# Presentation: 529834

## Phenylpropanolamine

**R. William Soller, Ph.D.**
- Senior Vice President and Director of Science & Technology
- Consumer Healthcare Products Association
- Washington, DC
- October 19, 2000

**Notes:**
Good morning.  I am Dr. Bill Soller, Senior Vice President and Director of Science & Technology for the Consumer Healthcare Products Association, the 119-year-old trade organization representing the manufacturers and distributors of nonprescription medicines and dietary supplements.

## Outline

**Background**
**Independent Expert Panel**
**Conclusion**

**Notes:**
Our presentation is in three parts.

I have background comments and will be followed by Dr. Noel Weiss and the Independent Expert Panel which reviewed the Hemorrhagic Stroke Project study.

I will close with proposed Next Steps.

## What did we know about PPA when the HSP study was started?

**Notes:**
I would like to start by answering the question:  What did we know about PPA when the HSP study was started?

## PPA is an Effective OTC Ingredient.

**Nasal Decongestion**
**25-37.5mg q4h up to 150mg/day**
**OTC Monograph**
**Two NDAs (‘81 and ‘92)**
**Weight Control**
**25mg t.i.d. up to 75mg/day**
**3-4 lb greater mean weight loss over baseline than placebo, over 6-8 weeks**

## PPA is Reasonably Safe for Continued Marketing

**Spontaneous AER Profile**
**low number of reports/year**
**no clear trend or signal**

**Notes:**
We knew PPA was reasonably safe for continued marketing, based on the adverse experience reporting profile from spontaneous reports to FDA and industry.

Typically there is a low number of reports per year, with no clear signal or trend, and this is the current picture as well, with an average of about 2 spontaneous reports per year over the last ten years.

## Blood Pressure
Clinical Studies:  
Normotensives, controlled hypertensives
Obese, non-obese
Single, multiple and ascending dose models
No clinically meaningful elevations in blood pressure, other vital signs, CNS stimulation or subjective effects at recommended doses
Blackburn et al.  (JAMA 261:3267-72,1989)

- _Clinical Studies_:
- Normotensives, controlled hypertensives
- Obese, non-obese
- Single, multiple and ascending dose models
**No clinically meaningful elevations in blood pressure, other vital signs, CNS stimulation or subjective effects at recommended doses**
- _Blackburn et al_.  (JAMA 261:3267-72,1989)

- PPA is Reasonably Safe for Continued Marketing

**Notes:**
Based on many clinical studies on normotensive, controlled hypertensives, obese, and non-obese individuals in single, multiple and ascending dose models, PPA causes no clinically meaningful elevations in blood pressure, other vital signs, CNS stimulation or subjective effects at recommended doses.

The largest of these studies is by Blackburn et al., and Dr. Blackburn is available today for Q&A.

## Two retrospective epidemologic studies
Boston Collaborative Drug Surveillance Program
National Hospital Discharge Survey 
No indication of a signal

**Boston Collaborative Drug Surveillance Program**
**National Hospital Discharge Survey**** **
**No indication of a signal**

- PPA is Reasonably Safe for Continued Marketing

**Notes:**
In addition, two retrospective epidemiologic studies were available, one derived from the database of the Boston Collaborative Drug Surveillance Program; and the other from the National Hospital Discharge Survey database.

There is no indication of a signal in either epidemiologic study.

## Aselton and Jick (1985):  PPA All Uses
Boston Collaborative Drug Surveillance Program
Based on Rx’s filled (253,334 scripts for <65 yo;‘77-’82; calculated on the basis of estimated person-days at risk) 
PPA users vs. non users (1 vs. 275 hospital admissions for thrombotic or nonthrombotic cerebrovascular events)

- Boston Collaborative Drug Surveillance Program
- Based on Rx’s filled (253,334 scripts for <65 yo;‘77-’82; calculated on the basis of estimated person-days at risk)** **
- PPA users vs. non users (1 vs. 275 hospital admissions for thrombotic or nonthrombotic cerebrovascular events)

- PPA is Reasonably Safe for Continued Marketing

**Notes:**
In the first of these studies, Aselton and Jick reviewed the Boston Collaborative Drug Surveillance program database.  Over the 1977-1982 period, Jick reported many fewer hospital admissions for PPA vs. nonusers for thrombotic or nonthrombotic cerebrovascular events --  1 for PPA covering 7 million person days vs 275 for nonusers covering 520 million person days.

RR .25 with 95% confidence interval o f.01-1.4)...upper bound for the attirbutable risk is 1.2 x 10 -7 person days.

