September 19, 2000

Dockets Management Branch (HFA-305)

Food and Drug Administration

5630 Fishers lane, Room 1061

Rockville, Maryland 20852

By Federal Express

Re: Dockets No. 81N-0022 and 76N-052N

To Whom It May Concern:

The investigators for the Hemorrhagic Stroke Project (HSP) submit the
enclosed response to comments by the Consumer Healthcare Products
Association (CHPA) Phenylpropanolamine (PPA) Working Group regarding our
recent report.

The CHPA consultants have described several theoretical and practical
constraints that may affect the conduct and interpretation of
case-control research. We acknowledge that some of these constraints are
pertinent to a careful consideration of the HSP, but we believe they do
not, alone or combined, weaken the HSP findings. In particular, we
believe that neither chance nor the biases cited by the CHPA consultants
are likely explanations for the associations we observed between PPA
used as an appetite suppressant among women or PPA used as a first dose
and risk for hemorrhagic stroke.

On Behalf of the HSP Investigators,

Ralph I. Horwitz, M.D.

Cc: Charles J. Ganley, M.D., Director, Division of Over the Counter Drug

Products

Robert DeLap, M.D., Director, Office of Drug Evaluation V

Enc: Computer diskette

September 19, 2000

Response to "Comments on the Hemorrhagic Stroke Project Report" by the
CHPA Phenylpropanolamine Working Group.

1\) The CHPA consultants state that the Hemorrhagic Stroke Project (HSP)
did not establish a causal relationship between PPA and hemorrhagic
stroke. We agree. A single study is rarely able to establish causation.
What the HSP does provide is substantial evidence that PPA is associated
with increased risk for hemorrhagic stroke. Causation is one explanation
for that association, especially since neither chance nor bias is a
likely explanation for the findings.

2\) We agree with the CHPA consultants that the results of the
Hemorrhagic Stroke Project must be considered in the context of existing
safety data on PPA. It was because of deficiencies in the existing data,
however, that the HSP was initiated. In particular, prior to the HSP
there were no scientifically rigorous data on the association between
PPA and risk for hemorrhagic stroke. Our study was designed to provide
that data using a case-control format. One of the reasons for choosing
the case-control format was because this method is suited to study risk
factors for rare diseases, such as hemorrhagic stroke in young persons.
Prospective observational research (e.g., clinical trials, cohort
studies) would not be practical for examining the association of PPA
with hemorrhagic stroke because of ethical objections (for randomized
trials) and because too few subjects would have the outcome (for
observational studies and randomized trials).

3\) We believe that the findings of the HSP suggest that PPA is an
independent risk factor for hemorrhagic stroke. We reject the
consultants' assertion that "the data are derived from too few cases and
controls to allow an unbiased assessment about any relationship between
exposure and stroke." The rate of exposure to first use of PPA among
female control subjects exceeded the rate we anticipated during design
of the study. With the observed exposure rate, the p-values for the
association between first use of PPA and stroke among women (0.042) and
PPA in appetite suppressants and stroke among women (0.011) met the
usual criteria for statistical significance. We address the possible
roles for bias and confounding in the report.

4\) We disagree with the consultants' contention that conclusions from
the study should be based on the odds ratio for any PPA exposure within
three days (in men and women) and risk for hemorrhagic stroke. The HSP
was designed (in a process that involved the industrial sponsors) with
three [co-equal]{.underline} specific aims: 1) Among men and women, to
estimate the association between any use of PPA and hemorrhagic stroke;
and 2) Among men and women, to estimate the association between PPA and
hemorrhagic stroke by type of PPA exposure; and 3) Among women, to
estimate the association between hemorrhagic stroke and PPA in appetite
suppressants and any first use of PPA (appetite suppressants or
cough/cold remedies). Contrary to what the consultants state, there was
no "first objective" for the HSP; the aims were always conceived as
co-equal. As a historical point, a prime motivation for initiating the
HSP was concern specifically regarding use of PPA in appetite
suppressants by young women. The sample size was calculated based on the
aim to have adequate power to detect a specified odds ratio for the
association between PPA used as a first dose among women. The findings
referred to by the consultants as "subset findings" were, in fact,
findings related to pre-specified aims.

5\) In comments regarding confounding variables, the consultants state
that confounding factors were not controlled for in the analysis. This
is not true. We controlled for confounding variables using two
conventional strategies. First, we matched cases to controls on four
potential confounders: age, black race, gender, and telephone exchange
(a feature that was intended to be a surrogate for socioeconomic
status). All cases and controls were matched on gender and telephone
exchange. Age matching was successful for 99% of controls and ethnicity
matching was successful for 96%. Odds ratios were subsequently derived
from conditional logistic regression models for matched sets using exact
statistical methods (LogXact Program, v 2.1, Cytel Software Corporation,
Cambridge, MA) and accounted for the matching features of age, sex,
race, and telephone exchange.

