APPENDIX B

STATISTICAL REVIEW OF EPIDEMIOLOGICAL REPORT

**DATE: September 26, 2000**

**STATISTICAL REVIEWER:** Yi Tsong, Ph.D., Mathematical Statistician

Quantitative Methods Research Staff, HFD-705

**DOCUMENT REVIEWED: Final Report of Yale Hemorrhagic Stroke Project,
CHPA Phenylpropanolamine Working Group Comments**

**EPIDEMIOLOGICAL REVIEWER:**

Lois La Grenade, M.D., M.P.H., Epidemiologist

Parivash Nourjah, Ph.D., Epidemiologist

Division of Drug Risk Assessment 1, HFD-430

**INTRODUCTION**

This consult is in response to a request from the Division of Drug Risk
Assessment I, Office of Postmarket Drug Risk Assessment to review CHPA
Phenylpropanolamine Working Group comments and the final report
submitted by Yale University, entitled Hemorrhagic Stroke Project
Report, provided by CHPA. This review consists of three parts, protocol
review, comments on the comments of CHPA Phenylpropanolamine Working
Group and summary review of the Yale's report of CHPA sponsored Yale
Hemorrhagic stroke study.

A.  **PROTOCOL REVIEW (BACKGROUND)**

As early as 1984, the FDA was alerted to the potential safety concerns
with risk of hemorrhagic stroke associated with the usage of
Phenylpropanolamine (PPA). Most of the reports prior to 1984 were case
reports. O'Neill and Van de Carr's case-control study using Medicaid
data of Michigan and Minnesota was the first retrospective
epidemiological study to address the issue \[1\]. In this unpublished
1984 study, prescription PPA was compared with prescription ephedrine,
phenylephrine and pseudoephedrine on their association with hemorrhagic
stroke. Based on a 60-day exposure window, they found association with
PPA usage in both genders and both states. However, only a moderate
association with PPA usage in a Michigan male patient population was
statistically significant. The report addressed many factors that would
bias the result towards a no association finding in a computerized
database. Jick, Aselton and Hunter's 1984 incidence density analysis
based on Group Health Cooperative of Puget Sound data provided the only
published epidemiological study addressing this issue. The PPA user
incidence rates of stroke were calculated by dividing the number of
events that occurred in the 60-day exposure window by the sum of all
60-day exposure windows in the study. The incidence rate for non-users
is the ratio of the number of stroke events divided by the sum of all
non-PPA exposure window times. Jick et al found no significant
association between PPA exposure and hemorrhagic stroke among the
prescription drug users. This study suffered similar problems to the
ones pointed out in O'Neill and Van de Carr's report.

Jolson \[3\] studied reports of CVA (cerebravascular stroke) in the FDA
spontaneous reporting system database. In her study, she compared the
proportions of reports of CVA of PPA with all other drugs reported to
SRS for women aged 10-59 years from 1977 through January 1991. She found
that **CVA is the single most commonly reported event for PPA-diet
products (35.3% overall, 40.8% in Direct reports, 0 in the manufacturer
reports), and represented 5.8% (overall, 5.7% of direct reports, 5.1% of
manufacturer reports)) of all PPA-cough/cold ADEs, in contrast to less
than 1% of all ADEs reported among all drugs (See Tables 1 and 2).**
**Most of the reports were associated with first use of the products.**

Table 1 PPA (phenylpropanolamine) and Number of CVA reports in women
aged 10-59 (1977- Jan. 1991)\*

+----------------------+----------------+-------------+---------------+
| #### Direct Reports  |                |             |               |
+----------------------+----------------+-------------+---------------+
| Product              | CVA            | Non-CVA     | Total         |
+----------------------+----------------+-------------+---------------+
| PPA-Diet             | 20 (40.8%)     | 29 (59.2%)  | 49            |
+----------------------+----------------+-------------+---------------+
| PPA-Cough/Cold       | 4 (5.7%)       | 66 (94.3%)  | 70            |
+----------------------+----------------+-------------+---------------+
| All Non-PPA          | 78 (0.5%)      | 14168       | 14246         |
|                      |                | (99.5%)     |               |
+----------------------+----------------+-------------+---------------+
| Total                | 102 (0.7%)     | 14263       | 14365         |
|                      |                | (99.3%)     |               |
+----------------------+----------------+-------------+---------------+
| # **Man              |                |             |               |
| ufacturers Reports** |                |             |               |
+----------------------+----------------+-------------+---------------+
| Product              | CVA            | Non-CVA     | Total         |
+----------------------+----------------+-------------+---------------+
| PPA-Diet             | 0 (0.0%)       | 3 (100%)    | 3             |
+----------------------+----------------+-------------+---------------+
| PPA-Cough/Cold       | 4 (5.1%)       | 74 (94.9%)  | 78            |
+----------------------+----------------+-------------+---------------+
| All Non-PPA          | 643 (0.9%)     | 72799       | 73442         |
|                      |                | (99.1%)     |               |
+----------------------+----------------+-------------+---------------+
| Total                | 647 (0.9%)     | 72876       | 73523         |
|                      |                | (99.1%)     |               |
+----------------------+----------------+-------------+---------------+

\* 1991 FDA memorandum "Epidemiologic Review of PPA Safety Issues"

Table 2 Direct Domestic Spontaneous Reports of CVA in Women Aged 10-59
Years Received by the FDA (1977- Jan. 1991)

  ----------------------------- ------------------- ----------------------
  Product Category              Number of CVA       \% of Total Reports
                                Reports             

  PPA-Diet                      19                  26%

  Oral Contraceptive            15                  20%

  Thrombolytic Agent            7                   10%

  Lactation Suppressive         6                   8%

  Chemotherapeutic              5                   7%

  Radiocontrast                 4                   5%

  Anticoagulant                 3                   4%

  PPA-Cough/Cold                3                   4%

  Miscellaneous                 11                  15%

  Total                         73                  100%
  ----------------------------- ------------------- ----------------------

With concerns raised in this 1991 report, the Nonprescription Drug
Manufacturers Association, NDMA (now Consumer Healthcare Products
Association, CHPA) initiated a contract with investigators of Yale
University to carried out the current case-control study as a
verification of the strong signals generated from the FDA SRS study.

The Protocol of the NDMA sponsored Yale Hemorrhagic Stroke project was
thoroughly discussed in many NDMA-FDA meetings and communications. In
general, FDA reviewers were concerned with

1)  the feasibility of the study in terms of assumed background rate
    used in sample size and power calculation,

2)  feasibility of the study in terms of sample size and power to detect
    the association between dietary suppressant and hemorrhagic stroke
    among the first PPA use,

3)  the potentially large misclassification error of using surrogate
    interview for case patient who can't communicate,

4)  interim analysis for study feasibility.

Through the multiple meetings and communications, the protocol was
revised by NDMA and the Yale investigators. The FDA concern #1 was taken
into consideration by NDMA and Yale investigators and the protocol was
modified to an interim analysis design for the feasibility study. Yale
investigators confirmed the FDA concern #3 and the case definition was
modified accordingly. The FDA concern #2 was accommodated with the
following four equally important primary objectives as given in the
current protocol

1)  To estimate the association between PPA and hemorrhagic stroke among
    men and women aged 18 -- 49 years.

2)  To estimate the association between PPA and hemorrhagic stroke by
    type of PPA exposure (diet suppressant and cough/cold product) among
    the same target population

3)  Among women aged 18-49 years to estimate the association between
    first use of PPA and hemorrhagic stroke

4)  Among the same target female population to estimate the association
    between PPA in appetite suppressants and hemorrhagic stroke.

Details of the comments and revisions in 1992-1993 were documented in
NDMA letters, FDA letters and FDA memoranda \[4-11\].

