 
variables into account, therefore, can only be considered general 
    Definitive pediatric drug dosage should be derived from data 
obtained in clinical trials with children using protocols similar to 
those used in adult patients. The Panel recognizes the extreme 
difficulties attendant upon such trials but also recognizes the 
immediate need to make recommendations for pediatric dosage pending 
availability of such definitive data.
    Traditionally, pediatric dosage calculations for infants and 
children have been based on body surface area, weight, or age of the 
child as a proportion of the ``usual adult dose.'' Dosage calculated 
on the basis of the age of the child, although convenient, may be 
the least reliable method because of the large variation in the 
weight of patients at a specific age. However, for OTC products that 
have a relatively wide margin of safety, the Panel has concluded 
that dosage recommendations based on age are the most reasonable 
since they would be most easily understood by the consumer * * *.
    Unless indicated contrarily, the Panel recommends the following 
guidelines for determining safe and effective pediatric dosages for 
the individual [CCABADP] ingredients discussed in this document: For 
infants under 2 years of age, the pediatric dosage should be 
established by a physician. For children 2 to under 6 years of age, 
the pediatric dosage is 1/4 the adult dosage; for children 6 to 
under 12 years of age, the dosage is 1/2 the adult dosage * * *.
    The differences between children under 2 years of age, and other 
age groups with respect to the anatomy and physiology disorders of 
their respiratory system, their responses to diseases affecting the 
respiratory system, and their responses to drugs make general 
labeling restrictions for this age group essential. For example, 
infants because of the smaller diameter of their respiratory airways 
are particularly prone to the complications of respiratory distress 
during an acute respiratory tract infection such as may occur in the 
``common cold.'' Therefore, parents of children under 2 years of age 
should be advised to consult a physician for diagnosis and 
individualized therapeutic recommendations, even for symptoms and 
conditions that are considered appropriate for self-medication in 
older children and adults. Because of these considerations, the 
Panel recommends that the general labeling of [CCABADP] products for 
use in children under 2 years of age requires the advice and 
supervision of a physician * * *.
41 FR 38312; 38333 (September 9, 1976).
    We estimate that there are approximately 10,000 products being 
marketed for cold, cough, or combined indications under the OTC Drug 
Review. (See 67 FR 78158 at 78166.) Depending on the dosage form and 
strength of these products, many of them are labeled for pediatric use, 
including some that are labeled for use in both adults and children. 
There are approximately 38 active ingredients in the final CCABADP 
monograph. Some combination cough and cold products contain as many as 
four of these active ingredients in a single dosage form, meaning that 
patients may be exposed to four different active ingredients when using 
a single product. From 2002 to 2006, there were approximately 36 
billion units of combination cough and cold products sold each year in 
the United States. For liquid formulations used for the youngest 
children, there were approximately 190 million units sold each year in 
the combined cough and cold categories during this period.\2\

    \2\ Transcript of joint meeting of the Nonprescription Drug 
Advisory Committee and the Pediatric Advisory Committee, October 18, 
2007, p. 10.

    During the past decade, there have been several important new 
developments in the evaluation of safety and efficacy of drugs for 
pediatric use. First, the Food and Drug Administration Modernization 
Act of 1997 (FDAMA) (Public Law 105-115) (Nov. 21, 1997) was enacted, 
and included a provision to create voluntary incentives to develop 
medications for use in the pediatric population. This program was 
reauthorized and expanded first in the Best Pharmaceuticals for 
Children Act of 2002 (Public Law 107-109) (January 4, 2002), and then 
again in Title V of the FDA Amendments Act of 2007 (FDAAA) (Public Law 
110-85) (September 27, 2007). The Pediatric Research Equity Act (PREA) 
of 2003 required that drugs be studied in pediatric patients in certain 
circumstances. The PREA requirements were reauthorized and expanded by 
Title IV of FDAAA in 2007. Collectively, these laws recognize that 
differences in metabolism between adults and children, as well as 
differences between pediatric age groups, may require individualized 
dosing. They also recognize that there are often differences in effects 
of drugs and in adverse events observed in pediatric patients when 
compared to adult patients. Although these laws do not apply to 
products marketed under an OTC monograph, data from studies performed 
under these provisions suggest that children are not small adults, but 
rather may have a response to medication, both beneficial and adverse, 
that is different from adults.
    Given the evolution in our thinking about the use of drugs in 
children, the passage of more than 30 years since the

