Phenylpropanolamine-Containing Drug Products for Over-the-Counter Human Use; Tentative Final Monographs, 75988-75998 [E5-7646]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 70, Number 245 (Thursday, December 22, 2005)]
[Proposed Rules]
[Pages 75988-75998]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: E5-7646]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 310, 341, and 357

[Docket Nos. 1976N-0052N (formerly 1976N-052N) and 1981N-0022 (formerly 
81N-0022)]
RIN 0910-AF34, 0910-AF45


Phenylpropanolamine-Containing Drug Products for Over-the-Counter 
Human Use; Tentative Final Monographs

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a notice of 
proposed rulemaking (notice) for over-the-counter (OTC) nasal 
decongestant and weight control drug products containing 
phenylpropanolamine preparations. This proposed rule reclassifies 
phenylpropanolamine preparations from their previously proposed 
monograph status (Category I) for these uses to nonmonograph (Category 
II)

[[Page 75989]]

status based on safety concerns. FDA is issuing this proposed rule 
after considering new data and information on the safety of 
phenylpropanolamine as part of its ongoing review of OTC drug products.

DATES: Submit written and electronic comments and new data by March 22, 
2006. Written and electronic comments on the agency's economic impact 
determination by March 22, 2006. Please see section X of this document 
for the effective date of any final rule that may be published based on 
this proposal.

ADDRESSES: You may submit comments, identified by Docket Nos. 1976N-
0052N and 1981N-0022 and/RIN number 0910-AF34 and 0910-AF45, by any of 
the following methods:

Electronic Submissions

    Submit electronic comments in the following ways:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments.
     Agency Web site: https://www.fda.gov/dockets/ecomments. 
Follow the instructions for submitting comments on the agency Web site.

Written Submissions

    Submit written submissions in the following ways:
     FAX: 301-827-6870.
     Mail/Hand delivery/Courier [For paper, disk, or CD-ROM 
submissions]: Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    To ensure more timely processing of comments, FDA is no longer 
accepting comments submitted to the agency by e-mail. FDA encourages 
you to continue to submit electronic comments by using the Federal 
eRulemaking Portal or the agency Web site, as described in the 
Electronic Submissions portion of this paragraph.
    Instructions: All submissions received must include the agency name 
and Docket No(s). and Regulatory Information Number (RIN) (if a RIN 
number has been assigned) for this rulemaking. All comments received 
may be posted without change to https://www.fda.gov/ohrms/dockets/
default.htm, including any personal information provided. For detailed 
instructions on submitting comments and additional information on the 
rulemaking process, see the ``Comments'' heading of the SUPPLEMENTARY 
INFORMATION section of this document.
    Docket: For access to the docket to read background documents or 
comments received, go to https://www.fda.gov/ohrms/dockets/default.htm 
and insert the docket number(s), found in brackets in the heading of 
this document, into the ``Search'' box and follow the prompts and/or go 
to the Division of Dockets Management, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Gerald M. Rachanow or Robert L. 
Sherman, Center for Drug Evaluation and Research, Food and Drug 
Administration, 10903 New Hampshire Ave., Bldg. 22, rm. 5426, Silver 
Spring, MD 20993, 301-796-2090.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of September 9, 1976 (41 FR 38312), FDA 
published an advance notice of proposed rulemaking (ANPR) under 21 CFR 
330.10(a)(6) to establish a monograph for OTC cold, cough, allergy, 
bronchodilator, and antiasthmatic drug products together with the 
recommendations of the Advisory Review Panel on OTC Cold, Cough, 
Allergy, Bronchodilator, and Antiasthmatic Drug Products (Cough-Cold 
Panel). This Panel was the advisory review panel responsible for 
evaluating data on the active ingredients in these drug classes. This 
Panel recommended monograph (Category I) status for phenylpropanolamine 
preparations (phenylpropanolamine bitartrate, phenylpropanolamine 
hydrochloride, and phenylpropanolamine maleate) as an oral nasal 
decongestant.
    In the Federal Register of February 26, 1982 (47 FR 8466), FDA 
published an ANPR to establish a monograph for OTC weight control drug 
products, together with the recommendations of the Advisory Review 
Panel on OTC Miscellaneous Internal Drug Products (Miscellaneous 
Internal Panel). This Panel was the advisory review panel responsible 
for evaluating data on the active ingredients in this drug class. This 
Panel recommended monograph status for phenylpropanolamine 
hydrochloride for weight control use. However, after the Panel 
submitted its report, FDA became aware of and discussed studies 
indicating that certain dosages of phenylpropanolamine cause blood 
pressure elevation (47 FR 8466). Therefore, in the preamble to the 
Panel's report, FDA specifically requested data and information on the 
extent to which phenylpropanolamine induces or aggravates hypertension 
(47 FR 8466 at 8468).
    In the Federal Register of January 15, 1985 (50 FR 2220), FDA 
published a proposed regulation for OTC nasal decongestant drug 
products in the form of a tentative final monograph. Because the issues 
concerning the safety of phenylpropanolamine for nasal decongestant and 
weight control use were closely related, FDA stated in that document 
that it was deferring phenylpropanolamine and would consider the issues 
concurrently in a future Federal Register publication (50 FR 2220 at 
2221).
    Phenylpropanolamine was not included in the October 30, 1990 (55 FR 
45788), proposed rule or the August 8, 1991 (56 FR 37792), final rule 
for OTC weight control drug products, in which 111 weight control 
active ingredients were determined to be nonmonograph. Benzocaine and 
phenylpropanolamine hydrochloride, the two ingredients the 
Miscellaneous Internal Panel classified as Category I, were deferred to 
a future publication. The current document addresses 
phenylpropanolamine. FDA will discuss benzocaine for weight control use 
in a future issue of the Federal Register.
    In a letter to the Nonprescription Drug Manufacturers Association 
dated March 9, 1993 (Ref. 1), FDA stated that, based on a relatively 
small number of spontaneous reports of intracranial bleeding associated 
with weight control drug products containing phenylpropanolamine, FDA's 
principal safety concern was the possibility that phenylpropanolamine 
might increase the risk of stroke. FDA further stated that although the 
available data could not support a conclusion that phenylpropanolamine 
increased the rate of strokes, these data could not rule out the 
possibility of an increased stroke risk associated with OTC 
phenylpropanolamine use.
    Phenylpropanolamine preparations also were not included in the 
final rule for OTC nasal decongestant drug products that published in 
the Federal Register of August 23, 1994 (59 FR 43386). FDA stated that 
because of still unresolved safety issues concerning 
phenylpropanolamine preparations, it was deferring action on this drug 
(59 FR 43386).
    In the Federal Register of February 14, 1996 (61 FR 5912), FDA 
published a proposed regulation requiring new warning labeling for all 
OTC phenylpropanolamine preparations. In that document, FDA stated that 
dose-response studies submitted by drug manufacturers to investigate 
phenylpropanolamine's effects on blood