The final protocol as given in Yale's report clearly demonstrated that
all the concerns discussed in 1992-1993 were taken into consideration
and all the necessarily steps were put in place to minimize the
potential bias often found in case-control studies Details of the
strengths and weaknesses of this protocol discussed between the
statistical reviewer of the Quantitative Methods Research Staff and
epidemiological reviewers of the Division of Drug Risk Assessment are
documented in the FDA's statistical and epidemiological review reports
\[4,5\].

B.  **REVIEWER'S RESPONSE TO THE STATEMENTS MADE IN THE CHPA'S REPORT OF
    CPHA PHENLPROPANOLAMINE WORKING GROUP'S COMMENTS ON YALE'S FINAL
    REPORT OF NDMA (now CHPA) SPONSORED HEMORRHAGIC STROKE STUDY**

In this section, reviewer's response was typed in "times new roman" font
in order to distinguish from CPHA Phenlypropanolamine Working Groupis
comments typed in "courier new" font.

1.  Yale Hemorrhagic Stroke Project did not establish a causal
    relationship between PPA use and hemhorragic stroke

> The objective of the project was to assess and evaluate the
> association between hemorrhagic stroke and PPA use. The study was
> initiated because of the FDA's concerns about the unusually high
> proportion of stroke reports among the ADE reports (attributed to PPA
> use) received in the FDA spontaneous reporting system. The study was
> proposed by Yale University Investigators (and sponsored voluntarily
> by CHPA) with a careful design in order to either confirm or refute
> the safety concerns. The investigation of the association (due to
> causality, promoting factor or ineffective OTC labeling, etc) between
> PPA use and hemorrhragic stroke was the goal as planned and discussed
> at its planning stage for OTC marketing concern. Nevertheless, the
> investigators detected a strong association between use of PPA in diet
> suppressant products and hemorrhagic stroke. They also detected a
> dose-response relationship between PPA and stroke which strengthened
> the association.

2.  The findings of the Hemorrhagic Stroke Project must be considered in
    the context of existing safety data on PPA. This evidence
    overwhelmingly supports the safety and effectiveness of PPA when
    used according to label directions.

> The NDMA sponsored Yale HS project was voluntarily initiated by NDMA
> based on the safety concerns raised from the information in the FDA
> spontaneous reporting system database. Its protocol was carefully
> reviewed through many NDMA and FDA meetings (see attached ref. 3-10).
> Because of bias involved with the earlier studies, the findings of
> this carefully planned and conducted study should be given greater
> weight as confirmatory safety evidence than to be equally weighted as
> one of the studies in a meta analysis form.
>
> With over 700 stroke cases, careful design and conduct, thorough
> analysis, the Yale HS project is unique in its standing among all PPA
> studies.

3.  The study findings of an apparent "association" between stroke and
    PPA exposure should not be relied upon as conclusive. Important
    biases and inadequate controlling for confounding factors (see
    below) could account for the reported association. A more
    appropriate conclusion is that the data are derived from too few
    cases and controls to allow an unbiased assessment of any
    relationship between exposure and stroke.

The fact that the sample size of the NDMA (now CHPA) sponsored study may
be "too small" was probably due primarily to the minimum sample size
requirement to detect a 5-fold odds ratio in all-PPA all users
population due to the practical feasibility concern with low stroke
incidence and low prevalence of PPA. However, FDA had more concerns with
compromised power than with potential bias speculated by CHPA due to a
"small sample". Because of the small size of the study, the consistency
of the association shown in all four primary objectives

and analyses that control for the confounders strengthen the findings
over and beyond the sample size dependent p-values. The consistency is
clearly shown across objectives and stratified analyses and subset
analyses as shown in the following summary tables.

**First, for objectives #2 and #4**, although the numbers are small, the
results are consistent and support the concern raised in the review of
the FDA spontaneous reports of an association between the PPA dietary
suppressant product and stroke. The association found in this study is
large (OR =11.98 in all subjects (adjusted p=0.013), and in females only
the odds ratio is 12.19 (adjusted p=0.01)(Table 3). When stratified by
the status of sentinal symptom, the OR is both large and statistically
significant (OR\>7, adjusted p-value=0.029) among patients with no
symptom. Though the number of patients with the symptom is small and the
number of exposures is also small, the odds ratio is large (unadj
OR=4.83, p=0.11). Among patients without a history of hypertension,
there are 3 matched exposed case- unexposed control pairs but no
unexposed case- exposed control pair. Of this cohort, the unmatched OR
is 10.26 (unadjusted p=0.01)(Table 7). The association is both strong
and statistically significant in subpopulations stratified by status of
aphasia (unadj OR=12.09, p=0.007, adjusted OR=15.5, p=0.013 among
patients without aphasia (rating 1-3)(Table 10). With a more restricted
definition of the status of without aphasia (rating=1), the unmatched
OR\>16.00, p=0.013 (4 exposed cases and no exposed control) among
patients without aphasia.

The associations between cough/cold PPA and hemorrhagic stroke is much
weaker, which is consistent with the findings in the Jolson report.

**Second, for objective #3, the results support the safety concern
raised from Jolson's review of the FDA spontaneous reports of a strong
association between PPA and stroke among first users exposed within 24
hours before the focal time.** The association found in this study is
large and statistically significant (unadj OR=3.20, adj OR=3.14, p-value
=0.029) of all PPA products (Table 3). The same association was detected
in patients without the sentinal symptom (unadj OR=3.0 , p=0.08, adj
OR=3.34, p=0.04). An association of the same magnitude was detected in
patients with the sentinal symptom present, even though the numbers are
small (unadj OR =4.0, p=0.259, adj OR=2.7, p=0.215) (Table 4).

In response to the FDA reviewers' request, the Yale investigators
performed analysis by controlling history of hypertension through
stratification (Tables 6 and 7). We detected that the association is
independent of hypertension history as shown in patients without a
history of hypertension (unadjusted OR=4.13, p-value=0.02, adjusted
OR=3.99, p-value=0.03). The same association was shown consistently in
subgroups stratified by the presence of aphasia (unadj OR=4.0, p=0.019,
adj OR=3.59, p=0.023 without aphasia present; unadj OR=5.33, p=0.009,
adj OR=4.60, p=0.015 with aphasia present) (Table 10).

**Third, for objective #1,** **the unadjusted odds ratios are between
1.5 and 2.6 in all analyses (the whole population and subgroups defined
by status of sentinal symptom, history of hypertension, or status of
aphasia).** With adjustment for smoking, hypertension, race and
education, the odds ratios are still greater than 1.30 though the
p-values vary. This finding is consistent with the safety concern raised
in Jolson's review of FDA spontaneous reports.