Our second strategy for controlling for confounding variables was to
adjust for them in logistic regression models as follows:

A.  [Adjustment for imperfect matching.]{.underline} Age matching
    (within 3 years for case subjects less than 30 years old; within 5
    years for case subjects 30 years or older) was not achieved for only
    9 control subjects and inclusion of age as a term in the models did
    not affect the estimated odds ratio. Race was not matched for 55
    control subjects and this feature was included as a term in all
    adjusted logistic models.

B.  [Adjustment for other (non-matching) features.]{.underline} Among
    demographic features examined, only one (educational level) affected
    the estimated odds ratio and was retained in the final adjusted
    model. Among non-demographic features (cigarette smoking, diabetes,
    alcohol use, cocaine use, oral contraceptive use, and body mass
    index, specific medication use), none affected the estimated odds
    ratio. Current cigarette smoking and hypertension were included in
    the final adjusted models because they were considered a priori
    potential confounders. They were not matched for in the design due
    to lack of data supporting an independent relationship to PPA use.

6\) The findings of the HSP are based on 27 exposed cases and 33 exposed
controls. The consultants suggest that misclassification of these
individuals regarding exposure to PPA "could easily and significantly
skew the results of the study". We acknowledge that misclassification
may affect case-control studies, but we also believe that a major
strength of the HSP was successful implementation of procedures to
prevent misclassification bias. These procedures are described in our
report to the FDA.

The consultants note that telephone interviews precluded the use of
visual aids to assist in exposure recall and that more controls (n=44)
than cases (n=3) were interviewed by telephone. As a consequence, the
consultants allege, it is more likely for a control subject to be
misclassified on reported product use. We believe this criticism is
without merit for several reasons. First, the Product Identification
Book was not used as an aid to assist in exposure recall. The book was
shown to case or control subjects only after they reported a specific
exposure to an appetite suppressant or cough/cold remedy. The book was
used as a secondary method to verify exposures to brand-name
medications. The primary method was examination of medicine containers.
Second, among the 44 controls interviewed by telephone call, only one
control subject (a male) reported exposure to a brand-name product
containing PPA. Because he had discarded the product container, he could
not give us a lot number. Accordingly, he was classified as non-exposed.
When we re-ran the analysis including him as exposed, none of the
findings were changed.

In reply to other comments under the consultants' item 6:

• Case subjects were eligible for enrollment in the HSP up to 30 days
after their stroke event. Some patients, therefore, were asked to recall
medication exposures that may have occurred up to 30 days before the
interview date. We believe a 30 day interval is reasonable because a
serious personal event, particularly a health event, is commonly
believed to serve as a stimulus to recall for antecedent happenings. For
control subjects, we maintained a shorter maximum interval between the
index day and the interview (7 days) to improve control subjects' recall
of pre-focal time exposures; although this technique may bias our study
toward a finding of no association between PPA and hemorrhagic stroke,
it was necessary to balance case subjects' greater stimulation for
recall of exposures occurring before their stroke.

•The consultants comment that the proportion of aphasic cases could have
affected accurate identification and classification of cases reported to
have used PPA products. When odds ratios were examined within strata
defined by the degree of case-aphasia, the reported associations were
increased (with lower p-values compared to the overall results) in the
group defined by no significant aphasia (levels 1-3; n=603 cases). This
was also true when cases with no aphasia present (level 1; n=388) were
examined separately. Therefore, exclusion of cases with some degree of
aphasia present would not have affected the conclusions of the study.

•The consultants assert that, because interviewers knew which subjects
were case subjects and which were control subjects, they could have
inadvertently prompted specific answers and thereby skewed the results.
We believe a strength of the HSP was the highly structured and scripted
interview that protected the research against this specific problem.
Interviewers were trained to adhere to the structured interview.

•The consultants state that differences in interview location for case
and control subjects could have skewed results. Interviews for both case
subjects and control subjects always took place in a setting that
afforded them adequate privacy.

•The consultants state that recall factors, such as those discussed
immediately above, may "have a significant and unpredictable impact on
the odds ratio in either direction" and refer to the study results as
"inconclusive." The consultants also assert that "no information is
provided to give a perspective on how such recall issues affect the
study results". Recall bias and exposure classification procedures were
discussed in our Final Report of May 10, 2000. We hope that the
additional information provided in this letter will help readers draw
appropriate inferences from the results of the Hemorrhagic Stroke
Project.

7\) The consultants suggest that exclusion of dead and non-communicative
case subjects from the HSP may have biased the findings. The consultants
suggest that the "higher apparent risk of hemorrhagic stroke among PPA
users might be due to a lengthening of their survival rather than an
increase in disease incidence." Although it seems very unlikely that PPA
protects against death and severe disability in stroke patients, we
acknowledge that this bias is remotely possible. We excluded dead and
non-communicative subjects because, based on other epidemiologic
research, we believed that accurate exposure data could not be obtained
from proxy respondents.