[[Page 75990]]

pressure were inadequate to alleviate FDA's concern that 
phenylpropanolamine used in OTC drug products might increase the risk 
of hemorrhagic stroke.
    Spontaneous case reports and published case series accumulated from 
1969 to 1991 suggested a possible association between 
phenylpropanolamine use and an increased risk of hemorrhagic stroke. 
Thus, the status of phenylpropanolamine had been deferred pending 
further study. In an effort to resolve these issues, representatives of 
the manufacturers of products containing phenylpropanolamine and FDA 
staff met in 1991 to plan a study that could further examine whether 
there was an association between phenylpropanolamine use and risk of 
hemorrhagic stroke. An epidemiologic case-control study was determined 
to be the most feasible study design to evaluate the possible 
association between exposure to phenylpropanolamine and a rare outcome 
such as hemorrhagic stroke. The industry sponsors of the study selected 
investigators at Yale University School of Medicine to conduct the 
study. The Yale investigators submitted protocols to FDA for review. 
The results of the study are discussed in section II of this document.
    In this proposed rule, FDA proposes to categorize all 
phenylpropanolamine preparations as nonmonograph (Category II) for OTC 
use in both nasal decongestant and weight control drug products. This 
action is based on reports published in the medical literature, FDA's 
initial review of adverse drug event reports associated with OTC 
phenylpropanolamine drug products between 1969 and 1991, continuing 
adverse drug event reports since 1991, and the results of the Yale 
Hemorrhagic Stroke Project (Ref. 2). Because safety concerns are the 
basis for this proposed nonmonograph status, FDA does not address the 
effectiveness of phenylpropanolamine preparations in this document.

II. Data on the Safety of Phenylpropanolamine from the Yale Hemorrhagic 
Stroke Project

A. Introduction and Rationale

    The following discussion was developed from the study report (Ref. 
2) submitted to FDA.
    The Yale Hemorrhagic Stroke Project (Ref. 2) was a case-control 
study. Because several case reports had involved strokes in young women 
who took phenylpropanolamine as an appetite suppressant, often after a 
first dose, the study examined three questions: (1) Whether all users 
of phenylpropanolamine, compared to nonusers, had an increased risk of 
hemorrhagic stroke, (2) the possible association between 
phenylpropanolamine and hemorrhagic stroke by type of exposure 
(appetite suppressant or cough-cold product), and (3) among women age 
18 to 49 years, the possible association between first use of 
phenylpropanolamine and hemorrhagic stroke and the possible association 
between use of phenylpropanolamine-containing appetite suppressants and 
hemorrhagic stroke.
    The study was performed between December 1994 and July 1999 and 
involved men and women 18 to 49 years old who were hospitalized with a 
primary subarachnoid hemorrhage (SAH) or a primary intracerebral 
hemorrhage (ICH) (unrelated to ischemic infarction, trauma, cerebral 
thrombosis, or thrombolytic therapy). The subjects were recruited from 
44 hospitals in 4 geographic regions of the United States.
    Both SAH and ICH were determined by clinical symptoms and specific 
diagnostic information from computed tomography. Magnetic resonance 
imaging was accepted for the diagnosis of SAH or ICH only if other 
procedures were not diagnostic. Because misclassification of exposure 
status by surrogate responders could increase or reduce the observed 
odds ratio and the true level of risk (Ref. 2), subjects were 
ineligible for enrollment if they died (n=389) or were not able to 
communicate (n=194) within 30 days after their event. Subjects were 
also ineligible if they had a previously diagnosed brain lesion 
predisposing to hemorrhage risk (e.g., arteriovenous malformation, 
vascular aneurysm, or tumor) (n=48), a prior stroke (n=120), or first 
experienced stroke symptoms after being in the hospital for 72 hours 
(e.g., for an unrelated matter) (n=33).
    For each case subject, random digit dialing (matched to the first 
three digits of the case subject's telephone number) was used to 
identify two control subjects who were matched on : (1) Gender, (2) 
race (African-American versus non-African-American), (3) age (within 3 
years for case subjects less than 30 years and within 5 years for 
subjects 30 years or over), (4) educational level, and (5) telephone 
exchange (as a surrogate for socioeconomic status). Case subjects and 
control subjects were interviewed to ascertain medical history, 
medication use, and habits affecting health, such as use of tobacco and 
alcohol. Interviews of control subjects were completed within 30 days 
of the case subject's stroke event to minimize seasonal differences in 
the likelihood of exposure to cough-cold drug products. Eligibility 
criteria for control subjects were the same as for case subjects except 
for the stroke event. During the consent procedure, all subjects (cases 
and controls) were told that the study was designed to examine causes 
of hemorrhagic stroke in young persons without specific mention of 
phenylpropanolamine or other potential risk factors. Case and control 
subjects were interviewed by a trained interviewer using a structured 
questionnaire developed for this study. Reported phenylpropanolamine 
exposures were verified by the study investigators, who documented the 
actual product(s) used and their ingredients.
    A focal time (the calendar day and the time of onset of symptoms 
plausibly related to hemorrhagic stroke that caused a subject to seek 
medical help) was identified for each case subject. The focal time used 
for each control subject was matched to the day of the week and the 
time of day that corresponded to the case subject's focal time. Control 
subjects were interviewed within 7 days of their focal time to minimize 
recall bias.
    The exposure window referred to the interval before the focal time 
(onset of symptoms) when the status of a subject's exposure to 
phenylpropanolamine was defined. For analyses other than those 
involving first use of phenylpropanolamine, the exposure window was 
defined as 4 days preceding the focal time. For first use of 
phenylpropanolamine, the exposure window was within 24 hours before the 
focal time, provided that the subject had not used any other 
phenylpropanolamine products during the preceding 2 weeks. To maintain 
a consistent reference group, nonexposure for all analyses was defined 
as no use of phenylpropanolamine within 2 weeks before the focal time. 
Exposure windows for control subjects were matched to those for the 
corresponding case subjects.

B. Statistical Analysis

    Case and control subjects were compared on a variety of clinical 
and demographic features, including those used in matching, to 
determine the comparability of the two groups. Statistical comparisons 
were made using chi-square tests and the Fisher's exact test (where 
appropriate) for categorical variables, and the Student t-test for 
continuous variables. For the

[[Page 75991]]

analyses of the primary endpoints, conditional logistic models for 
matched sets (with a variable number of controls per case) were used to 
estimate odds ratios, lower limits of the one-sided 95 percent 
confidence intervals, and p-values for the risk factors under 
investigation. One-tailed statistical results were reported because the 
focus of the study was whether phenylpropanolamine use increased the 
risk of stroke and this was the pre-specified analysis. Each logistic 
model was estimated with two mutually exclusive binary exposure terms: 
(1) The subject's primary exposure status as defined by the specific 
aim (e.g., phenylpropanolamine use in the 3-day window; yes/no), and 
(2) phenylpropanolamine users who were not exposed within the 3-day 
window (but with some exposure within 2 weeks of the focal time).
    In multivariate conditional logistic models (using asymptotic 
methods), adjustments were made for race (African-American compared 
with non-African-American), history of hypertension (yes/no), and 
current cigarette smoking (current compared with never or ex-smoker) 
because these are the major risk factors for stroke. Other underlying 
diseases and/or conditions (i.e. diabetes, polycystic kidney disease, 
congestive heart failure, sickle cell anemia, and clotting disorders) 
were also examined to determine if any of them, when added to this 
basic adjusted model, altered the matched odds ratio by at least 10 
percent.