Table 3 Analyses of the four primary objectives

+-------------+-----------+----------+-------------+---+------------------+
|             | Case      | Controls | Unadjusted  | A |                  |
|             |           |          | Matched OR  | d |                  |
|             | (n=702)   | (n=1376) |             | j |                  |
|             |           |          |             | u |                  |
|             | No. %     | No. %    |             | s |                  |
|             |           |          |             | t |                  |
|             |           |          |             | e |                  |
|             |           |          |             | d |                  |
|             |           |          |             | f |                  |
|             |           |          |             | o |                  |
|             |           |          |             | r |                  |
|             |           |          |             | s |                  |
|             |           |          |             | m |                  |
|             |           |          |             | o |                  |
|             |           |          |             | k |                  |
|             |           |          |             | i |                  |
|             |           |          |             | n |                  |
|             |           |          |             | g |                  |
|             |           |          |             | , |                  |
|             |           |          |             | h |                  |
|             |           |          |             | y |                  |
|             |           |          |             | p |                  |
|             |           |          |             | e |                  |
|             |           |          |             | r |                  |
|             |           |          |             | t |                  |
|             |           |          |             | e |                  |
|             |           |          |             | n |                  |
|             |           |          |             | s |                  |
|             |           |          |             | i |                  |
|             |           |          |             | o |                  |
|             |           |          |             | n |                  |
|             |           |          |             | , |                  |
|             |           |          |             | r |                  |
|             |           |          |             | a |                  |
|             |           |          |             | c |                  |
|             |           |          |             | e |                  |
|             |           |          |             | a |                  |
|             |           |          |             | n |                  |
|             |           |          |             | d |                  |
|             |           |          |             | e |                  |
|             |           |          |             | d |                  |
|             |           |          |             | u |                  |
|             |           |          |             | c |                  |
|             |           |          |             | a |                  |
|             |           |          |             | t |                  |
|             |           |          |             | i |                  |
|             |           |          |             | o |                  |
|             |           |          |             | n |                  |
|             |           |          |             |   |                  |
|             |           |          |             | O |                  |
|             |           |          |             | R |                  |
|             |           |          |             | L |                  |
|             |           |          |             | C |                  |
|             |           |          |             | L |                  |
|             |           |          |             | p |                  |
|             |           |          |             | - |                  |
|             |           |          |             | v |                  |
|             |           |          |             | a |                  |
|             |           |          |             | l |                  |
|             |           |          |             | u |                  |
|             |           |          |             | e |                  |
+-------------+-----------+----------+-------------+---+------------------+
| No use      | 664 94.6  | 1310     |             |   |                  |
|             |           | 95.2     |             |   |                  |
+-------------+-----------+----------+-------------+---+------------------+
| **Use in    |           |          |             |   |                  |
| 3-day       |           |          |             |   |                  |
| window**    |           |          |             |   |                  |
+-------------+-----------+----------+-------------+---+------------------+
| Any PPA     | 27 3.8    | 33 2.4   | **1.67**    |   | **1.49** 0.95    |
|             |           |          |             |   | 0.084            |
+-------------+-----------+----------+-------------+---+------------------+
| Cough/cold  | 22 3.1    | 32 2.3   | **1.38**    |   | **1.23** 0.75    |
|             |           |          |             |   | 0.245            |
+-------------+-----------+----------+-------------+---+------------------+
| Appetite    | 6 0.9     | 1 0.1    | **11.98**   |   | **15.92** 2.04   |
| suppressant |           |          |             |   | 0.013            |
+-------------+-----------+----------+-------------+---+------------------+
| **Current   |           |          |             |   |                  |
| Use within  |           |          |             |   |                  |
| 24 hrs of   |           |          |             |   |                  |
| Focal       |           |          |             |   |                  |
| Time**      |           |          |             |   |                  |
+-------------+-----------+----------+-------------+---+------------------+
| Current Use | 21 3.0    | 21 1.5   | **1.98**    |   | **1.61** 0.93    |
|             |           |          |             |   | 0.078            |
+-------------+-----------+----------+-------------+---+------------------+
| First use   | 8 1.1     | 5 0.4    | **3.20**    |   | **3.14** 1.16    |
|             |           |          |             |   | 0.029            |
+-------------+-----------+----------+-------------+---+------------------+
| Non-first   | 13 1.9    | 16 1.2   | **1.62**    |   | **1.20** 0.61    |
| use         |           |          |             |   | 0.329            |
+-------------+-----------+----------+-------------+---+------------------+
| Prior use   | 6 0.9     | 12 0.9   | **1.01**    |   | **1.16** 0.47    |
|             |           |          |             |   | 0.393            |
+-------------+-----------+----------+-------------+---+------------------+
| **By Gender |           |          |             |   |                  |
| Analysis**  |           |          |             |   |                  |
+-------------+-----------+----------+-------------+---+------------------+
| Female Case |           |          |             |   |                  |
| Controls    |           |          |             |   |                  |
|             |           |          |             |   |                  |
| (n=383)     |           |          |             |   |                  |
| (n=750)     |           |          |             |   |                  |
+-------------+-----------+----------+-------------+---+------------------+
| No use      | 355 92.7  | 713 95.1 |             |   |                  |
+-------------+-----------+----------+-------------+---+------------------+
| Any PPA     | 21 5.5    | 20 2.7   | **2.15      | * |                  |
|             |           |          | (p=0.014)** | * |                  |
|             |           |          |             | 1 |                  |
|             |           |          |             | . |                  |
|             |           |          |             | 9 |                  |
|             |           |          |             | 8 |                  |
|             |           |          |             | * |                  |
|             |           |          |             | * |                  |
|             |           |          |             | 1 |                  |
|             |           |          |             | . |                  |
|             |           |          |             | 1 |                  |
|             |           |          |             | 2 |                  |
|             |           |          |             | 0 |                  |
|             |           |          |             | . |                  |
|             |           |          |             | 0 |                  |
|             |           |          |             | 2 |                  |
|             |           |          |             | 4 |                  |
+-------------+-----------+----------+-------------+---+------------------+
| Cough/cold  | 16 4.2    | 19 2.5   | **1.70      | * |                  |
|             |           |          | (p=0.089)** | * |                  |
|             |           |          |             | 1 |                  |
|             |           |          |             | . |                  |
|             |           |          |             | 5 |                  |
|             |           |          |             | 4 |                  |
|             |           |          |             | * |                  |
|             |           |          |             | * |                  |
|             |           |          |             | 0 |                  |
|             |           |          |             | . |                  |
|             |           |          |             | 8 |                  |
|             |           |          |             | 5 |                  |
|             |           |          |             | 0 |                  |
|             |           |          |             | . |                  |
|             |           |          |             | 1 |                  |
|             |           |          |             | 1 |                  |
|             |           |          |             | 6 |                  |
+-------------+-----------+----------+-------------+---+------------------+
| Appetite    | 6 1.6     | 1 0.1    | **12.19     | * |                  |
|             |           |          | (p=0.006)** | * |                  |
|             |           |          |             | 1 |                  |
|             |           |          |             | 6 |                  |
|             |           |          |             | . |                  |
|             |           |          |             | 5 |                  |
|             |           |          |             | 8 |                  |
|             |           |          |             | * |                  |
|             |           |          |             | * |                  |
|             |           |          |             | 2 |                  |
|             |           |          |             | . |                  |
|             |           |          |             | 2 |                  |
|             |           |          |             | 2 |                  |
|             |           |          |             | 0 |                  |
|             |           |          |             | . |                  |
|             |           |          |             | 0 |                  |
|             |           |          |             | 1 |                  |
|             |           |          |             | 1 |                  |
+-------------+-----------+----------+-------------+---+------------------+
| Male Case   |           |          |             |   |                  |
| Controls    |           |          |             |   |                  |
|             |           |          |             |   |                  |
| (n=319)     |           |          |             |   |                  |
| (n=626)     |           |          |             |   |                  |
+-------------+-----------+----------+-------------+---+------------------+
| No use      | 309 96.9  | 597 95.4 |             |   |                  |
+-------------+-----------+----------+-------------+---+------------------+
| Any PPA     | 6 1.9     | 13 2.1   | 0.90        | 0 |                  |
|             |           |          | (p=0.529)   | . |                  |
|             |           |          |             | 6 |                  |
|             |           |          |             | 2 |                  |
|             |           |          |             |   |                  |
|             |           |          |             | - |                  |
|             |           |          |             | 0 |                  |
|             |           |          |             | . |                  |
|             |           |          |             | 2 |                  |
|             |           |          |             | 0 |                  |
|             |           |          |             | 3 |                  |
+-------------+-----------+----------+-------------+---+------------------+
| Cough/cold  | 6 1.9     | 13 2.1   | 0.90        | 0 |                  |
|             |           |          | (p=0.529)   | . |                  |
|             |           |          |             | 6 |                  |
|             |           |          |             | 2 |                  |
|             |           |          |             |   |                  |
|             |           |          |             | - |                  |
|             |           |          |             | 0 |                  |
|             |           |          |             | . |                  |
|             |           |          |             | 2 |                  |
|             |           |          |             | 0 |                  |
|             |           |          |             | 3 |                  |
+-------------+-----------+----------+-------------+---+------------------+
| Appetite    | 0 0.0     | 0 0.0    |             |   |                  |
+-------------+-----------+----------+-------------+---+------------------+

