> These summary minutes for the February 16, 17 and 18, 2005, Joint
> meeting of the Arthritis Advisory Committee and the Drug Safety and
> Risk Management Advisory Committee were approved on
> \_\_\_[3/7/05]{.underline}\_\_\_\_.
>
> I certify that I attended the February 16, 17 and 18, 2005, Joint
> meeting of the Arthritis Advisory Committee and the Drug Safety and
> Risk Management Advisory Committee of the Food and Drug Administration
> and that these minutes accurately reflect what transpired.
>
> \_\_\_\_\_\_\_\_//S//\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
> \_\_\_\_\_\_\_\_//S//\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
>
> LCDR Dornette Spell-LeSane, MHA, NP-C Alastair Wood, M.D.
>
> Supervisory Health Science Administrator Chair
>
> For, Kimberly Topper, M.S., Executive Secretary
>
> Joint Meeting of the Arthritis Advisory Committee and the Drug Safety
> and Risk Management Advisory Committee

**February 16, 17, and 18, 2005**

> The following is an internal report, which has not been reviewed. It
> is not meant to be a comprehensive review of the meeting. A verbatim
> transcript will be available in approximately two weeks, sent to the
> Division and posted on the FDA website at
> <http://www.fda.gov/ohrms/dockets/ac/cder05.html#ArthritisDrugs>.
> Slides shown at the meeting will be available at the same website.
>
> All external requests for the meeting minutes and transcripts should
> be submitted to the CDER Freedom of Information office.
>
> **\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_**

Joint Meeting of The Arthritis Advisory Committee and the Drug Safety
and Risk Management Advisory Committee of the Food and Drug
Administration, Center for Drug Evaluation and Research met on February
16, 17 &18, 2005, at the Hilton, located at 620 Perry Parkway,
Gaithersburg, Maryland to discuss the overall benefit to risk
considerations (including cardiovascular and gastrointestinal safety
concerns) for COX-2 selective nonsteroidal anti-inflammatory drugs and
related agents. The meeting was chaired by

Alastair J.J. Wood, M.D.

**Arthritis Advisory Committee Members Present (voting):**

Joan Bathon, M.D., Dennis Boulware, M.D., John J. Cush, M.D., Michael
Finley, D.O.,

Allan Gibofsky, M.D., Gary Hoffman, M.D., Norman Ilowite, M.D., Susan
Manzi, M. M.D., M.P.H.

**Drug Safety and Risk Management Advisory Committee Members Present
(voting):**

Stephanie Y. Crawford, Ph.D., Ruth S. Day, Ph.D., Curt D. Furberg, M.D.,
Ph.D.,

Jacqueline S.Gardner, Ph.D., MPH, Peter A. Gross, M.D., Eric S. Holmboe,
M.D.

Arthur A. Levin, M.P.H., Louis A. Morris, Ph.D., Richard Platt, M.D.,
M.Sc,

Robyn S. Shapiro, J.D., Annette Stemhagen, Dr.Ph

**SGE Consultants (voting):**

Alastair J.J. Wood, M.D., Steve Abramson, M.D., Steven L. Shafer, M.D.,

Robert H. Dworkin, Ph.D., Steven Nissen, M.D., Charles H. Hennekens,
M.D.,

Emile Paganini, M.D., Leona Malone, L.C.S.W., (Patient Rep) **,** Thomas
Fleming, Ph.D.,

John T. Farrar,M.D., Janet Elashoff, Ph.D., Ralph D'Agostino, Ph.D.

**SGE Consultants (non voting):**

Cryer, Byron, M.D., (Speaker and Discussant) Packer, Milton M.D.,
(Speaker only)

**National Institute of Health Participants (voting):**

Richard O. Cannon III, M.D., Michael J. Domanski, M.D., Lawrence
Friedman, M.D.

**FDA Invited Guest Speakers (non-voting):**

Garret A. FitzGerald, M.D., Ernest Hawk, M.D., M.P.H., Constantine
Lyketsos, M.D., M.H.S., Bernard Levin, M.D.

**FDA Participants at the Table:**

Jonca Bull, M.D., Brian Harvey, M.D., John Jenkins, M.D., Sandra Kweder,
M.D., Robert O\'Neil, Ph.D., Paul Seligman, M.D., Steve Galson, M.D.,
Robert Temple, M.D., Anne Trontell, M.D., M.P.H.

**FDA Presentors:**

David Graham, M.D., M.P.H., Sharon Hertz, M.D., Joel Schiffenbauer,
M.D.,

Lourdes Villalba, M.D., James Witter, M.D.