C. Study Results

    There were 702 case subjects, including 425 subjects (60 percent) 
with an SAH and 277 (40 percent) with an ICH, and 1,376 control 
subjects. Hemorrhage was associated with an aneurysm in 307 subjects 
(44 percent), an arteriovenous malformation in 50 subjects (7 percent), 
and a tumor in one subject (0.1 percent). Two control subjects were 
located for each of 674 case subjects (96 percent) and one control 
subject for each of 28 case subjects (4 percent). All control subjects 
were matched to their case subjects on gender and telephone exchange. 
Age matching was successful for 1,367 controls (99 percent) and race 
matching was achieved for 1,321 controls (96 percent). Twenty-seven 
case subjects and 33 control subjects reported phenylpropanolamine use 
within the 3-day exposure window.
    Compared to control subjects, case subjects were significantly more 
likely to be African-American (21 percent compared with 17 percent). 
Case subjects were also more likely to report lower educational 
achievement (20 percent did not graduate from high school compared with 
9 percent of control subjects), current cigarette smoking (51 percent 
compared with 30 percent), a history of hypertension (39 percent 
compared with 20 percent), family history of hemorrhagic stroke (9 
percent compared with 5 percent), heavy alcohol use (14 percent 
compared with 7 percent), and recent cocaine use (2 percent compared 
with less than 1 percent). For all other clinical variables examined, 
case and control subjects were not dissimilar. Case subjects were 
significantly (0.05) less likely to report use of nonsteroidal anti-
inflammatory drugs and significantly more likely to report use of 
caffeine and nicotine in the 3 days before their event. Of the factors 
examined, only education changed the adjusted odds ratio for the 
association between phenylpropanolamine and hemorrhagic stroke by more 
than 10 percent, and this demographic factor was included in all 
subsequent models.
    Analyses of the study results demonstrated an association between 
hemorrhagic stroke and use of phenylpropanolamine (in both nasal 
decongestant and weight control drug products) in the 3 days prior to 
the event. Such use of phenylpropanolamine, compared to no use in the 
prior 2 weeks, was associated with a relative risk for hemorrhagic 
stroke of 1.67 (unadjusted odds ratio) (p=0.040). The corresponding 
adjusted odds ratio was 1.49 (lower limit of the one-sided 95 percent 
confidence interval (LCL)=0.93, p=0.084).
    The relative risks of hemorrhagic stroke observed with use of the 
two types of phenylpropanolamine-containing products (in the 3-day 
exposure window, compared to no use in the prior 2 weeks) were as 
follows. For cough-cold products, the unadjusted odds ratio was 1.38 
(p=0.163) and the adjusted odds ratio (AOR) was 1.23 (LCL=0.75, 
p=0.245). For weight control products, the unadjusted odds ratio was 
11.98 (p=0.007) and the AOR was 15.92 (LCL=2.04, p=0.013).
    To analyze the relation between recency of phenylpropanolamine 
exposure and risk for hemorrhagic stroke, odds ratios were also 
calculated according to the timing of the most recent 
phenylpropanolamine use. The pre-specified definition for current use 
was use of any phenylpropanolamine-containing product on the day of the 
event (before focal time) or the preceding calendar day. Prior use was 
defined as use 2 or 3 calendar days before the focal time. The odds 
ratio was slightly higher for current use (AOR=1.61, LCL=0.93, p=0.078) 
than for prior use (AOR=l.16, LCL=0.47, p=0.393). Within current use, 
odds ratios were then calculated according to first use or non-first 
use. First use was defined as current use with no other use within the 
prior 2 weeks. Non-first use included other uses within the 2-week 
interval. The odds ratio was higher for first use (AOR=3.14, LCL=l.16, 
p=0.029) than for non-first use (AOR=1.20, LCL=0.61, p=0.329). All 
first uses of phenylpropanolamine (n=13) reported in these data were in 
cough-cold products.
    In women using phenylpropanolamine in weight control drug products 
(3-day exposure window, versus no use in the prior 2 weeks), the 
unadjusted odds ratio for hemorrhagic stroke was 12.19 (p=0.006) and 
the AOR was 16.58 (LCL=2.22, p=0.0l1). All hemorrhagic stroke events 
that occurred within the 3-day exposure window were in women. In the 
analyses of the association between hemorrhagic stroke and first-day 
use of phenylpropanolamine, 11 of the 13 first-day use events were in 
women (7 cases compared with 4 controls). The unadjusted odds ratio was 
3.50 (p=0.039) and the AOR was 3.13 (LCL=1.05, p=0.042).
    Based on the findings that risk for hemorrhagic stroke seemed to be 
concentrated among current users, the association between current 
phenylpropanolamine dose and risk for hemorrhagic stroke was examined. 
Among 21 exposed control subjects, the median current dose of 
phenylpropanolamine (i.e., total amount taken on the index day or 
preceding day) was 75 milligrams (mg). Analysis according to dose shows 
that the odds ratio was higher for current doses above the median 
(greater than 75 mg) (AOR=2.31, LCL=l.10, p=0.031) than for lower doses 
(AOR=l.0l, LCL=0.43, p=0.490). Among first-dose users, four of eight 
cases and two of five controls were exposed to greater than 75 mg of 
phenylpropanolamine. To examine the potential effect of ambiguity in 
the correct focal time, the odds ratios were recalculated after 
excluding all 154 case subjects who were classified as having a 
definite (n=76) or uncertain (n=78) sentinel symptom preceding the 
stroke event. The magnitude of the AORs did not change substantially.

D. Study Conclusions

    According to the investigators, several features of the study 
supported the validity of the study findings regarding a demonstrated 
association between phenylpropanolamine use and risk of hemorrhagic 
stroke in subjects between

[[Page 75992]]

18 and 49 years of age. First, in addition to the finding of elevated 
odds ratios that reached statistical significance, the magnitude of the 
odds ratios for phenylpropanolamine use as an appetite suppressant 
(15.92) and as a first-dose use (3.14) remained large even after 
adjustment for important clinical features. Second, the data 
demonstrate an association between both types of phenylpropanolamine 
drug products (nasal decongestant and weight control) and hemorrhagic 
stroke. Because so few men were exposed to phenylpropanolamine in this 
study (n=19), it was not possible to determine whether their risk for 
hemorrhagic stroke (when using phenylpropanolamine) is different from 
that of women.