Table 4 subgroup analysis by Sentinal Symptom

+-------------+-----------+----------+-------------+------------------+
| **No        |           |          |             |                  |
| Sentinal    |           |          |             |                  |
| Symptom**   |           |          |             |                  |
|             |           |          |             |                  |
| **(n=548)   |           |          |             |                  |
| (n=1075)**  |           |          |             |                  |
+-------------+-----------+----------+-------------+------------------+
| No use      | 519 94.7  | 1022     |             |                  |
|             |           | 95.1     |             |                  |
+-------------+-----------+----------+-------------+------------------+
| Any PPA     | 20 3.6    | 26 2.4   | **1.55      | **1.33** 0.77    |
|             |           |          | (p=0.104)** | 0.194            |
+-------------+-----------+----------+-------------+------------------+
| Cough/cold  | 17 3.1    | 25 2.3   | **1.35      | **1.12** 0.64    |
|             |           |          | (p=0.221)** | 0.371            |
+-------------+-----------+----------+-------------+------------------+
| Appetite    | 4 0.7     | 1 0.1    | **7.08      | **12.10** 1.39   |
| suppressant |           |          | (p=0.046)** | 0.029            |
+-------------+-----------+----------+-------------+------------------+
| Current use | 17 3.1    | 18 1.7   | **1.85      | **1.42** 0.78    |
|             |           |          | (p=0.054)** | 0.169            |
+-------------+-----------+----------+-------------+------------------+
| First use   | 6 1.1     | 4 0.4    | **3.00      | **3.34** 1.08    |
|             |           |          | (p=0.077)** | 0.040            |
+-------------+-----------+----------+-------------+------------------+
| Not-first   | 11 2.1    | 14 1.3   | **1.55      | **1.02** 0.50    |
| use         |           |          | (p=0.196)** | 0.479            |
+-------------+-----------+----------+-------------+------------------+
| Prior use   | 3 0.6     | 8 0.7    | 0.76        | 0.98 \-- 0.489   |
|             |           |          | (p=0.481)   |                  |
+-------------+-----------+----------+-------------+------------------+
| **Sentinal  |           |          |             |                  |
| Symptom     |           |          |             |                  |
| Present or  |           |          |             |                  |
| Uncertain** |           |          |             |                  |
|             |           |          |             |                  |
| **(n=154)   |           |          |             |                  |
| (n=301)**   |           |          |             |                  |
+-------------+-----------+----------+-------------+------------------+
| No use      | 145 94.2  | 288 95.7 |             |                  |
+-------------+-----------+----------+-------------+------------------+
| Any PPA     | 7 4.6     | 7 2.3    | **2.13      | **2.19** 0.80    |
|             |           |          | (p=0.141)** | 0.099            |
+-------------+-----------+----------+-------------+------------------+
| Cough/cold  | 5 3.2     | 7 2.3    | **1.48      | **1.71** 0.58    |
|             |           |          | (p=0.365)** | 0.206            |
+-------------+-----------+----------+-------------+------------------+
| Appetite    | 2 1.3     | 0 0.0    | **4.83      | \- - -           |
|             |           |          | (p=0.111)** |                  |
+-------------+-----------+----------+-------------+------------------+
| Current use | 4 2.6     | 3 1.0    | **2.67      | **2.95** 0.76    |
|             |           |          | (p=0.173)** | 0.096            |
+-------------+-----------+----------+-------------+------------------+
| First use   | 2 1.3     | 1 0.3    | **4.00      | **2.70** 0.34    |
|             |           |          | (p=0.259)** | 0.215            |
+-------------+-----------+----------+-------------+------------------+
| Not-first   | 2 1.3     | 2 0.7    | **2.06      | **3.17** 0.53    |
| use         |           |          | (p=0.395)** | 0.145            |
+-------------+-----------+----------+-------------+------------------+
| Prior use   | 3 2.0     | 4 1.3    | **1.53      | **1.51** 0.36    |
|             |           |          | (p=0.418)** | 0.318            |
+-------------+-----------+----------+-------------+------------------+

Furthermore, the Yale investigators observed that the odds ratio was
2.31 (LCL=1.10, p=0.031) among patients with current use of dose above
75mg (i.e. median daily dose of users of controls) comparing to an odds
ratio of 1.01 (LCL=0.43, p=0.490) among patients using less than 75 mg
(Table 5). These results suggest a possible dose response relationship.

Table 5 Dose Group Subgroup Analysis

  -------------------- --------------------------------------------------
  Current dose         OR LCL p-value

  \> 75 mg (=median)   **2.31** 1.10 0.031

  ≤75 mg               **1.01** 0.43 0.490
  -------------------- --------------------------------------------------

4.  Conclusions from the study should be based on overall PPA exposure,
    which is the study's first objective (i.e., "Do PPA uses have an
    increased risk?"). The overall analysis based on this endpoint
    resulted in an odds ratio that does not demonstrate increased risk
    \[i.e., OR=1.49, p=0.084\] of PPA use and hemorrhagic stroke. No
    meaningful conclusions can be derived from analyses of very small,
    selected subsets. There are too few cases and controls in the
    subgroups that reportedly took PPA to allow for effective
    controlling for confounding factors.

The strength of this epidemiological finding is not limited to a
significant p-value. It is the consistency of the findings with the
signals generated from FDA spontaneous reports. It is also in the
consistency of the ORs in the study when adjusted for the potential
confounders through modeling or stratified analysis. In addition,
although the four objectives were specified as of equal importance as
proposed by Yale investigator and endorsed by NDMA (now CHPA)
(NDMA-to-FDA letter, October 14, 1993, ref. 11), the priority of the
objectives #3 and #4 (first use, dietary suppressant PPA women only)
were suggested by Jolson's findings in FDA spontaneous reports. .

5.  Confounding factors, which are independent risk factors that are
    associated with both PPA product use and the occurrence of stroke
    and include lifestyle habits and pre-existing medical conditions
    that could independently contribute to stroke, such as hypertension
    and cigarette smoking, were not controlled for in the study
    analyses. Cases and controls were not adequately matched for
    confounding factors, which is the deviation from the study protocol.

-   Some examples of confounders that were not adequately controlled for
    included the following,

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-   Educational level and socioeconomic status were quite different
    between the cases and the controls, and cases were more likely to be
    black than were controls. Lower socioeconomic status and a lower
    educational level are known risk factors typically associated with
    greater morbidity and mortality in a number of diseases, including
    stroke. Those and several other risk factors for stroke are
    significantly more prevalent among cases than among controls. Cases
    were more likely to be current smokers, consume more alcoholic
    beverages, be illicit drug users, be reported to have hypertension,
    and/or have a family history of stroke.

-   Hypertension is a risk factor for hemorrhagic stroke and for an
    increased risk of aneurysm formation and rupture, and is associated
    with obesity. Obese persons might be expected to be more likely to
    use PPA-containing appetite suppressants, but notably few persons in
    the study taken PPA appetite suppressants. Although the use of
    antihypertensive medication and degree of blood pressure control are
    potentially important risk factors, they were not assessed nor,
    therefore, controlled for as confounders.

