Pulmonary Allergy Drugs Advisory Committee

**September 6, 2002**

**Holiday Inn Gaithersburg**

**Minutes**

**New Drug Application (NDA) 21-395, Spiriva (Tiotropium bromide) by
Boehringer-Ingelheim for chronic obstructive pulmonary disease (COPD).**

**COMMITTEE**

Mark S. Dykewicz, M.D.

Andrea J. Apter, M.D.

Polly E. Parsons, M.D.

T. Prescott Atkinson, M.D., Ph.D.

Erik Swenson, M.D.

Peter E. Morris, M.D., FACP, FCCP

Jesse Joad, M.D.

Vernon Chinchilli, Ph.D.

**CONSUMER REPRESENTATIVE**

Karen Schell, RRT

**INDUSTRY REPRESENTATIVE**

William Kennedy, Ph.D.

**EXECUTIVE SECRETARY**

Kimberly Littleton Topper

**Consultants** (voting)

James K. Stoller, M.S., M.D.

Donald Patrick, Ph.D.

**Guest Speaker** (non-voting)

Michael Schatz, M.D.

**FDA PARTICIPANTS**

Robert Meyer, M.D.

Badrul Chowdhury, M.D.

Eugene Sullivan, M.D.

Lisa Kammerman, Ph.D.

I certify that I attended the September 6, 2002 meeting of the
Pulmonary-Allergy Drugs Advisory Committee and that these minutes
accurately reflect what transpired.

**[/S/ \_\_\_\_\_\_\_]{.underline} [/S/]{.underline}**

Kimberly L. Topper, MS Date Mark S. Dykewicz, M.D. Date

Executive Secretary Chairman

A verbatim transcript of this meeting is available for more detailed
information.

# Pulmonary Allergy Drugs Advisory Committee

**September 6, 2002**

**Minutes**

**New Drug Application (NDA) 21-395, Spiriva (Tiotropium bromide) by
Boehringer-Ingelheim for chronic obstructive pulmonary disease (COPD).**

The meeting was called to order by Dr. Mark Dykewicz at 7:30 AM.
Introductions of the committee members, consultants and guests were made
and the Conflict of Interest statement was read into the record. Dr.
Robert Meyer welcomed the committee and thanked them for attending and
Dr. Badrul Chowdhury set the stage for the topic of the day\'s
discussions.

Boehringer Ingelheim had the following presentations:

Introduction and Overview Dr. Burkhard Blank

Dr. Blank provided the BI introduction to the topic by explaining what
COPD is and giving statistics about the disease progression and
mortality rates. He stated their major topics for the day were 24-hour
bronchodilation, the relief of dyspnea and the safety profile. The
proposed indication was presented as:

> *SPIRIVA® (tiotropium) is indicated for the long-term, once-daily,
> maintenance treatment of bronchospasm and dyspnea associated with
> Chronic Obstructive Pulmonary Disease (COPD) including bronchitis and
> emphysema.*

He then introduced each speaker and the topics they would present.

Bronchodilator Efficacy in COPD Dr. Bernd Disse

Dr. Disse concluded Tiotropium once-daily provides sustained improvement
of spirometric measures for 24 hours, patient improvements were
maintained over one year, with no evidence of tachyphylaxis, and
secondary endpoints and exploratory analyses show improvements of
related lung function, exacerbations, and the patient health status.

Quantification of Dyspnea Dr. Paul Jones

Dr. Jones discussed the quantification of dyspnea and covered the
measurement of breathlessness, the validation of BDI and TDI and the
identification of clinically significant thresholds.

Dyspnea and Related Measures Dr. Theodore Witek

Dr. Witek discussed the use of dyspnea assessments in clinical trials
stating the long-term assessments are particularly important in chronic
disease maintenance treatment. He also stated that the instrument needs
to be practical in a multi-center and multi-national setting, dyspnea
assessment needs to be in context of a clinic visit and supportive
assessments should be included to assist in determining validity and
consistency. He closed by stating that the effect of tiotropium on
dyspnea was supported by the use of a validated instrument,
prespecification of a primary endpoint, statistical significance
observed in two independent studies, meaningful change supported by mean
responses and dyspnea response reflected in related measures.