E. FDA's Evaluation of the Study

    Observational studies, particularly case-control studies, are 
potentially subject to a number of biases, and this case-control study 
is no exception. The hallmark of a good case-control study is that 
biases are anticipated and measures are instituted in the design and 
analysis stages to minimize biases to the greatest extent possible.
    Strict diagnostic criteria, as described previously, were developed 
to ensure accurate identification of hemorrhagic stroke cases in the 
target population. A number of steps were taken to minimize 
misclassification bias. One of the investigators confirmed the stroke 
by reviewing the medical records of suspected cases, without knowledge 
of the exposure status. Inclusion and exclusion criteria were clearly 
defined for both cases and controls. Exposure was clearly defined, an 
exposure window was identified, and exposure was ascertained by trained 
interviewers. Interviewers were randomly assigned to cases or controls, 
and questions were asked about multiple medications, thus blinding 
subjects to the exact exposure under study. The interviews were highly 
structured and scripted to protect against interviewer bias. Because 
phenylpropanolamine use might be seasonal, controls were identified and 
interviewed within 30 days of the date of their matched case subject's 
stroke, to ensure that cases and controls had similar opportunities for 
exposure. Controls were also matched to cases for day of the week and 
time of day of the stroke. This matching strategy helped increase the 
probability that exposure to any seasonal medication or other 
covariates (e.g., alcohol drinking or cigarette smoking) was similar 
between cases and controls.
    The investigators attempted to identify two controls per case by 
using random digit dialing (with a match for the first three digits of 
the telephone number). Because controls were population-based, the 
results were generalizable to the source population from which the 
cases and controls were drawn. Matching on race and educational level 
was slightly unequal between cases and controls. The investigators 
further controlled for these inequalities by adjustment during 
analysis. The agency concludes that matching was largely successful.
    The investigators reduced the possibility of misclassification of 
phenylpropanolamine use by using a highly structured questionnaire. 
Each reported medication was verified by asking subjects to present the 
actual container or by picking out reported brand-name medications from 
a book containing photographs. Verification of medication use in the 3-
day window prior to the focal time was 96 and 94 percent for cases and 
controls, respectively. The investigators conducted two additional 
steps to further ensure that the possibility of exposure 
misclassification error was reduced to an absolute minimum: (1) Only 
``definite'' and ``possible'' exposure responses were considered in the 
analyses, and (2) the use of other OTC drugs between cases and controls 
were compared to ensure that the cases did not have greater recall of 
the use of any drugs as a reason for their stroke. Based on this 
analysis, FDA did not find any evidence of recall or misclassification 
bias.
    Several key elements of study design and conduct determine the 
success of a case-control study. Studies must have adequate sample size 
and/or power to detect a difference between treatment groups if a 
difference really exists, and detection of rare events can require 
substantial numbers of study subjects. FDA had concerns that the 
protocol might result in an underpowered study because the sample size 
calculation was based on an odds ratio of five for an association 
between first-day use of phenylpropanolamine and hemorrhagic stroke. 
This ratio was derived primarily from study conduct considerations, 
such as time and cost, rather than on predictive epidemiologic data 
that may have suggested that a greater number of subjects would be 
needed to show a difference between groups. Because case-control 
studies also demand adherence to strict matching criteria between case 
and control subjects, the duration of this study was longer than 
expected due to difficulties in recruiting well-matched controls.
    The resultant study was the largest prospective case-control study 
ever conducted on hemorrhagic stroke. FDA finds that, despite these 
limitations, this study was well-conducted and the statistical analyses 
demonstrate an association between phenylpropanolamine and hemorrhagic 
stroke, as explained as follows.
    FDA notes that the three most important risk factors (race, history 
of hypertension, and cigarette smoking) were included in the 
multivariate analysis (basic adjusted model). The confounding effect of 
the other covariates was examined if adding any of them to the basic 
model altered the odds ratio estimate by 10 percent. High school 
education was the only covariate determined to change the odds ratio by 
at least 10 percent.
    Because the study had a matched design, FDA considers the 
conditional logistic regression model appropriate to calculate both 
unadjusted and AORs. In addition, the number of exposures was small, 
particularly for analysis of appetite suppressant and first use, thus, 
the authors calculated the confidence interval of the unadjusted odds 
ratio based on an exact method.
    Hypertension is the single most important risk factor for a stroke. 
Misclassification of hypertension status could result in residual 
confounding. FDA examined the possible effects of this residual 
confounding on the results of the study. FDA found that the odds ratio 
for appetite suppressant use was 15.92, a substantial increase in risk. 
Its very magnitude makes it difficult to explain by confounding alone. 
Because product labeling advises hypertensive persons to avoid 
phenylpropanolamine use, the association of phenylpropanolamine use 
with hypertension should be negative. Such a negative association would 
result in biasing the result towards no association if the confounding 
factor is not controlled for. In addition to the steps taken by the 
investigators, FDA examined this further by additional analyses 
restricted to subjects without a past history of hypertension, and the 
results were not significantly different, thereby providing additional 
evidence that confounding by hypertension was not present in the study.
    FDA requested the Yale investigators to explore the possible impact 
of cigarette smoking and alcohol consumption in more detail. The 
investigators found that the odds ratios for phenylpropanolamine and 
stroke were essentially unchanged by inclusion of several qualitative 
and quantitative measures of smoking and alcohol consumption.
    The investigators examined the association between current

[[Page 75993]]

phenylpropanolamine dose and risk for hemorrhagic stroke. Among 21 
exposed control subjects, the median current dose of 
phenylpropanolamine (i.e., the total amount taken on the index day or 
preceding day) was 75 mg. The AOR was higher for current doses above 75 
mg than for lower doses. Among first dose users, four of eight cases 
and two of five controls were exposed to greater than 75 mg of 
phenylpropanolamine. As 75 mg is a single dose of many OTC extended-
release phenylpropanolamine cough-cold drug products with recommended 
adult dosing every 12 hours (150 mg a day), the agency further 
evaluated the association between risk of hemorrhagic stroke and a 
range of current phenylpropanolamine doses. Exploratory analyses 
suggest that there may be an increased risk of hemorrhagic stroke with 
labeled doses at or above 75 mg a day. Although not statistically 
significant, a trend toward a dose-ordering of odds ratios was seen. 
The odds ratio was higher (AOR=2.31, LCL=1.10, p=0.031) for current 
doses above 75 mg than for doses below 75 mg (AOR=1.01, LCL=0.43, 
p=0.490).
    FDA concludes that the Yale study (Ref. 2) was well-designed and 
demonstrated an association between use of phenylpropanolamine and an 
increased risk of hemorrhagic stroke. The increased risk was most 
striking in women and was associated with both use in appetite 
suppressants and first-dose use in cough-cold products. The case-
control design was best suited for this study because the outcome under 
investigation was rare. The investigators took reasonable steps to 
minimize bias and confounding and built quality control measures into 
the study design. Analysis was appropriate for the type of study and 
was performed according to the protocol. The study had clear objectives 
and sound epidemiology practices were used in its design and execution.