**[Open Public Hearing Speakers:]{.underline}**

+---------------------------+------------------------------------------+
| > **Joan Brierton Johnson |                                          |
| > and Sabrina**           |                                          |
+---------------------------+------------------------------------------+
| > **Sidney M. Wolfe, MD** | > Director, Public Citizen\'s Health     |
|                           | > Research Group                         |
+---------------------------+------------------------------------------+
| > **Linda Suydam**        | > Vice President, Regulatory and         |
|                           | > Scientific Affairs, Consumer           |
|                           | > Healthcare Products Association - CHPA |
+---------------------------+------------------------------------------+
| > **Jennifer Lo, Ph.D.    | > CEO & President, BioJENC, LLC,         |
| > and**                   | > Louisiana Business & Technology Center |
| >                         |                                          |
| > **Gene Luther, D.V.M.,  |                                          |
| > Ph.D.**                 |                                          |
+---------------------------+------------------------------------------+
| > **Jim Tozzi**           | > Member, Board of Advisors, Center for  |
|                           | > Regulatory Effectiveness               |
+---------------------------+------------------------------------------+
| > **Diana Zuckerman,      | > President, National Research Center    |
| > Ph.D.**                 | > for Women & Families                   |
+---------------------------+------------------------------------------+
| > **Elizabeth Tindall,    | > President, American College of         |
| > MD**                    | > Rheumatology                           |
+---------------------------+------------------------------------------+
| > **Dimitra Poulos**      |                                          |
+---------------------------+------------------------------------------+
| > **John Pippin, M.D.**   | > Physicians Coomittee for Responsible   |
|                           | > Medicine                               |
+---------------------------+------------------------------------------+
| > **MAJ Christopher       | > Womack Army Medical Center, Department |
| > Grubb, M.D.**           | > of Anesthesiology and Pain Management  |
+---------------------------+------------------------------------------+
| > **Janet                 | > President, Arrowsmith-Lowe Consulting, |
| > Arrowsmith-Lowe, MD**   | > Inc.                                   |
+---------------------------+------------------------------------------+
| > **Mark H. Einstein,     | > Assistant Professor, Division of       |
| > M.D.**                  | > Gynecologic Oncology, Department of    |
|                           | > Obstetrics & Gynecology and Women\'s   |
|                           | > Health Montefiore Medical Center       |
+---------------------------+------------------------------------------+
| > **John Abramson M.D.**  | > Harvard Medical School                 |
+---------------------------+------------------------------------------+
| > **Herbert S. B. Baraf,  | > Clinical Professor of Medicine, George |
| > MD, FACP, FACR**        | > Washington University                  |
+---------------------------+------------------------------------------+
| > **Max Hamburger MD**    |                                          |
+---------------------------+------------------------------------------+
| > **Waqar Qureshi, MD,    | > Associate Professor of Medicine, Chief |
| > FACP, FACG**            | > of Endoscopy, Baylor College of        |
|                           | > Medicine                               |
+---------------------------+------------------------------------------+
| > **David P. Matthews**   |                                          |
+---------------------------+------------------------------------------+
| > **W. Hayes Wilson, MD\  | > Chief of Rheumatology, Piedmont        |
| > **                      | > Hospital\                              |
|                           | > President, Piedmont Rheumatology       |
|                           | > Consultants, PC                        |
+---------------------------+------------------------------------------+
| > **Gary W. Williams,     | > Chairman, Department of Medicine and   |
| > M.D., Ph.D.**           | > Vice President of Medicine Services,   |
|                           | > at Scripps Clinic and Research         |
|                           | > Foundation                             |
+---------------------------+------------------------------------------+
| > **Rebecca Burkholder**  | > Director of Health Policy, National    |
|                           | > Consumers League                       |
+---------------------------+------------------------------------------+
| > **Amye L. Leong, MBA**  | > President & CEO, Healthy Motivation,   |
|                           | > Spokesperson, UN-endorsed Bone and     |
|                           | > Joint decade 2000-2010                 |
+---------------------------+------------------------------------------+
| > **Donna Marie Fox-      |                                          |
| > Keidel**                |                                          |
+---------------------------+------------------------------------------+
| > **Theresa Ray**         |                                          |
+---------------------------+------------------------------------------+
| > **Judith Whitmire**     |                                          |
+---------------------------+------------------------------------------+
| > **Judy Fogel**          | > Brigham & Women\'s Hospital, Harvard   |
|                           | > Medical School                         |
+---------------------------+------------------------------------------+
| > **R. Preston Mason,     | > Brigham & Women\'s Hospital, Harvard   |
| > Ph.D.**                 | > Medical School                         |
+---------------------------+------------------------------------------+
| > **Gurkirpal Singh, MD** | > Adjunct Clinical Professor of          |
|                           | > Medicine\                              |
|                           | > Division of Gastroenterology and       |
|                           | > Hepatology\                            |
|                           | > Stanford University School of Medicine |
+---------------------------+------------------------------------------+
| > **Dr. Allan N. Fields** |                                          |
+---------------------------+------------------------------------------+
| > **Grant Johnson**       |                                          |
+---------------------------+------------------------------------------+
| > **Necole Kelly**        | > President, American Chronic Pain       |
|                           | > Association                            |
+---------------------------+------------------------------------------+
| > **Robert Thibadeau,     |                                          |
| > Ph.D.**                 |                                          |
+---------------------------+------------------------------------------+
| > **Lawrence Goldkind     | > Assistant Professor of Medicine,       |
| > MD**                    | > Department of Gastroenterology,        |
|                           | > Uniformed Services University of       |
|                           | > Health Sciences                        |
+---------------------------+------------------------------------------+
| > **Susan Winckler, RPh,  | > APhA's Vice President of Policy and    |
| > Esq**.,                 | > Communications and Staff Counsel       |
+---------------------------+------------------------------------------+
| > **Virginia Ladd**       | > President American Autoimmune Related  |
|                           | > Diseases Association (AARDA)           |
+---------------------------+------------------------------------------+
| > **Paola Patrignani,     | > Professor of Pharmacology, Department  |
| > Ph.D.**                 | > of Medicine and Center of Excellence   |
|                           | > on Aging, \"G. d\'Annunzio\"           |
|                           | > University                             |
+---------------------------+------------------------------------------+
| > **Betsy Chaney**        |                                          |
+---------------------------+------------------------------------------+
| > **Dr. John Klippel**    | > President and CEO of the Arthritis     |
|                           | > Foundation                             |
+---------------------------+------------------------------------------+
| > **Carol Spitz**         |                                          |
+---------------------------+------------------------------------------+
| > **Eileen Lacijan**      |                                          |
+---------------------------+------------------------------------------+
| > **Gloria Barthelmes**   |                                          |
+---------------------------+------------------------------------------+
| > **Rebecca Dachman**     |                                          |
+---------------------------+------------------------------------------+
| > **Michael D.            | > President, *Psoriasis Cure Now!*       |
| > Paranzino**             |                                          |
+---------------------------+------------------------------------------+
| > **Dr. Glenn Eisen**     | > Oregon Health Sciences University      |
+---------------------------+------------------------------------------+
| > **Yvonne Sherrer,       |                                          |
| > M.D.**                  |                                          |
+---------------------------+------------------------------------------+