Clinical Safety Evaluation Dr. Steven Kesten

Dr. Kesten discussed the clinical safety evaluating stating that
tiotropium has had extensive clinical safety evaluations with a large
patient population and long-term exposures. He indicated that the safety
profile is similar to that of ipratropium. The safety data included
long-term studies of 1,308 tiotropium treated patients, adverse events
were consistent with anticholinergic pharmacology, there were no
associations of treatment with life-threatening events and the
tiotropium safety profile is consistent with established inhaled
anticholinergic therapy.

Clinical Perspective Dr. James Donohue

Dr. Donohue discussed the typical patient with COPD and the disease
progression and the challenges in demonstrating dyspnea relief in
clinical studies. He stated that he believes that tiotropium would be a
valuable addition to the medical armamentarium.

Conclusions Dr. Burkhard Blank

Dr. Blank them concluded the BI presentations by stating the major
topics for discussion were the safety profile, the 24-hour
bronchodilation and the relief of dyspnea.

The Food and Drug Administration had the following presentations:

Transition Dyspnea Index (TDI) Dr. Lisa Kammerman

Dr. Kammerman discussed the Baseline Dyspnea Index (BDI)/Transition
Dyspnea Index (TDI), the history of the use of the TDI as a co-primary
endpoint in the tiotropium program, and FDA concerns regarding the
BDI/TDI, including clinical trial design issues, development and
validation issues, implementation issues, and the importance of
establishing a threshold for a clinically meaningful difference. She
concluded that the patient level issues were the unknown level of
patient involvement in the development of the instrument and in the
determination of a minimal clinically important difference. The
interviewer level issues were the blinding of patient status, training
of interviewers, open-ended questions, non-standardized questions,
recall to baseline and the review of the SGRQ before completion of the
TDI. She stated that the clinically meaningful difference appeared to be
determined with no prespecified plan and no patient involvement to
determine the clinically meaningful difference. There were also concerns
about who administered the TDI and the impact of multinational
populations as it impacts development, validation and interpretation of
results.

PK/PD, Safety & Efficacy Dr. Eugene Sullivan Dr. Sullivan covered the
proposed indications, the PK/PD characteristics, a brief overview of the
P3 clinical program, and the safety and efficacy findings. He summarized
his findings by stating some of the PK/PD features of tiotropium are
unique among inhaled bronchodilators. Concerns about safety are, the dry
mouth, which shows interactions with age and gender and is more frequent
in tiotropium than with ipratropium, a higher frequency of AE\'s with
tiotropium than with placebo and the possible effect on the heart
rate/rhythm may merit further evaluation. Dr. Sullivan\'s discussions on
the efficacy showed that Spiriva appears to provide clinically
meaningful bronchodilation, the duration of action supports once-daily
dosing, the maximum bronchodilator effect is reached after multiple
daily doses and it has an demonstrable statistical effect on the TDI
however, the clinical significance of this effect is not known.

Following the presentations the committee questioned the presenters for
clarification on specific points of the presentations.

The Open Public Hearing had one presenter, Vlady Rozenbaum, Ph.D. He
encouraged getting Spiriva® to the market as soon as safely possible.
There were also 55 e-mails and letters that were given to the committee
from others that would like to see Spiriva® on the market in the US.

The committee started the discussion of the issues and both FDA and BI
participated in the discussions. The Committee members then moved on to
the questions.