F. Additional Reports

    FDA reviewed its adverse events reporting system for spontaneous 
reports of hemorrhagic stroke from 1991 to 2000 and identified 22 
cases, 16 in the 18 to 49 age group with 13 cases in women (Ref. 3). In 
all cases, the suspect drug was an extended-release product containing 
75 mg of phenylpropanolamine per unit dose. Of 11 cases for which the 
indication for use was provided, 10 reported use for respiratory 
symptoms. FDA believes that the fact that there were no reports 
associated with immediate release drug products marketed under the OTC 
drug monograph system may be related to the lack of a requirement to 
submit any such reports to the agency.
    Therefore, the absence of such reports does not indicate these 
products are not associated with adverse events.

G. Advisory Committee Recommendations

    On October 19, 2000, at a public meeting, FDA presented to its 
Nonprescription Drugs Advisory Committee (NDAC) the regulatory history 
of OTC phenylpropanolamine (including FDA's concerns about case reports 
of hemorrhagic stroke associated with phenylpropanolamine prior to 
1991), the data from the Yale Hemorrhagic Stroke Project, and 
additional case reports of stroke since 1991.
    The Yale investigators presented the study results and their 
conclusions. Industry representatives raised concerns about the design 
of the study that they believed made interpretation of the results 
difficult (Ref. 4). NDAC evaluated whether the Yale study showed an 
association between phenylpropanolamine use and an increased risk of 
stroke in different populations aged 18 to 49 (female, male, both) and 
for different uses (nasal decongestant, appetite suppressant, all) 
(Ref. 5). More importantly, NDAC was asked if the data support the 
conclusion that there is an association between phenylpropanolamine and 
an increased risk of hemorragic stroke, taking into account all 
currently available information, including: (1) Phenylpropanolamine's 
effects on blood pressure, (2) spontaneous reports of hemorrhagic 
stroke associated with phenylpropanolamine from 1969 to 1991, (3) case 
reports in the medical literature, (4) continuing adverse drug reports 
to FDA from 1991 to the present, and (5) the results of the Yale 
Hemmorhagic Stroke Project. Thirteen of 14 NDAC members voted (with 1 
voting ``uncertain'') that there is such an association (Ref. 5). When 
asked whether phenylpropanolamine can be generally recognized as safe 
for use as a nasal decongestant, 12 of the 14 NDAC members voted (with 
2 abstaining) that phenylpropanolamine could not be considered to be 
generally recognized as safe for OTC nasal decongestant use. In 
addition, when asked whether phenylpropanolamine can be generally 
recognized as safe for use as an appetite suppressant, 13 of the 14 
NDAC members voted (with 1 abstaining) that phenylpropanolamine could 
not be considered to be generally recognized as safe for OTC weight 
control use.

III. FDA's Tentative Conclusions on the Safety of Phenylpropanolamine

    FDA believes that the known scientific evidence supports the 
conclusion that nasal decongestant and weight control drug products 
containing phenylpropanolamine cannot be generally recognized as safe 
and should no longer be available for OTC use. This evidence includes 
the results of the Yale study suggesting an association between 
phenylpropanolamine and hemorrhagic stroke, previous and continuing 
adverse event reports, reports in the published medical literature, and 
the biological plausibility related to phenylpropanolamine's ability to 
cause increases in blood pressure. As stated in section II.E of this 
document, FDA concludes that the Yale study (Ref. 2) was well-designed 
and demonstrated an association between use of phenylpropanolamine and 
an increased risk of hemorrhagic stroke. The increased risk was most 
striking in women and was associated with both use in appetite 
suppressants and first-dose use in cough-cold products. The case-
control design was best suited for this study because the outcome under 
investigation was rare. The investigators took reasonable steps to 
minimize bias and confounding and built quality control measures into 
the study design. Analysis was appropriate for the type of study and 
was performed according to the protocol. The study had clear objectives 
and sound epidemiology practices were used in its design and execution. 
Regardless of the analytic methods used, the findings were consistent.
    Although the Yale study focused on men and women 18 to 49 years of 
age, FDA has no data to show that the increased risk of hemorrhagic 
stroke is limited to a specific age range. While the Yale study was 
being conducted, FDA received spontaneous reports of hemorrhagic stroke 
in people 28 to 54 years of age with cough-cold products that contain 
OTC doses of phenylpropanolamine.
    Because the factors that may cause some individuals to be 
particularly sensitive to the effects of phenylpropanolamine are 
unknown, individuals at risk cannot be adequately warned through 
labeling. Although there is no other active ingredient that is 
generally recognized as safe and effective for OTC weight control use, 
OTC nasal decongestant drug products can be reformulated with other 
ingredients, such as pseudoephedrine and phenylephrine. Because 
hemorrhagic strokes often lead to catastrophic, irreversible outcomes,

[[Page 75994]]

FDA concludes that the benefits of the intended uses of 
phenylpropanolamine do not outweigh the potential risk, and that 
phenylpropanolamine is not considered to be generally recognized as 
safe.

IV. Analysis of Impacts

    FDA has examined the impacts of this proposed rule under Executive 
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the 
Unfunded Mandates Reform Act of 1995 (2 U.S.C. 1501 et seq.). Executive 
Order 12866 directs agencies to assess all costs and benefits of 
available regulatory alternatives and, when regulation is necessary, to 
select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). Under the Regulatory 
Flexibility Act, if a rule might have a significant economic impact on 
a substantial number of small entities, an agency must consider 
alternatives that would minimize any significant economic impact of the 
rule on small entities. Section 202(a) of the Unfunded Mandates Reform 
Act of 1995 requires that agencies prepare a written statement of 
anticipated costs and benefits before proposing any rule that may 
result in an expenditure by state, local, and tribal governments, in 
the aggregate, or by the private sector, of $100 million (adjusted 
annually for inflation) in any one year.
    FDA tentatively concludes that this proposed rule is consistent 
with the principles set out in Executive Order 12866 and in these two 
statutes. As shown as follows, FDA does not believe the proposed rule 
will be economically significant as defined by the Executive order. 
Based on its preliminary Regulatory Flexibility Analysis, FDA 
tentatively concludes that this proposed rule would not impose a 
significant economic impact on a substantial number of small entities. 
The Unfunded Mandates Reform Act of 1995 does not require FDA to 
prepare a statement of costs and benefits for the proposed rule, 
because the proposed rule is not expected to result in an expenditure 
that would exceed $100 million adjusted for inflation in any one year. 
The current inflation-adjusted statutory threshold is about $110 
million.
    The purpose of the proposed rule is to establish that 
phenylpropanolamine preparations are not generally recognized as safe 
for OTC use both as a nasal decongestant and for weight control. This 
proposed rule would assure the removal of OTC drug products containing 
phenylpropanolamine, if any are still marketed, and prohibit future 
marketing of such products.
    FDA believes that the benefits of this rule justify the costs. Our 
estimate of the benefits of complete elimination of phenylpropanolamine 
preparations suggests that they could be as high as $250 million to 
$625 million annually, if estimated using a willingness to pay 
approach. The vast majority of these benefits are not directly 
attributable to this rule, however, because industry previously took 
voluntary action to discontinue production and marketing of 
phenylpropanolamine preparations.
    Similarly, most costs of product withdrawal or reformulation have 
already been incurred because of the voluntary actions. However, a few 
affected products may still be available and products that have been 
withdrawn could still, in principle, be reintroduced in the absence of 
the rule. Any remaining products containing phenylpropanolamine will 
need to cease OTC marketing upon the effective date of any final rule, 
but can be reformulated with another ingredient, where applicable. 
Products that are reformulated will also need to be relabeled.