8\) The consultants state that "The study report fails to acknowledge
that the findings cannot be entirely generalized to the U.S. Population,
as the enrolled cases and controls were not adequately population-based.
. ." We make no claim in the report that the findings are generalizable
beyond the HSP cohort. However, the case and control subjects are
probably fairly representative of their populations, at least in two of
the four largest research centers. In both Connecticut and Ohio, we
actively surveyed for eligible patients by monitoring admissions and
discharges at all major hospitals. In these two research centers, we
believe case ascertainment was complete. Across all four centers, we
enrolled 76% of eligible subjects (708/930). This percentage actually
underestimates the true recruitment percentage of eligible subjects
enrolled because 182 of the 930 patients never underwent a full screen
for eligibility; had they been fully reviewed some would have been found
to be ineligible.

The consultants state that another reason the results of the HSP cannot
be generalized to the U. S. population is that the subjects do not
represent typical consumers who use PPA drug products. The HSP was never
designed to sample typical PPA consumers. Instead, the HSP was designed
to sample young men and women with hemorrhagic stroke. We know of no a
priori reason why young persons with hemorrhagic stroke would be
expected to closely match the demographic features of PPA consumers.
Nevertheless, despite our sampling strategy and contrary to statements
of the CHPA consultants, HSP participants are actually very similar to
typical PPA consumers. Results of a survey provided to us by the
Consumer Healthcare Products Association indicates that 62% of PPA users
are female, 41% are less than 40 years, and 43% are college educated.
These figures are similar to characteristics of case subjects in the HSP
(55% female, 42% less than age 40 years, 40% college educated). Control
subjects in the HSP were more highly educated than typical users from
the industry survey (62% college educated in the HSP), but were
otherwise similar (55% female, 43% less than age 40 years).

The consultants comment that the study's case population does not appear
to be totally representative of the hemorrhagic stroke population among
18-49 year old persons, especially in terms of the distribution of
stroke type (subarachnoid hemorrhage compared with intracerebral
hemorrhage). We believe this criticism is not well-founded. There is
surprisingly little research on the relative incidence of SAH or ICH
among persons aged 18-49 years of age. Among studies that do report
rates by age and gender, estimates vary widely. In The Oxfordshire
Community Stroke Study, among persons aged 0-54 years with hemorrhagic
stroke 30% had an ICH compared with 71% for SAH(1). In Greater
Cincinnati, rates of ICH and SAH are roughly equal up to age 54
years(2). Comparison of rates of ICH and SAH among these and other
studies(3, 4) is difficult because diagnostic criteria vary and are not
necessarily the same as the criteria used in the HSP. Among persons
enrolled in the HSP, 39% had an ICH and 61% had a SAH. We believe there
is no basis for saying these proportions from the HSP are not consistent
with the range of results reported in the literature.

9\) We acknowledge a differential in participation rates between control
subjects (36%) and case subject (75%), but we strongly disagree with the
comment that "inadequate data are provided to allow independent
verification of the findings . . .". The HSP investigators have made
available to the study sponsors complete copies of the research data and
supporting files (in a format that protects patient confidentiality).

10\) Fully adjusted models (including terms for hypertension, smoking,
race and education) were not calculable using exact statistical
techniques due to computing memory constraints. However, reduced models
for the association of PPA use in appetite suppressants and stroke risk
in women were estimable using exact methods. For each single-adjustment
term model (including hypertension, smoking, race and education alone)
and two-adjustment term model (including smoking and race; and education
and race) estimated with exact methods, we found minimal changes in the
estimated odds ratios (equal to within 0.01 for all measures) and a
slight but uniform [reduction]{.underline} in all p-values when compared
with the asymptotic model results. These comparisons give us confidence
that the use of asymptotic methods to report the fully adjusted model
was appropriate for these data.

11\) The HSP was not designed to provide insight into the biological
mechanism for the association between PPA and hemorrhagic stroke.
Medical history is replete, however, with examples of important
associations that were discovered before their mechanism was understood.
Examples include cigarette smoking and coronary heart disease, cigarette
smoking and lung cancer, and diethylstilbestrol and clear cell carcinoma
of the vagina.

Response to the consultants' concluding point. We agree that the
findings of the HSP must be interpreted in the context of existing
safety data on PPA. As stated above, however, the HSP was undertaken
because of inadequacies in these data. Clinical trials involving PPA,
for example, have not enrolled enough patients to be able to detect the
occurrence of rare side effects, such as hemorrhagic stroke. Our data
suggest that a re-appraisal of the safety of PPA is appropriate.

REFERENCES

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Neurology, Neurosurgery, and Psychiatry*. 1990;53:16-22.

2\. **Broderick JP, Brott T, Tomsick T, Miller R, Huster G.**
Intracerebral hemorrhage more than twice as common as subarachnoid
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intracerebral hemorrhage: Natural history, prognosis, and precursive
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4\. **Broderick JP, Brott T, Tomsick T, Huster G, Miller R.** The risk
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