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-   The reported apparent "association" of hemorrhagic stroke and PPA in
    this study could arise from the comparison of high-risk group for
    hemorrhagic stroke (hypertension, cocaine and alcohol abuse,
    caffeine consumption, family history of hemmorrhagic stroke,
    obesity) with controls drawn from the general population, with
    limited control of confounding.

> The protocol of this NDMA (now CHPA) sponsored project was fully
> discussed between NDMA and Yale investigators before it was submitted
> for discussion with the FDA. The limitations of controlling for all
> confounding factors were carefully considered. In the analyses
> reported by the Yale investigators, the most serious and common
> confounding risks of hemorrhagic stroke, namely smoking, hypertension,
> race and education, were studied and included in the logistic
> regression adjustment of the association. This reviewer believes that
> the last bullet item is more speculation than real for this data. For
> example, in order to eliminate the impact of hypertension on the
> association, the Yale investigator estimated the odds ratio also using
> logistic regression with hypertension as a covariate. In addition, the
> FDA reanalyzed the data limited to the population with no history of
> hypertension and found that PPA is independently associated with
> hemorrhagic stroke from hypertension.
>
> First, in the following table of patients with hypertension history,
> it is shown that there was actually a lower percentage of hypertension
> history among PPA users than non-users in cases.

Table 6 Subjects with hypertension history among PPA users

  ---------------- --------------- ------------- --------------- ------------- --------------- -------------
  **Hypertension   **All                         **Cases**                     **Controls**    
  History**        subjects**                                                                  

                   **Unexposed**   **Exposed**   **Unexposed**   **Exposed**   **Unexposed**   **Exposed**

  **3-day exposure                                                                             
  window**                                                                                     

  **Yes**          536 (26%)       17 (28%)      263 (39%)       9 (33%)       273 (20%)       8 (24%)

  **No**           1551 (74%)      43 (72%)      482 (61%)       18 (67%)      1069 (80%)      25 (76%)

  **Total**        2087            60            375             27            1342            33

  **Cough/cold PPA                                                                             
  Users**                                                                                      

  **Yes**          537 (27%)       16 (30%)      264 (39%)       8 (36%)       273 (20%)       8 (25%)

  **No**           1486 (73%)      38 (70%)      416 (61%)       14 (64%)      1070 (80%)      24 (75%)

  **Total**        2023            54            680             22            1343            32

  **Appetite                                                                                   
  suppressant PPA                                                                              
  Users**                                                                                      

  **Yes**          551 (27%)       2 (29%)       270 (40%)       2 (33%)       281 (20%)       0 (0%)

  **No**           1519 (73%)      5 (71%)       426 (60%)       4 (67%)       1093 (80%)      1 (100%)

  **Total**        2070            7             716             6             1374            1

  **1^st^ Users**                                                                              

  **Yes**          552 (27%)       1 ( 8%)       271 (39%)       1 (15%)       281 (21%)       0 (0%)

  **No**           1512 (73%)      12 (92%)      423 (61%)       7 (85%)       1089 (79%)      5 (100%)

  **Total**        2064            13            694             8             1370            5
  ---------------- --------------- ------------- --------------- ------------- --------------- -------------

> On the other hand, when the data were reanalyzed for the subset of
> patients with no hypertension history, the association was consistent
> though not always statistically significant, with 3-day exposure
> window, cough/cold PPA exposure, current exposure, first exposure and
> even not first exposure patients.

## 

## Table 7 Analyses in patients without a hypertension history 

+---------+----------+-----------+-----------------+------------------+
|         | **Case** | **        | **Matched       | **Adjusted**     |
|         |          | Control** | p-value**       |                  |
|         | **No.    |           |                 | **OR LCL         |
|         | %**      |           | **OR LCL        | p-value**        |
|         |          |           | p-value**       |                  |
|         |          |           |                 | **/UCL**         |
|         |          |           | **/UCL**        |                  |
+---------+----------+-----------+-----------------+------------------+
| **3-day |          |           |                 |                  |
| E       |          |           |                 |                  |
| xposure |          |           |                 |                  |
| W       |          |           |                 |                  |
| indow** |          |           |                 |                  |
+---------+----------+-----------+-----------------+------------------+
| Yes     | 18 3.0   | 25 2.3    | **1.934** 1.08  | **2.05** 1.10    |
|         |          |           | 0.03            | 0.03             |
|         |          |           |                 |                  |
|         |          |           | 3.47            | 3.82             |
+---------+----------+-----------+-----------------+------------------+
| No      | 482 97.0 | 1069 97.7 |                 |                  |
+---------+----------+-----------+-----------------+------------------+
| **Cou   |          |           |                 |                  |
| gh/Cold |          |           |                 |                  |
| APP     |          |           |                 |                  |
| Users** |          |           |                 |                  |
+---------+----------+-----------+-----------------+------------------+
| Yes     | 14 3.3   | 24 2.2    | **1.461** 0.79  | **1.643** 0.87   |
|         |          |           | 0.15            | 0.10             |
|         |          |           |                 |                  |
|         |          |           | 2.69            | 3.10             |
+---------+----------+-----------+-----------------+------------------+
| No      | 416 96.7 | 1070 97.8 |                 |                  |
+---------+----------+-----------+-----------------+------------------+
| **A     |          |           |                 |                  |
| ppetite |          |           |                 |                  |
| APP     |          |           |                 |                  |
| Users** |          |           |                 |                  |
+---------+----------+-----------+-----------------+------------------+
| Yes     | 4 0.9    | 1 0.1     | **10.26^a^**    | \-- \-- \--      |
|         |          |           | 1.75 0.01       |                  |
|         |          |           |                 | \--              |
|         |          |           | 60.34           |                  |
+---------+----------+-----------+-----------------+------------------+
| No      | 426 99.1 | 1093 99.9 |                 |                  |
+---------+----------+-----------+-----------------+------------------+
| **      |          |           |                 |                  |
| Current |          |           |                 |                  |
| Users** |          |           |                 |                  |
+---------+----------+-----------+-----------------+------------------+
| Yes     | 14 3.3   | 15 1.4    | **2.424** 1.22  | **2.422** 1.17   |
|         |          |           | 0.02            | 0.023            |
|         |          |           |                 |                  |
|         |          |           | 4.82            | 5.04             |
+---------+----------+-----------+-----------------+------------------+
| No      | 416 96.7 | 1079 98.6 |                 |                  |
+---------+----------+-----------+-----------------+------------------+
| **1^st^ |          |           |                 |                  |
| Uses**  |          |           |                 |                  |
+---------+----------+-----------+-----------------+------------------+
| Yes     | 7 1.6    | 5 1.4     | **4.130** 1.32  | **3.997** 1.21   |
|         |          |           | 0.02            | 0.03             |
|         |          |           |                 |                  |
|         |          |           | 12.95           | 13.25            |
+---------+----------+-----------+-----------------+------------------+
| No      | 423 98.4 | 1089 98.6 |                 |                  |
+---------+----------+-----------+-----------------+------------------+
| **Non   |          |           |                 |                  |
| 1^st^   |          |           |                 |                  |
| Users** |          |           |                 |                  |
+---------+----------+-----------+-----------------+------------------+
| Yes     | 7 1.6    | 10 0.9    | 749. 0.72 0.15  | **1.746** 0.67   |
|         |          |           |                 | 0.17             |
|         |          |           | 4.26            |                  |
|         |          |           |                 | 4.57             |
+---------+----------+-----------+-----------------+------------------+
| No      | 423 98.4 | 1084 99.1 |                 |                  |
+---------+----------+-----------+-----------------+------------------+

a: Unmatched odds ratio. The only exposed control has an exposed case
for match.