A. Background for Analysis of Impact

    In November 2000, FDA issued a public health advisory on the safety 
of phenylpropanolamine and announced that it would take steps to remove 
phenylproanolamine from all drug products and had requested all drug 
companies to voluntarily discontinue marketing products containing 
phenylpropanolamine (Ref. 6). As a result of this announcement and the 
publication of the Yale Hemorrhagic Stroke Project, national chain 
drugstore and major and smaller manufacturers voluntarily removed 
phenylpropanolamine-containing OTC drug products from the market. 
Manufacturers of phenylpropanolamine-containing OTC drug products were 
aware of the potential health problem and some manufacturers of OTC 
nasal decongestant drug products containing phenylpropanolamine had 
already reformulated or were in the process of reformulating their 
products to remove phenylpropanolamine in advance of FDA's 
announcement. Nevertheless, a number of factors markedly accelerated 
this trend:
     The recommendation of FDA's NDAC
     The publication of the results of the Yale Hemorrhagic 
Stroke Project
     FDA's subsequent announcement of its intent to reclassify 
phenylpropanolamine as a Category II ingredient, and FDA's request for 
a voluntary recall.
These events led to the voluntary removal from the market of most 
remaining phenylpropanolamine-containing OTC drug products. Both market 
forces (i.e., avoidance of tort liability) and FDA's request for a 
voluntary recall contributed to the decision by retail establishments 
and manufacturers to discontinue sales. Because public awareness, 
market forces, and FDA's announcement and request to voluntarily 
withdraw occurred within a short span of time, it is not possible for 
FDA to disentangle the impact these various factors had on 
manufacturers' decisions to voluntarily recall phenylpropanolamine drug 
products.
    OMB guidelines on economic impact analyses direct agencies to 
estimate costs and benefits from an appropriate baseline. ``This 
baseline should be the best assessment of the way the world would look 
absent the proposed regulation'' (Ref. 7). We do not believe that the 
conditions prior to FDA's announcement of its intent to classify this 
ingredient as nonmonograph are the appropriate baseline because the 
publication of the Yale Hemorrhagic Stroke Project in a leading medical 
journal alone would have generated a market response. We acknowledge 
that the timing and wording of FDAs public announcement and request for 
voluntary recalls contributed to the magnitude of the incurred costs. 
However, because the costs attributable to the withdrawal of 
phenylpropanolamine-containing OTC drug products have already occurred, 
and may have occurred absent this proposed rule, albeit at a slower 
pace, FDA believes present conditions are the appropriate baseline from 
which to estimate the impact of this proposed rule.
    Even if all of these costs were attributed to this proposed rule, 
however, they would not rise to the $100 million per year threshold 
sufficient to categorize this rule as economically significant under 
section 3.f. of E.O. 12866. Nonetheless, we account for as much of the 
cost as possible using 2000 as the baseline year for the number of 
affected products

B. Costs of Regulation

    a. Costs of removing products from the market. FDA finds that a 
number of affected firms incurred substantial costs from these 
voluntary product withdrawals. In addition, we are not aware of any 
phenylpropanolamine-containing OTC drug products currently marketed, so 
we believe the removal-

[[Page 75995]]

related costs have already been incurred.
    The voluntary product withdrawals primarily affected two major OTC 
drug markets--weight control and cough-cold medications. The weight 
control drug products sector reported $48 million in annual sales for 
phenylpropanolamine-containing drug products in 2000. The much larger 
cough-cold products sector had total sales of about $1.2 billion (Ref. 
8), but FDA does not have an estimate of the proportion of this figure 
that included only phenylpropanolamine-containing products. As a 
result, FDA cannot estimate the total sales of all OTC drug product 
lines that contained phenylpropanolamine.
    In 2000, FDAs drug listing system included approximately 400 drug 
products containing phenylpropanolamine, with approximately 100 
manufacturers and 250 distributors and repackers. Many of the 400 
products were marketed by distributors and hence do not represent 
unique formulations. FDA estimates that there may have been around 150 
distinct products for both cough-cold and weight loss. Not all of these 
products, however, were reformulated. Some manufacturers had already 
added product lines containing a substitute active ingredient and had 
no plans to reformulate the older product. The sales volume of some 
products was too small to cover the cost of reformulation. Also, only 
one substitute active ingredient was available for weight control drug 
products. Hence, FDA estimates that only about 100 products were 
reformulated.
    The cost to reformulate a product varies greatly depending on the 
nature of the change in formulation, the product, the process, and the 
size of the firm. To reformulate, manufacturers also have to redo 
validation (product, process, new supplier), conduct stability tests, 
and change master production records. FDA estimates that the full cost 
of reformulation ranged from $100,000 to $500,000 per product. Assuming 
that 100 products were reformulated implies a total estimated one-time 
reformulation cost of from $10 million to $50 million.
    Manufacturers that reformulated would also have incurred costs to 
relabel their products. They would have had to revise the active (and 
for some the inactive) ingredient list and may have had to make other 
labeling changes if they removed the phenylpropanolamine from a 
combination product and did not replace it with another ingredient. FDA 
believes that relabeling costs of the type required by this proposed 
rule generally averaged about $3,000 to $4,000 per stockkeeping unit 
(SKU) (individual products, packages, and sizes). Assuming 350 OTC SKUs 
in the marketplace were relabeled, the total one-time costs of 
relabeling would have ranged from $1.05 to $1.4 million.
    Using 2000 as the baseline year for affected products, the total 
estimated one-time costs for reformulation and labeling range from $11 
million to $51 million. Annualized over 20 years yields annual costs of 
$0.7 - $3.4 million (at 3 percent) and $1.0 - $4.8 million (at 7 
percent).
    b. Distributional issues and impact on industry. Other costs 
incurred by the industry include costs associated with the recall and 
destruction of inventory and the loss of product sales. FDA does not 
have reliable information to estimate either the incremental impacts of 
recalling and destroying product or to distinguish the market response 
to the results of the Yale study from FDAs announcement and request for 
voluntary withdrawal . Moreover, industry costs would be offset 
substantially by countervailing events including avoided lawsuits 
associated with continued marketing of products containing 
phenylpropanolamine and possibly reduced insurance costs. The value of 
lost profit due to lost product sales would generally be offset as 
firms gain sales by distributing substitute products. These gains and 
losses represent transfers within the industry and are not a social 
cost.
    Reports of withdrawal related expenses from trade press and some 
10-K filings with the Securities and Exchange Commission include other 
costs not attributable to costs of this regulation, such as set-asides 
for potential litigation. Because of this, we cannot use these reports 
as a basis for estimating regulatory costs. These reports, however, 
provide anecdotal information about the magnitude of the impact of the 
voluntary actions on specific firms. One of the hardest hit large 
multinational firms explained that the Company immediately ceased 
global production and shipments of any products containing 
phenylpropanolamine and voluntarily withdrew any such products from 
customer warehouses and retail store shelves. As a result, the Company 
recorded a special charge of $80,000,000 to provide primarily for 
product returns and the write-off of inventory'' (Ref. 9). Another 
heavily impacted large firm claimed that withdrawal would cost between 
$51 and $68 million (Ref. 10). Similarly, a large private-label 
manufacturer reportedly took a $24 million charge against earnings 
(Ref. 11). These last two figures likely included costs of product 
reformulation as well as lost inventory value and sales revenues. These 
accounts represent projections and are estimates for financial 
reporting requirements but do not accurately reflect actual costs used 
for regulatory impact analyses.
    FDA believes that the lost sales estimates may be overstated, as 
alternative cough-cold drug products were widely available. Most 
manufactures quickly offered alternative products and received 
offsetting increases in sales revenues. OMB guidelines for economic 
analysis state that, ``[t]he preferred measure of cost is the 
`opportunity cost of the resources used or the benefits forgone as a 
result of the regulatory action'' (Ref. 7).
    The costs of reformulation, recalls, and lost inventories are 
clearly ``opportunity costs,'' but the company sales revenues lost from 
recalled phenylpropanolamine-containing cough-cold drug products were 
likely matched by increased sales of other phenylpropanolamine-free 
products, frequently manufactured by the same or competing drug 
companies. These distributional effects are important to individual 
firms, but are not considered ``opportunity costs.''
    c. Summary of costs. The regulatory costs of the proposed rule 
would include: (1) The one-time costs to reformulate and relabel 
affected products, (2) lost inventory, and (3) the cost of recalls. We 
estimate one-time costs of $11 million to $51 million for reformulation 
and labeling. Annualized over 20 years yields annual costs of $0.7 - 
$3.4 million (at 3 percent) and $1.0 - $4.8 million (at 7 percent). We 
lack sufficient information to estimate the value of lost inventories 
or the costs of recall. The uncertainty associated with the costs 
presented in financial reports and the inability to adjust for 
transfers makes it impossible to use these data to estimate the 
potential incremental regulatory impact of this proposed rule.