## National Hospital Discharge Survey Analysis (1991):  Diet Aids, 15-44 yo
Morbidity Ratios 
Observed:expected hemorrhagic strokes under first dose or multiple dose exposure assumptions
Background rate: 16.31/100,000 females (15-44y)
Estimated Morbidity Ratios:  
First dose, 0.02
Multiple dose, 0.36

- Morbidity Ratios
- Observed:expected hemorrhagic strokes under first dose or multiple dose exposure assumptions
- Background rate: 16.31/100,000 females (15-44y)
- Estimated Morbidity Ratios:
- First dose, 0.02
- Multiple dose, 0.36

- PPA is Reasonably Safe for Continued Marketing

**Notes:**
In addition we reviewed the National Hospital Discharge Survey database calculating morbidity ratios for observed to expected hemorrhagic strokes, in the context of diet aid use by women 15-44 years of age.

With a background hemorrhagic stroke rate of about 16/100,000 in women 15-44 years of age, we estimated morbidity ratios of 0.02 for a first dose paradigm and 0.36 for exposure under a multiple dosing pardigm. 

These epidemiologic studies thus support a favorable safety profile.
-----------------------
ICD codes 430 (SAH), 431 (Intracerebral hemorrhage) and 432 (other unspecified  intracranial hemorrhage).

## Summary

- So, at the start of the HSP study, a hypothesis had been generated, despite clinical and epidemiologic support for PPA’s safety as well as clinical demonstration of benefit.

**Notes:**
So, at the start of the HSP study, a hypothesis had been generated, despite clinical and epidemiologic support for PPA’s safety as well as clinical demonstration of benefit.

## CHPA & the HSP Study

**Consensus view prior to HSP Study**
- Continued OTC availability with additional study to optimize our understanding of PPA’s safety profile, given:
- AER profile, blood pressure studies, available epi studies
**Industry’s involvement in the study**
- Input on design, and funding, but...virtually no involvement in conduct/analysis
**Apparent over-interpretation of the study results**
- CHPA contacted leading independent experts.

**Notes:**
Prior to starting the HSP study, the consensus was therefore:  continued OTC availability of PPA with additional study to optimize our understanding of PPA’s safety profile, based on PPA’s known efficacy, favorable AER profile, and favorable clinical findings on blood pressure. 

Our involvement with the HSP study was very limited.  We had input on design and funding, of course, but virtually no involvement in conduct and analysis.  We understood that we might face clearly positive, clearly negative or ambiguous findings needing an advisory committee deliberation.

When we received the initial study report, we were struck by an apparent over-interpretation of the study results, and contacted leading epidemiologic and statistical experts, many of whom are here today.

## Outside Expert Reviewers

**George L. Blackburn**, M.D., Ph.D., Associate Professor of Surgery & Nutrition, Harvard Medical School, Beth Israel Deaconess Medical Center
**Charles H. Hennekens**, M.D., DrPH, Visiting Professor of Medicine and Epidemiology and Public Health, University of Miami School of Medicine
**Robert Hirsch**, Ph.D., Professor of Epidemiology and Biostatistics, George Washington University School of Public Health
**Brian ****B. Hoffman**, M.D., Professor of Medicine, Stanford University
**Carlos S. Kase**, M.D., Professor of Neurology, Boston University School of Medicine
**Philip D. Walson**, M.D., Professor of Pediatrics,  University of Cincinnati and Director CHRF Clinical Trials Office, Children’s Hospital
**Philip A. Wolf**, M.D., Professor of Neurology, Chief, Cerebrovascular Disease Section, Research Professor of Medicine (Preventive Medicine and Epidemiology), Boston University School of Medicine; Principal Investigator, The Framingham Study

**Notes:**
These experts are shown here, and Drs. Blackburn,. Hennekens, Hirsch,. Hoffman and Walson will present and/or be available to you for Q&A during your discussion.

## Independent Expert Panel

**Noel Weiss, M.D., Dr. P.H., **University of Washington*Chairman of the Expert Panel*

**Notes:**
We also contacted an Independent Expert Panel for a second view about the HSP study.  At this time, I will turn the podium over to Dr. Noel Weiss, who chaired this panel of leading members of the U.S. epidemiologic community.

## Slide 14

## Conclusions

**Current FDA OTC Policy**
**Recommended Next Steps**

**Notes:**
In conclusion, I would like to comment on FDA’s OTC Policy in this area and provide industry’s recommended next steps.