6.  Because of the small number of cases of hemorrhagic stroke
    reportedly associated with PPA use identified in this five-year
    study, errors in classification of exposure could easily and
    significantly skew the results of the study. This could be caused by
    errors in participant recall and/or product misclassification. The
    apparent association between PPA appetite suppressant use and stroke
    reported by Yale investigators would be apparent if only four
    controls were misclassified as unexposed to PPA.

With double-blind (interviewer and patients blinded from knowing the
drug of interest) setup and careful verification through picture
identification, the chance of misclassification was minimized if not
totally eliminated. The impact regarding to CHPA PPA Working Group's
hypothetical concerns on the CHPA sponsored Yale project can be
illustrated as follow. For example, the CHPA PPA working group pointed
out with only 4 exposed controls misclassified as unexposed, the
significant OR would nullified. This means that the CHPA PPA Working
Group assumed a highly unlikely 80% (4/5) misclassification rate of
exposed controls.

The odds ratio can be corrected if the misclassification rates were
known. Let p~0~ denote the misclassification rate of exposed-control and
p~1~ denote the misclassification rate of exposed-case. Let the true and
observed case-control/exposure frequencies be represented by the
following two tables.

**Table 8 Notation Table of Misclassification**

True Case-Control/Exposure Table

  ------------------- -------------------------- ------------------------
                      Case                       Control

  Exposed             K~11~                      K~01~

  Unexposed           K~10~                      K~00~
  ------------------- -------------------------- ------------------------

Observed Frequency Table of Case-Control/Exposure

  ------------------- -------------------------- ------------------------
                      Case                       Control

  Exposed             N~11~ (=K~11~(1-p~1~))     N~01~ (=K~01~(1-p~0~)

  Unexposed           N~10~ (=K~10~ +p~1~K~11~)  N~00~ (=K~00~
                                                 +p~0~K~01~)
  ------------------- -------------------------- ------------------------

Hence K~10~ = N~10~ - N~11~ (p~1~/(1-p~1~)), K~11~ = N~11~ /(1-p~1~),
K~00~ = N~00~ - N~01~ (p~0~/(1-p~0~)), K~01~ = N~01~ /(1-p~0~).

With p~0~, p~0~ given or estimated, the true odds ratio OR=
(K~11~K~00~)/(K~01~K~10~) can be estimated by the observed frequencies
as follow,

OR = {\[N~00~ - N~01~ (p~0~/(1-p~0~))\] N~11~ /(1-p~1~)}/{\[N~10~ -
N~11~ (p~1~/(1-p~1~))\] N~01~ /(1-p~0~)}

Under various assumption on misclassification rate ranges from 20% to
40%, the true odds ratio is estimated to be greater than 7.10 even under
the most conservative situation (Table 9).

Table 9 Estimate of True Odds Ratio Under Various Exposure
Misclassification Assumptions

+-----------------------------+---------------------------+------------+
| p~1~ :                      | p~0~:                     | Corrected  |
|                             |                           | OR         |
| prob(case-exposed being     | Prob (control-exposed     |            |
| misclassified to case-      | being misclassified to    |            |
| unexposed)                  | control-unexposed)        |            |
+-----------------------------+---------------------------+------------+
| 0%                          | 20%                       | 9.47       |
+-----------------------------+---------------------------+------------+
| 10%                         | 20%                       | 10.53      |
+-----------------------------+---------------------------+------------+
| 20%                         | 20%                       | 11.86      |
+-----------------------------+---------------------------+------------+
| 0%                          | 30%                       | 8.28       |
+-----------------------------+---------------------------+------------+
| 10%                         | 30%                       | 9.21       |
+-----------------------------+---------------------------+------------+
| 20%                         | 30%                       | 10.38      |
+-----------------------------+---------------------------+------------+
| 30%                         | 30%                       | 11.88      |
+-----------------------------+---------------------------+------------+
| 0%                          | 40%                       | 7.10       |
+-----------------------------+---------------------------+------------+
| 10%                         | 40%                       | 7.90       |
+-----------------------------+---------------------------+------------+
| 20%                         | 40%                       | 8.89       |
+-----------------------------+---------------------------+------------+
| 30%                         | 40%                       | 10.18      |
+-----------------------------+---------------------------+------------+
| 40%                         | 40%                       | 11.90      |
+-----------------------------+---------------------------+------------+

-   Since there are cough/cold products and appetite suppressants that
    do not contain PPA, a participant could incorrectly recall that they
    took product A (with PPA), when in fact they took product B (without
    PPA).

-   Telephone interviewers preclude the use of visual aids to assist
    subjects in their recall of exposure. More than twice as many
    controls as cases were interviewed over telephone, suggesting it was
    more for an exposed control to be misclassified on reported product
    use.

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-   Many other factors could also affect the accuracy of exposure
    classification. For example,

-   Study participants were asked to recall the specifics of medicine
    taken more than two weeks before, a substantial time between
    reported use and time of interview.

> Verification of each reported medication was done after the interview
> with the help of a Product Identification Book with photographs (see.
> page 11 of Yale study report).

-   Forty percent of the interviewed cases had a degree of aphasia. The
    proportion of aphasia cases could have affected accurate
    identification of a case reported to have used PPA products.

> The Yale Investigators' additional analysis stratified by aphasia
> status showed that except in patients with no prior use of PPA, the
> associations were consistent in all subsets.