C. Benefits of Regulation

    The benefit of removing phenylpropanolamine-containing products 
from the market was the reduction in the number of hemorrhagic strokes 
that would otherwise occur each year. Because phenylpropanolamine-
containing OTC drug products have already been removed from the market, 
most of the expected health benefits are attributable to these past 
voluntary product withdrawals, rather than to FDA's future regulatory 
action. FDA has estimated that phenylpropanolamine causes 200 to 500 
hemorrhagic strokes per year in people 18 to 49 years old (Ref. 5).

[[Page 75996]]

    Assigning a monetary value to the prevention of strokes is 
problematic and there is no consensus on how it should be calculated. 
Taylor (Ref. 12) used a lifetime cost model to estimate the cost, by 
type of stroke. The model accounts for direct medical costs and 
indirect costs, such as earnings and premature mortality and morbidity. 
Updating this estimate to 2003 dollars (Ref. 13) and weighting it for 
the occurrence rate of subarachnoid and intracerebral hemorrhage (60 
percent and 40 percent, respectively) (Ref. 14) results in an estimated 
figure of about $304,719 for the lifetime cost of stroke per person. 
With these values, the monetized benefit of preventing from 200 to 500 
strokes per year by removing all phenylpropanolamine-containing OTC 
drug products from the market ranges from $60.9 million to $152.4 
million per year. When groups less than 18 and over 49 years old (the 
ages of the subjects in the Yale Hemorrhagic Stroke Project) are 
included, the total yearly benefits will be higher.
    Another method of calculating benefits is to value the statistical-
lives saved due to the removal of drug products containing 
phenylpropanolamine. Assuming a mortality rate from 
phenylpropanolamine-caused strokes of about 25 percent, an estimated 50 
to 125 lives saved per year in people 18 to 49 years old would be 
attributed to the removal of products containing phenylpropanolamine. 
The value of a statistical-life has been estimated to range from $1.6 
million to $8.5 million 1986-dollars (Ref. 15). Using a rough midpoint 
value of $5 million per statistical-life, the estimated benefit of 
averting these stroke-induced fatalities ranges from $250 million to 
$625 million per year. Again, FDA is not asserting that this proposed 
rule will generate such benefits, because the benefit-producing 
activities have already occurred. Nevertheless, to the extent that some 
phenylpropanolamine-containing OTC drug products might remain available 
or might return to the market, some fraction of these benefits would be 
attributable to the issuance of this proposed rule.

D. Small Business Impacts

    A drug manufacturer is defined as small by the Small Business 
Administration if it employs fewer than 750 people. Approximately 70 
percent of all OTC drug manufacturers meet the definition of a small 
entity, and FDA believes that the same rate applies to manufacturers of 
phenylpropanolamine-containing OTC drug products. Hence, 70 of the 100 
manufacturers were classified as small. The cost to distributors and 
repackers was not significant because the manufacturers of the products 
bore the brunt of the recall costs, product destruction, and usually 
were responsible for designing new labels. As explained in this 
section, to the extent that there are still phenylpropanolamine-
containing OTC drug products being marketed, the impact on a 
manufacturer can vary greatly depending on the number and type of 
phenylpropanolamine-containing products it produces, the availability 
of substitute ingredients, and the number of SKUs that will require 
reformulation and/or relabeling. For example, a small branded product 
manufacturer may have to reformulate three products and relabel nine 
SKUs for a total one-time reformulation and relabeling cost ranging 
from $327,000 (3 products x $100,000 reformulation + 9 SKUs x $3,000 
label) to $1.536 million (3 products x $500,000 reformulation + 9 SKUs 
x $4,000 label). Because there is only one substitute available for OTC 
weight control drug products, the manufacturer would have to cease 
production of its existing product and the impact to the firm would be 
lost sales. The lost sales could be partially offset by sales of a 
substitute product, if marketed. The cost of the voluntary product 
recall would also vary by firm and again depend on the number and 
quantity of products that needed to be recalled and destroyed.
    Because these products must be manufactured in compliance with the 
pharmaceutical current good manufacturing practices (21 CFR parts 210 
and 211), all firms would have the necessary skills and personnel to 
perform these tasks either in-house or by contractual arrangement. No 
additional professional skills are needed. In addition, there are no 
other Federal rules that duplicate, overlap, or conflict with the 
proposed rule.
    FDA considered but rejected alternatives such as leaving products 
containing this ingredient on the OTC market, or not publicly 
announcing our intent to reclassify phenylpropanolamine as a Category 
II ingredient. These alternatives were unacceptable because the health 
risk posed by products containing phenylpropanolmine was greater than 
the benefits the products provided, especially given the number of 
substitute OTC drug products available that did not pose such risks. To 
have further delayed the removal of OTC phenylpropanolamine drug 
products from the market would have left consumers exposed to an 
unacceptable level of risk.
    Because the cost of removal and reformulation of 
phenylpropanolamine containing OTC drug products has already been 
incurred when the products were voluntarily recalled, and FDA has 
chosen to use the present as a baseline for its analysis, FDA 
tentatively concludes that this proposed rule will not have a 
significant impact on a substantial number of small entities.