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recommendations from the advisory review panels were made, and the 
concerns about pediatric cough and cold products that have been 
presented to FDA, including those raised by the March 1, 2007, citizen 
petition, the agency has taken a new look at the assumptions that were 
used to create the pediatric conditions for cough and cold medicines 
contained in the CCABADP monograph. As part of this review, FDA 
convened a joint meeting of the Nonprescription Drugs Advisory 
Committee and the Pediatric Advisory Committee on October 18 and 19, 
2007, to discuss the safety and efficacy of these OTC cough and cold 
products marketed for pediatric use. The discussion at the Advisory 
Committee meeting addressed a variety of issues including the 
extrapolation of efficacy data from adults to children of any age for 
cough and cold products; the safety profile of these products in 
children; the basis for dosing recommendations in the CCABADP monograph 
and the use of pharmacokinetic data to determine appropriate dosing in 
children; the basis of dosing recommendations for various age intervals 
of less than 2 years, 2 to 5 years of age, and 6 to 11 years of age; 
the use of the products in children less than 2 years of age; the 
potential for misuse, unintentional overdose, and excessive dosing; the 
ability of parents or caregivers to correctly dose and administer cough 
and cold products to their children; and the labeling changes 
recommended by the petitioner and the effects they would have on the 
use of these products in children and the recommendations of health 
care providers. The 22 person Advisory Committee was nearly unanimous 
in agreeing that new studies were necessary because extrapolation of 
efficacy data for the common cold indication from adults to children 
was not acceptable for children less than 2 years old or for children 2 
years to less than 12 years. The vote was 22 to 0 and 21 to 1, 
respectively, for the two age groups. The committee understood that 
changing the OTC drug monographs required rulemaking that would take 
several years to complete. The Advisory Committee also voted 13 to 9 to 
recommend that pediatric cough and cold drugs should not be used for 
children under 6 years of age while rulemaking proceeded, and voted 15 
to 7 to recommend that the products should continue, for the time 
being, to be sold for use in children ages 6 to under 12 while new 
studies are conducted.
    On January 17, 2008, FDA issued a Public Health Advisory (PHA) 
available at: http://www.fda.gov/cder/drug/advisory/cough_cold_2008.htm. The PHA recommended that these drugs not be used to treat 
infants and children under 2 years of age because serious and 
potentially life-threatening side effects can occur. The PHA also 
indicated that FDA had not yet completed its review of the safety of 
these medicines in children 2 through 11, and the agency committed to 
completing the review as quickly as possible. Pending completion of 
this review, the PHA recommended a number of precautions for parents 
and caregivers using OTC cough and cold medicines in children 2 years 
of age and older, including carefully following the directions in the 
Drug Facts label; using appropriate measuring spoons or instruments 
made for measuring medicines; choosing products with safety caps; 
avoiding concurrent use of different OTC cough and cold medications to 
avoid unintentional overdose; not using these products to sedate 
children; and consulting a physician, pharmacist, or other health care 
professional with any questions about using these products in children.
    In the PHA, we also announced strong support for the voluntary 
action taken by many pharmaceutical manufacturers to withdraw cough and 
cold medicines that were being sold for use in children under 2 years 
of age.
    Since we issued the Public Health Advisory, we have continued our 
review of available data concerning the use of cough and cold 
medications in children, including information from the Advisory 
Committee meeting about the efficacy of the products, information from 
FDA's drug Adverse Event Reporting (AERS) database, and a published 
report in the medical literature from the Centers for Disease Control 
and Prevention (CDC) about children who ingested cough and cold 
medicines and had side effects that were serious enough to require an 
emergency room visit.\3\ While many of the observed adverse events were 
due to overdoses associated with accidental ingestions or dosing 
errors, allergic and non-allergic adverse events occurred with the 
labeled dose in children. FDA reviewed the CDC study and underlying 
data, particularly looking at the type of events that occurred with the 
labeled dose of OTC cough and cold medications, and noted that children 
under 4 years of age are more likely to experience non-allergic adverse 
events than older children.

    \3\ Schaefer MK, Shehab N, Cohen AL, Budnitz DS. Adverse Events 
From Cough and Cold Medications in Children. Pediatrics 
2008;121;783-787; originally published online Jan 28, 2008.

    Cough and cold products are commonly used in children. A recent 
report suggested that 1 in 10 children uses one or more cough and cold 
products during a given week with exposure being highest among 2 to 5 
year olds, and high in children under 2.\4\ Based on the number of 
cases of serious adverse events reported to FDA and the number of 
serious adverse events in the CDC emergency room study, we believe that 
serious adverse events are relatively rare given the extensive use of 
the drug products.

    \4\ Boston University's Slone Epidemiology Center presention at 
the 2008 Pediatric Academic Societies' & Asian Society for Pediatric 
Research Joint Meeting in Honolulu, Hawaii. Vernacchio L, Kelly JP, 
Kaufman DW, Mitchell AA. Cough and Cold Medication Use by US 
Children, 1999-2006: Results From the Slone Survey, Pediatrics 2008; 

     Despite the fact that serious adverse events are relatively rare 
in children using cough and cold drugs, we have determined that the 
collection of additional data using modern standards is warranted to 
support the current dosing or to establish new dosing regimens for 
children, given the concerns that have been raised about the safety and 
efficacy of these products, particularly in younger age groups. Lack of 
safety and efficacy data for specific pediatric age groups also 
inhibits the conduct of a meaningful risk benefit analysis under 21 CFR 
    We recognize that many scientific issues must be addressed and 
resolved to support the development and review of data that, in the 
long term, will provide increased confidence in the safe and effective 
pediatric use of these OTC cough and cold products, either under the 
monograph or approved NDAs. FDA has decided to hold a Part 15 hearing 
to hear from the public, including parents, health care practitioners, 
manufacturers of cough and cold products, retailers, and other 
interested persons, about these issues. FDA will consider this public 
input in developing a proposed rule to amend the CCABADP monograph to 
reflect the new data and any appropriate changes to the conditions 
necessary to ensure that these medications can be considered GRAS/E.