Table 10 Association analysis in subset of patients with no aphasia
present

+-------------+-----------+----------+-------------+------------------+
|             | **Case**  | **Co     | *           | **Adjusted for   |
|             |           | ntrols** | *Unadjusted | smoking,         |
|             | **        |          | Matched     | hypertension,    |
|             | (n=702)** | **(n     | OR**        | race and         |
|             |           | =1376)** |             | education**      |
|             | **No. %** |          |             |                  |
|             |           | **No.    |             | **OR LCL         |
|             |           | %**      |             | p-value**        |
+-------------+-----------+----------+-------------+------------------+
| No use      | 664 94.6  | 1310     |             |                  |
|             |           | 95.2     |             |                  |
+-------------+-----------+----------+-------------+------------------+
| **No        |           |          |             |                  |
| Aphasia     |           |          |             |                  |
| present     |           |          |             |                  |
| Case        |           |          |             |                  |
| Controls**  |           |          |             |                  |
|             |           |          |             |                  |
| **rating =  |           |          |             |                  |
| 1-3 (n=603) |           |          |             |                  |
| (n=1184)**  |           |          |             |                  |
+-------------+-----------+----------+-------------+------------------+
| No use      | 567 94.0  | 1129     |             |                  |
|             |           | 95.3     |             |                  |
+-------------+-----------+----------+-------------+------------------+
| Any PPA     | 26 4.3    | 27 2.3   | 1.98        | 1.65 1.00 0.050  |
|             |           |          | (p=0.013)   |                  |
+-------------+-----------+----------+-------------+------------------+
| Cough/cold  | 21 3.5    | 26 2.2   | 1.63        | 1.35 0.80 0.175  |
|             |           |          | (p=0.072)   |                  |
+-------------+-----------+----------+-------------+------------------+
| Appetite    | 6 1.0     | 1 0.1    | 12.09       | 15.50 2.04 0.013 |
|             |           |          | (p=0.007)   |                  |
+-------------+-----------+----------+-------------+------------------+
| Current use | 20 3.3    | 18 1.5   | 2.23        | 1.70 0.95 0.066  |
|             |           |          | (p=0.012)   |                  |
+-------------+-----------+----------+-------------+------------------+
| First use   | 8 1.3     | 4 0.3    | 4.00        | 3.59 1.26 0.023  |
|             |           |          | (p=0.019)   |                  |
+-------------+-----------+----------+-------------+------------------+
| Not first   | 12 2.0    | 14 1.2   | 1.73        | 1.20 0.59 0.334  |
| use         |           |          | (p=0.123)   |                  |
+-------------+-----------+----------+-------------+------------------+
| Prior use   | 6 1.0     | 9 0.8    | 1.63        | 1.45 0.57 0.257  |
|             |           |          | (p=0.368)   |                  |
+-------------+-----------+----------+-------------+------------------+
| **No        |           |          |             |                  |
| Aphasia     |           |          |             |                  |
| present     |           |          |             |                  |
| (more       |           |          |             |                  |
| restricted  |           |          |             |                  |
| definition) |           |          |             |                  |
| (rating = 1 |           |          |             |                  |
| only)**     |           |          |             |                  |
|             |           |          |             |                  |
| **Case      |           |          |             |                  |
| Controls**  |           |          |             |                  |
|             |           |          |             |                  |
| **(n=388)   |           |          |             |                  |
| (n=759)**   |           |          |             |                  |
+-------------+-----------+----------+-------------+------------------+
| No use      | 363 93.6  | 726 95.6 |             |                  |
+-------------+-----------+----------+-------------+------------------+
| Any PPA     | 17 4.4    | 13 1.7   | 2.60        | 2.07 1.10 0.029  |
|             |           |          | (p=0.008)   |                  |
+-------------+-----------+----------+-------------+------------------+
| Cough/cold  | 14 3.6    | 13 1.7   | 2.16        | 1.80 0.93 0.070  |
|             |           |          | (p=0.035)   |                  |
+-------------+-----------+----------+-------------+------------------+
| Appetite    | 4 1.0     | 0 0.0    | \>16.00\*   | \-               |
|             |           |          | (p=0.013)   |                  |
+-------------+-----------+----------+-------------+------------------+
| Current use | 16 4.1    | 10 1.3   | 3.17        | 2.66 1.34 0.009  |
|             |           |          | (p=0.003)   |                  |
+-------------+-----------+----------+-------------+------------------+
| First use   | 8 2.1     | 3 0.4    | 5.33        | 4.60 1.45 0.015  |
|             |           |          | (p=0.009)   |                  |
+-------------+-----------+----------+-------------+------------------+
| Not first   | 8 2.1     | 7 0.9    | 2.33        | 1.93 0.80 0.110  |
| use         |           |          | (p=0.082)   |                  |
+-------------+-----------+----------+-------------+------------------+
| Prior use   | 1 0.3     | 3 0.4    | 0.67        | 0.25 \-- 0.158   |
|             |           |          | (p=0.593)   |                  |
+-------------+-----------+----------+-------------+------------------+

> \* Unmatched OR

-   Interviewers knew which subjects were cases and which were controls,
    and could have inadvertently prompted specific answers and thereby
    skewed the results.

-   The difference in the severity of the event for cases versus
    controls and in the location of the interview (hospital versus home)
    could also contributed to skewing the results.

-   Because such factors as those suggested above may have a significant
    and unpredictable impact on the odds ratio in either direction and
    virtually no information is provided to give a perspective on how
    such recall issues affect the study results, the scientific
    documentation supporting a putative exposure is, at best,
    inconclusive.

One of the strength of this CHPA sponsored case-control study was the
double blind feature. With it, neither the interviewers nor the patients
knew the exposure drug of interest. Hence it is difficult to comprehend
the potential bias speculated by CHPAWorking Group.

7.  The study was based on prevalent cases. Cases who died before
    interview and those who were unable to communicate within 30 days
    (i.e. 34%) were excluded. Studies based on prevalent cases could be
    misleading. A 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, and excluded cases may differ in
    their exposure to PPA and other risk factors for hemorrhagic stroke
    that would likely be confounder of the association of interest.
    Exclusion of the most severe patients could have affect the results,
    overestimating the risk associated with the use of PPA. This bias
    does not allow any posterior control for confounding factors
    associated with survival from hemorrhagic stroke.

> Since it has been pointed out in many epidemiologic reports that
> surrogate interviews of patients who were unable to communicate was
> the major source of bias, the FDA reviewers raised these concerns and
> proposed to exclude these patients from the study. This concern was
> verified by the Yale investigators with pilot information. Regarding
> the exposure difference between the excluded cases and study cases,
> there were no data found in either the literature or in this study for
> support.

8.  The study report fails to acknowledge that the findings cannot be
    entirely generalized to the U.S. population, as the controlled cases
    and controls were not adequately population-based and differ in
    sociodemographic characteristics from typical U.S. consumers who use
    PPA drug products. Furthermore, the study's case population does not
    appear to be totally representative of the hemorrhagic stroke
    population among 18- to --49-year-olds in the United States (i.e.
    the study shows a different distribution by stroke type), as well as
    excluding final stroke.

### The ability to generalize the study findings into a more general population was never an issue when the protocol was proposed and sponsored by NDMA and it was not an issue when it was reviewed by FDA reviewers in 1992-1993. It was not an issue then and it is not an issue now. Conducting an epidemiological study with simple random sample of whole U.S. consumer population is not realistic. The strength of an epidemiological study is in controlling the potential confounding factors and in minimizing the bias in the conducting and data gathering phase. Hence results of regional epidemiological studies such as Framingham Study can be generalized to U.S. population.

### 

### This strength of this study was verified through internal validity. As one of the matching factors, potential bias due to social-economic status is minimized in the study design. If there is indeed a difference in stroke type distribution between this study and the general population, it is mainly due to the exclusion of cases with communication difficulties in order to minimize bias. It would be the same if the sampling frame were the U.S. general population instead. 

9.  The large differential in participation rates between cases and
    controls could affect the findings and is not adequately explained
    in the report. Likely, inadequate data are provided to allow
    independent verification of the findings or to verify that
    sensitivity analyses do not alter the confidence limits or p-values
    for the findings.

The difference in participation rates between cases and controls does
not bias the study findings. It is the participation associated with
exposure status or with the confounders of exposure may bias the
findings. The majority of the non-enrolled cases (82%) were not enrolled
because case subjects were not contacted within the 30 days window.
Hence non-enrollment of cases is clearly independent of exposure status.
As for non-enrolled controls, no information was available regarding
exposure status. However, since both the interviewer and patients were
not informed of the drug of interest, there is no reason to believe that
non-enrollment is exposure related.

10. Choice of analytical methodology is also of concern. Inappropriate
    statistical methods were used, given the small numbers of exposed
    cases. Likewise, inappropriate and/or inadequate methods were used
    to control for confoundings.

-   The number of subjects exposed to appetite suppressants is too few
    to meet the criterion for the use of asymptotic statistical methods.
    These methods require a minimum of five observations in each
    exposure-disease category. Seven exposed subjects divided between
    cases and controls do not satisfy the criterion. Therefore, analysis
    of exposure to appetite suppressant should use exact, rather than
    asymptotic, statistical methods.

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-   The attempt to control for confounding by including cofounders in
    the exact method of analysis was unsuccessful due to the few exposed
    subjects. Therefore, interpretation of the results of the exact
    analysis must include cofounders as a very likely explanation for
    the observed association. Further, these cofounders cannot be
    considered controlled in the asymptotic analysis, since the
    assumption for this analysis is violated.