1.  Is the safety database for tiotropium bromide inhalation powder for
    the treatment of COPD patients adequate?

> **YES \_\_\_[8]{.underline}\_\_\_\_\_\_ NO
> \_\_\_\_[3]{.underline}\_\_\_\_\_\_**
>
> **Schell - yes Chinchilli -- yes Apter -- yes Swenson -- no Dykewicz
> -- yes Stoller -- yes Joad -- no Morris -- no**
>
> **Atkinson -- yes Parsons -- yes Patrick - yes**

A)  If not, what further safety data should be obtained?

-   **Regarding the renal excretion of the drug , there is a concern in
    patients with renal insufficiency**

-   **Phase 4 studies are needed to track urinary retention or urinary
    difficulty, fecal impaction, tachycardia and atrial fibrillation**

-   **Phase 4 studies in non-tested populations and labeling to indicate
    the drug is not approved in those populations**

-   **Diabetes and hyperglycemia should be monitored in the appropriate
    patients**

B)  Which of the safety data should be obtained prior to approval?

-   **Would like to see safety data on excluded subsets (cardio,
    kidney)**

-   **There is a data gap due to the lack of Holter monitors -- it would
    better if there were more Holter data**

-   **Would like to see the numbers of COPD patients in the excluded
    groups (concern the drug will be used in then when approved and no
    data is available**)

2.  Are there specific safety concerns regarding the use of tiotropium
    bromide inhalation powder in the COPD patient population that merit
    specific attention in the product label?

-   **Serious concerns about widespread use in patients such as cardiac
    patients without additional data**

-   **Phase 4 studies should be required for patient populations
    excluded from original study**

-   **Education of health practitioners on safety data and populations
    of concern**

-   **Education to prescribers that it is not like any of the other
    drugs that are currently out there**

3.  Do the data provide substantial and convincing evidence that
    tiotropium bromide inhalation powder provides a clinically
    meaningful bronchodilator effect when used in the chronic treatment
    of patients with COPD?

> **Yes \_\_\_[11]{.underline}\_\_\_\_\_ No
> \_\_\_[0]{.underline}\_\_\_\_\_**
>
> **Schell -- yes Chinchilli -- yes Apter -- yes Swenson -- yes**
>
> **Dykewicz -- yes Stoller -- yes Joad -- yes Morris -- yes**
>
> **Atkinson -- yes Parsons -- yes Patrick -- yes**

-   **Using the trough FEV response as a primary endpoint is a useful
    endpoint**

4.  Do the data provide substantial and convincing evidence that
    tiotropium bromide inhalation powder provides a clinically
    meaningful effect for the symptom of dyspnea in patients with COPD?

> **Yes \_\_\_[0]{.underline}\_\_\_\_\_ No
> \_\_\_\_[11]{.underline}\_\_\_\_**
>
> **Schell -- no Chinchilli - no Apter- no Swenson- no**
>
> **Dykewicz- no Stoller -- no Joad -- no Morris - no**
>
> **Atkinson -- no Parsons -- no Patrick - no**

5.  In general, what quality and quantity of data would constitute
    substantial and convincing evidence of a clinically meaningful
    benefit for the symptom of dyspnea in patients with COPD?

> **Quality:**

-   **Validated in a diverse population**

-   **Define dyspnea very specifically and clearly**

-   **Must have substantial data on minimally important differences**

-   **Use combination clinical interview and patient report**

-   **Tie concept to something reproducible, objective and that applies
    to the dyspnea scale**

-   **Address each of Dr. Kammerman's concerns and must be reproducible
    in different populations**

-   **Define the longitudinal properties of the BDI**

-   **Instrument that is patient reported symptoms and asks if specific
    changes are significant to the patient**

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-   **Patient evaluations are critical and they should be questioned
    about how much value the regimen had to them and what the value was
    and what would they be willing to sacrifice**

> **Quantity**

-   **The quantity of data presented by BI were good but they must be
    rigorous in the data collected and the way it is captured for
    analysis**

The Chair and FDA staff thanked everyone for their participation and the
meeting was adjourned at 3:05 PM.