V. Paperwork Reduction Act of 1995

    FDA tentatively concludes that there are no paperwork requirements 
in this document under the Paperwork Reduction Act of 1995 (44 U.S.C. 
3501 et seq.).

VI. Environmental Impact

    The agency has determined under 21 CFR 25.31(a) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

VII. Federalism

    FDA has analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. FDA has determined that 
the proposed rule does not contain policies that have substantial 
direct effects on the States, on the relationship between the National 
Government and the States, or on the distribution of power and 
responsibilities among the various levels of government. Accordingly, 
the agency tentatively concludes that the proposed rule does not 
contain policies that have federalism implications as defined in the 
Executive order and, consequently, a federalism summary impact 
statement has not been prepared.

VIII. Request for Comments

    Three copies of all written comments are to be submitted. 
Individuals submitting written comments or anyone submitting electronic 
comments may submit one copy. Comments are to be identified with the 
docket numbers found in brackets in the heading of this document and 
may be accompanied by a supporting memorandum or brief. Received 
comments may be seen in the Division of Dockets Management between 9 
a.m. and 4 p.m., Monday through Friday.

IX. Time for Submission of New Data

    The OTC drug review procedures (21 CFR 330.10(a)(7)(iii)) provide 
for a 12-month period after publication of a TFM for any interested 
person to file new data and information to support a condition excluded 
from the monograph

[[Page 75997]]

in the TFM. As discussed in section I of this document, FDA has 
published proposed and final rules for OTC nasal decongestant and 
weight control drug products and deferred a decision on the status of 
phenylpropanolamine so new data on this ingredient could be included in 
the record before a TFM or notice of proposed rulemaking was published. 
Manufacturers have been aware of this deferral for a number of years 
and have waited for the results of the study described in section II of 
this document to resolve the monograph status of phenylpropanolamine. 
It has taken many years for the phenylpropanolamine study to be 
completed, and the results indicate a major safety concern about this 
ingredient. FDA does not believe that any additional significant new 
safety data and information will be presented in the next 12 months. 
Because of the need to address and finalize FDA action on the existing 
safety concerns, and because there has already been public 
consideration of the issues before an FDA advisory committee, the 
comment period and the time for submission of new data is 90 days. FDA 
considers it an important public health concern to complete its 
classification of phenylpropanolamine preparations in OTC drug products 
as quickly as possible.

X. Proposed Effective Date

    FDA is proposing that any final rule that may issue based on this 
proposal become effective 30 days after its date of publication in the 
Federal Register.

XI. References

    The following references are on display in the Division of Dockets 
Management (see ADDRESSES) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday. (FDA has verified the 
Web site address, but we are not responsible for subsequent changes to 
the Web site after this document publishes in the Federal Register.)
    1. Comment No. LET86, Docket No. 1981N-0022 (formerly Docket No. 
81N-0022).
    2. Horwitz et al., ``Phenylpropanolamine & Risk of Hemorrhagic 
Stroke: Final Report of The Hemorrhagic Stroke Project,'' May 10, 2000 
in Comment No. C230, Docket No. 1976N-0052N (formerly Docket No. 76N-
052N) and Comment No. RPT14, Docket No. 1981N-0022 (formerly Docket No. 
81N-0022).
    3. Phenylpropanolamine case reports from 1991 to 2000 on file in 
Docket Nos. 1976N-0052N (formerly 76N-052N) and 1981N-0022 (formerly 
81N-0022).
    4. Consumer Healthcare Products Association (CHPA), ``Comments on 
the Hemmorhagic Stroke Project Report,'' May 24, 2000, in Comment No. 
C231, Docket No. 1976N-0052N (formerly Docket No. 76N-052N) and Comment 
No. C113, Docket No. 1981N-0022 (formerly Docket No. 81N-0022).
    5. Food and Drug Administration, Transcript of Nonprescription 
Drugs Advisory Committee meeting, October 19, 2000, in Docket Nos. 
1976N-0052N, (formerly 76N-052N) and 1981N-0022 (formerly 81N-0022).
    6. Food and Drug Administration, Public Health Advisory, ``Safety 
of Phenylpropanolamine,'' November 6, 2000, Comment No. M1 in Docket 
No. 1976N-0052N (formerly 76N-052N) and Comment No. M7 in Docket No. 
1981N-0022 (formerly 81N-0022).
    7. Office of Management and Budget, ``Guidelines to Standardized 
Measures of Costs and Benefits and the Format of Accounting 
Statements,'' M0008, March 22, 2000, downloaded from https://
www.whitehouse.gov/omb/memoranda/, accessed June, 13, 2001.
    8. Jarvis, Lisa, ``PPA Ban Is a Serious Threat to OTC Diet Aids,'' 
Chemical Market Reporter, November 20, 2000.
    9. U.S. Security and Exchange Commission, Form 10-K, Voluntary 
Market Withdrawals, fiscal year ended December 31, 2000, American Home 
Products Corp., in Docket Nos. 1976N-0052N (formerly Docket No. 1976N-
052N) and 1981N-0022.
    10. F-D-C Reports-``The Tan Sheet,'' ``Dexatrim Natural Fattens 
Chattem's First Quarter; Extensions Planned,'' vol. 9, no. 14, April 2, 
2001.
    11. F-D-C Reports-``The Tan Sheet,'' ``AHP Dimetapp, Robitussin PPA 
Withdrawals Lead To $80 Mil. Charge In 2000,'' vol. 9, no. 5, January 
29, 2001.
    12. Taylor, Thomas N., ``The Medical Economics of Stroke,'' Drugs, 
supp. 3:51-58, 1997.
    13. U.S. Census Bureau, No. 768, Consumer Price Index by Major 
Group., downloaded from https://www.census.gov/statab/freq/00s0768.txt, 
accessed June 12, 2001. U.S. Bureau of Labor Statistics, accessed July 
23, 2004. Updated 1999 data to 2003 (18.56 percent increase in medical 
care CPI).
    14. Kernan, Walter N. et al., ``Phenylpropanolamine and the Risk of 
Hemorrhagic Stroke,'' The New England Journal of Medicine, 343: 1826-
1832, 2000.
    15. Fisher, A., L., G. Chestnut, and D. M. Violette, ``The Value of 
Reducing Tisks of Death: a Note on New Evidence,'' Journal of Policy 
Analysis and Management, 8: 88-100, 1989.

List of Subjects

21 CFR Part 310

    Administrative practice and procedure, Drugs, Labeling, Medical 
devices, Reporting and recordkeeping requirements.

21 CFR Part 341

    Labeling, Over-the-counter drugs.

21 CFR Part 357

    Labeling, Ove