## FDA OTC Policy

- Three Part Hurdle
- Product availability and warnings should be “_scientifically documented_, _clinically significant_, and i_mportant to the safe and effective use_ of the product by the consumer.”**Final Rule Regarding Label Warning for Pregnant or Nursing Women; Delegations of Authority and Organization [47 *****Fed.Reg.*****  54754 (12/3/82)]****Internal Analgesic, Antipyretic, and Anti-rheumatic Drug Products for Over-the-Counter Human Use; Tentative Final Monograph; Notice of Proposed Rulemaking [53 *****Fed.Reg.***** 46213 (11/16/88)]**

**Notes:**
FDA’s OTC policy is that product availability and labeling should be scientifically documented, clinically significant and important to the safe and effective use of the product by the consumer.

The value of this three part policy cannot be under-estimated.  The first hurdle, scientific documentation, forces us to look very closely at the quality and strength of the underlying data before reaching clinical or in-use conclusions. 

## HSP in context of FDA Policy

**The first hurdle of FDA’s OTC policy (“scientifically documented”) is not met.**
- Because of:
- The inherent limitations of studies like the HSP
- Its small numbers of exposed cases and controls,
- Inherent bias
- Inadequate control for confounding
- Concerns about the chosen statistical methods
- the HSP study does _not_ provide the quality and extent of scientific documentation necessary to support a change in OTC status of PPA.

**Notes:**
Based on the expert epidemiologic review, the first hurdle of FDA’s policy is not met by the HSP study.

Read slide.

## HSP in context of FDA Policy

- Prior to the HSP, industry committed to further research on PPA.
- Industry commitment unchanged
- While of limited value in terms of its questionable results, the HSP nevertheless provides new insights on optimal design of future studies.

**Notes:**
However, prior to the HSP study, industry was committed to further research on PPA, and this commitment remains unchanged.

While of limited value in terms of its questionable results, the HSP nevertheless shows that exposure to PPA among patients with hemorrhagic stroke is very rare...
and it provides new insights on optimal design of future studies.

## Recommended Next Steps

- Further epidemiologic study
- Finalization of labeling requirements
- Stepped-up surveillance

**Notes:**
Hence, we recommend three next steps, which are outlined in our handout to the committee.

First, further epidemiologic study, undertaken either by or in conjunction with PHS.
Second, finalization of FDA’s labeling requirements.
Third, stepped up surveillance through voluntary submission of serious AERs reportedly associated with PPA-containing OTC products, noting that some of our members are doing this.

I thank you for your attention, and our team is prepared to answer your questions.  

## Slide 20

## AER Profile:  FDA SRS/AERSDiet Aid and Cough/Cold: Hemorrhagic Stroke-related, all ages

- Galt Associates, 2000
- Total n=35, 1981 - 1989

**Congressional hearings (Rep.M.R.Okar)**

**CSPI issues public call for AERs**

**Notes:**
During the time that PPA’s effectiveness was under consideration, interest turned to PPA’s adverse experience report profile, shown here for spontaneous reports to FDA from ‘81 to ‘89 for PPA diet and cough-cold products.

You can see the result of publicity in the 1984-5 timeframe. 

This was basically the picture prior to the HSP study. 

.  

## AER Profile: 

- Covance, 2000.
- Total n = 21, 1990-June 2000
- Includes 2 of unknown age.

- FDA  SRS/AERS & Spontaneous Reports to Companies
- Diet Aid and Cough/Cold: Hemorrhagic Stroke-related, 18-54yr

**Notes:**

By way of update, ‘90 to June 2000, the pattern, shown here as prepared for CHPA by Covance, is characterized by low numbers, on average about 2 per year, with no clear trend or pattern suggesting any  increase in recent years, despite continued substantial exposure to PPA in both the cough/cold and appetite suppressant categories.

With the exception of the stimulated reporting in 1984-5, this is basically the same pattern for the last 20 years.

## PPA-related AERs: ‘81-’00

## Obesity - the second leading cause of unnecessary deaths

- Affects at least 70 million Americans:
- more than one-third of all adults and one in five children.
- Causes at least 300,000 excess deaths in the U.S./year
- Costs the country more than $100 billion/year.
- Continual trend in the number of overweight and obese Americans since 1960
- 2000:  55% of adult Americans (97 million) are categorized as being overweight or obese.
- From:  **American Obesity Association, 2000**** ****(http://www.obesity.org/what.htm)**

## Obesity/Overweight

- BMI _>_ of 30 = obese
- BMI 25 - 29.9 = overweight
- A BMI of 30 is about 30 pounds overweight and is equivalent to 221 pounds in a 6' person and to 186 pounds in someone who is 5'6".