II. Scope of Hearing

    FDA is interested in obtaining public comment on the following 
issues relating to the use of pediatric cough and cold medicines:
    1. What types of studies, if any, should be conducted to assess 
effectiveness and/or safety, and

[[Page 50036]]

determine appropriate dosing of cough and cold ingredients in the 
pediatric population? How should these studies be designed and powered?
    2. Should cough and cold products for the pediatric population 
continue to be available OTC, or should they be made available only by 
    3. If the pediatric indications and dosing for cough and cold 
products were no longer available OTC, would the public use the adult 
formulations of the OTC monograph products for children, and thus 
create a greater risk of misuse or overdose?
    4. Do the answers to the previous questions depend on the age of 
the pediatric patients? If so, how should age be considered in making 
regulatory decisions for these products?
    5. At the time the monograph was established, FDA routinely 
extrapolated safety and efficacy data from adults to children age 12 
and over. Current PREA standards permit extrapolation of pediatric 
efficacy -- but not safety-- based upon sufficient adult data. Does it 
remain appropriate to recommend in the cough and cold monograph that 
children 12 and over should receive the same dose of medication as 
adults, without requiring any additional studies in children in this 
age group? What additional safety and/or efficacy studies should be 
required in this age group?
    6. What is the most appropriate method for determining pediatric 
doses that could be used as an alternative to the quarter- and half-
dose assumptions used in the monograph? Should products be dosed by 
age, by weight, or both?
    7. There are monographs for topical and intranasal ingredients to 
treat the common cold. Should these monographs be considered in a 
similar fashion to the oral cough and cold products? Are the answers to 
the previous questions different for any subcategories of cough and 
cold medicines (e.g., topical or intranasal products)?
    8. The CCABADP monograph allows for the combination of ingredients 
to treat colds and/or coughs. Should combination products be permitted 
for all pediatric age groups? Should data be provided to support each 
unique combination?
    9. Can measurement errors in dosing be reduced using more 
standardized measuring devices or alternative dosage forms and, if so, 
what is the best way to effect this change?

III. Notice of Hearing Under 21 CFR Part 15

    The Commissioner is announcing that the public hearing will be held 
in accordance with part 15 (21 CFR part 15). The hearing will be 
conducted by a presiding officer, accompanied by FDA senior management 
from the Office of the Commissioner and the Center for Drug Evaluation 
and Research.
    Under Sec.  15.30(f), the hearing is informal, and the rules of 
evidence do not apply. No participant may interrupt the presentation of 
another participant. Only the presiding officer and panel members may 
question any person during or at the conclusion of each presentation. 
Public hearings under part 15 are subject to FDA's policy and 
procedures for electronic media coverage of FDA's public administrative 
proceedings (part 10 (21 CFR part 10), subpart C)). Under Sec.  10.205, 
representatives of the electronic media may be permitted, subject to 
certain limitations, to videotape, film, or otherwise record FDA's 
public administrative proceedings, including presentations by 
participants. The hearing will be transcribed as stipulated in Sec.  
15.30(b). To the extent that the conditions for the hearing, as 
described in this document, conflict with any provisions set out in 
part 15, this document acts as a waiver of those provisions as 
specified in 21 CFR 15.30(h).

IV. Comments

    Regardless of attendance at the public hearing, interested persons 
may submit written or electronic comments to the Division of Dockets 
Management (see ADDRESSES). Submit a single copy of electronic comments 
or two paper copies of any mailed comments, except that individuals may 
submit one paper copy. Comments should be identified with the docket 
number found in brackets in the heading of this document. To ensure 
consideration, submit comments by (see DATES). Received comments may be 
seen in the Division of Dockets Management between 9 a.m. and 4 p.m., 
Monday through Friday.
    Please note that on January 15, 2008, the FDA Division of Dockets 
Management Web site transitioned to the Federal Dockets Management 
System (FDMS). FDMS is a Government-wide, electronic docket management 
system. Electronic comments or submissions will be accepted by FDA 
through FDMS only.

V. Transcripts

    Please be advised that as soon as a transcript is available, it 
will be accessible at http://www.regulations.gov. It may be viewed at 
the Division of Dockets Management (see ADDRESSES). A transcript will 
also be available in either hard copy or on CD-ROM, after submission of 
a Freedom of Information request. Written requests are to be sent to 
Division of Freedom of Information (HFI-35), Office of Management 
Programs, Food and Drug Administration, 5600 Fishers Lane, rm. 6-30, 
Rockville, MD 20857. Interested persons may submit to the Division of 
Dockets Management (see ADDRESSES) written or electronic notices of 
participation and comments for consideration.

    Dated: August 20, 2008.
Jeffrey Shuren,
Associate Commissioner for Policy and Planning.
[FR Doc. E8-19657 Filed 8-22-08; 8:45 am]