> As pointed out earlier, the strength of this CHPA sponsored
> case-control study is not in the significance level of the p-values.
> The level of significance is hampered by the sample size, which was
> determined as the minimum required sample size under a pre-assumed
> exposure rate in the control population and a large targeted odds
> ratio (OR=5) for the population of objective #1. The sample size
> requirement was not reasonably attained for other equally important
> objectives of the protocol. However, it is clear from the data that
> the association between hemorrhagic stroke and appetite suppressant
> use existed and the associations across all four objectives and all
> subset analyses are consistent internally and with Jolson's findings
> with FDA spontaneous reports in general. The issue on the criterion
> between asymptotic method and exact method is often over emphasized.
> In an early published simulation study, it was shown that the
> asymptotic method controls type I error rate even with minimum
> expected cell frequency as small as two. On the other hand, the exact
> method is still conservative at this level for it has type I error
> rate less than 5%. To be more specific, in this study, the minimum
> cell frequency is 2.5 for cases exposed to PPA-appetite suppressant.

-   A reflection of the inappropriateness of the asymptotic statistical
    analysis is the fact that the strength of the association between
    exposure and disease increased when confounders were "controlled".
    This is contrary to what is usually observed in control of
    confounding variables, where the adjusted odds ratio is expected to
    be smaller than the unadjusted odds ratio.

The statement given by CHPA Working Group is incorrect. It is often
observed in clinical trials that the treatment effect may be greater and
with more statistical significance when the confounder such as baseline
measurement is adjusted. It is often also happen in epidemiological
study that the odds ratios increase in the analysis with stratified
table when the association is consistent across stratum.

-   The study provided no insight on a biologically plausible mechanism
    for any relationship between use of PPA and hemorrhagic stroke.
    Although recommended doses of PPA have been shown to cause small,
    transient, but clinically insignificant, changes in blood pressure,
    these minor changes are within the range of usual increase
    associated with such daily activities as climbing stairs or mowing a
    lawn. Hence, alteration of blood pressure is not a clear underlying
    mechanism for a putative association between PPA and stroke, nor is
    any other biologically plausible mechanism known.

The CHPA PPA Working Group's comment emphasizes on 1) blood pressure
increases in clinical trials and 2) when used according to label
recommended dose. However, it is well understood that clinical trial is
not designed with the capability to detect rare adverse event such as
hemorrhagic stroke. In addition, without advise by a physician,
consumers of OTC drug products often do not use the product according to
label recommendations as they would when they take it as prescription
product. Hence, this CHPA sponsored case-control study plays a much more
important role than any previous studies. This is a well-planed
postmarketing study designed to confirm the safety concerns raised from
the FDA Spontaneous Response System findings dated in 1993.

# 

# **C. SUMMARY OF REVIEW**

1.  This is a well-designed and conducted case-control trial. Both NDMA
    (now CHPA) and FDA scientists carefully reviewed its protocol before
    the study was conducted. Its unique double-blind feature (i.e. both
    interviewers and interviewees were blinded from the target exposure
    drug) minimized the potential bias of an observational study. It is
    clear in this FDA reviewers' experience that it is one of the best
    planned, conducted and most thoroughly analyzed studies reviewed in
    the last ten years.

2.  The study was designed with four equally important objectives:

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1)  To estimate the association between PPA and hemorrhagic stroke among
    men and women aged 18 -- 49 years.

2)  To estimate the association between PPA and hemorrhagic stroke by
    type of PPA exposure among the same target population

3)  Among women aged 18-49 years to estimate the association between
    first use of PPA and hemorrhagic stroke

4)  Among women aged 18-49 years to estimate the association between PPA
    in appetite suppressants and hemorrhagic stroke.

The level of importance of objectives #3 and #4 should be emphasized
because of the safety concerns raised in Jolson's review of the FDA
spontaneous reports.

3.  Positive associations between PPA use and hemorrhagic strike were
    shown in all study objectives. All except in the cohort of the first
    objective, the associations were statistically significant. In the
    cohort of the first objective, the association was near significant.
    The strength of the study is in the consistency of the associations.
    First, the ranking of the associations under the four objectives
    found in this study was consistent with the primary safety concerns
    in Jolson's review of the FDA spontaneous reports. Second, the
    strong consistency of the associations found through internal
    validation of the study data and multiple analyses with adjustment
    for confounders and within subgroups stratified by the confounders.
    The weak association found for objective #1 was due partially to the
    lack of association among male patients in this data.

4.  The strength of the associations was strengthened by the strong
    association found in the subset of patients with no history of
    hypertension. The associations suggest that PPA use is a risk factor
    independent of hypertension history.

5.  In an ad hoc analysis of a subset of patients with proper dosage
    information, the association was further strengthened by the
    statistically significant association within current PPA users of
    more than 75mg PPA (median dose). There was no significant
    association among patients currently using no more than 75 mg PPA.

**ACKNOWLEDGEMENT**

Contributions from Dr. Parivash Nourjah of Division of Drug Assessment 1
in addressing CHPA PPA Working Group's Comments on Yale report of
hemorrhgic stroke study are to be acknowledged.

**\_\_\_\_\_\_\_\_\_\_**\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Yi Tsong, Ph.D., Mathematical Statistician

Quantitative Methods Research Staff

Concur: \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Stella G. Machado, Ph.D.

Director, Quantitative Methods Research Staff

copies: HFD-430 Beitz/Trontell/La Granade/Nourjah/Guinn

HFD-705 QMRS Chron/Machado/Tsong

Electronic copy/O:/QMR/chron00/pdra/ppa.yale.review.

**References:**

1.  O'Neill RT, Van De Carr SW, A case-control study of adrenergic
    decongestants and hemorrhagic CVA using a Medicaid database. *FDA
    report*, CDER/FDA, Rockville, MD, 1984.

2.  Jick H, Aselton P, Hunter JR, Phenylpropanolamine and cerebral
    hemorrhage. *Lancet*, 1984:1017.

3.  Jolson HM, Epidemiological reviews of phenylpropanolamine safety
    issue, FDA Memorandum, CDER/FDA, Rockville, MD, April 1991.

4.  Tsong Y, Statistical review of Yale proposal to study hemorrhagic
    stroke and PPA, *FDA Internal Memorandum*, Rockville, MD, 1993.

5.  Graham DJ, Tsong Y, Phenylpropanolamine (PPA) and Yale hemorrhagic
    stroke project (OTC Trac No. 310-04), *FDA Internal Memorandum*,
    1993.

6.  *Memorandum of November 9, 1992 Meeting:* Between Nonprescription
    Drug Manufacturers Association and FDA, CDER/FDA, Rockville, Md.

7.  *Memorandum of August 15, 1993 Meeting:* Between Nonprescription
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8.  Freiman J, Review of a revised protocol entitled "Hemorrhagic Stroke
    Project: Case-control study of PPA and hemorrhagic stroke", *FDA
    Internal Memorandum*, June 16, 1994.

9.  Gilbertson WE, FDA Letter to R. William Soller, Senior Vice
    President of Nonprescription Drug Manufacturers Association, FDA
    Docket No. 81N-0022, Comment No. PR7, CDER/FDA, Rockville, MD, June
    17, 1993.

10. Soller RW, NDMA Letter to William E. Gilbertson, Director of
    Monograph Review Staff, Office of OTC Drug Evaluation, CDER/FDA,
    August 11, 1993

11. Soller RW, NDMA Letter to William E. Gilbertson, Director of
    Monograph Review Staff, Office of OTC Drug Evaluation, CDER/FDA, FDA
    Docket No. 81N-0022, October 14, 1993.

12. Soller RW, Totman LC, Consumer Healthcare Product Association
    (CHPA), Letter to Docket management Branch (HFA-305), Office of OTC
    Drug Evaluation, CDER/FDA, May 24, 2000.