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

> **The members and the invited consultants were provided with the
> background material from the FDA, Merck, Pfizer, Novartis, Hoffmann-La
> Roche Inc., and Bayer Healthcare LLC, Consumer Care Division prior to
> the meeting.**
>
> **The meeting was called to order at 8:00 a.m. each day by Alastair
> Wood, M.D. The Committee members, consultants, and FDA participants
> introduced themselves. The conflict of interest statement was read
> into the record each day by the Executive Secretary, Kimberly
> Littleton Topper, M.S. There were approximately 600 people in
> attendance. The agenda proceeded as follows:**

**Wednesday, February 16, 2005**

Call to Order Alastair J. J. Wood, M.D., Chair

Conflict of Interest Statement Kimberly Littleton Topper, M.S.

Executive Secretary

Welcome Steven Galson, M.D., M.P.H.

Acting Director, Center for Drug

Evaluation and Research (CDER)

Regulatory History Jonca Bull, M.D.

Director, Office of Drug

> Evaluation V, CDER

Gastrointestinal Effects of NSAIDs and Byron Cryer, M.D.

COX-2 Specific Inhibitors University of Texas

> Southwestern Medical School

Mechanism Based Adverse Cardiovascular Garret A. FitzGerald, M.D.

Events and Specific Inhibitors of COX-2 University of Pennsylvania

School of Medicine

Committee Questions to Speakers

Break

**[Vioxx (rofecoxib)]{.underline}**

***[Sponsor Presentation:]{.underline}***

Rofecoxib Ned S. Braunstein, M.D.

> Senior Director
>
> Merck Research Laboratories

***[FDA Presentation:]{.underline}***

Vioxx Lourdes Villalba, M.D.

Cardiovascular Safety Medical Officer, CDER

Committee Questions to Speakers

Lunch

**[Celebrex (celecoxib]{.underline})**

***[Sponsor Presentation:]{.underline}***

Introduction Joseph M. Feczko, M.D.

> Senior Vice President,
>
> Pfizer Global Research and Development, and President, Worldwide
> Development

**Wednesday, February 16, 2005 (cont.)**

Cardiovascular Safety and Kenneth M. Verburg, Ph.D.

Risk/Benefit Assessment of Celecoxib Vice President, Inflammation and

> Immunology, Clinical Research and Development, Pfizer Global Research
> and Development

***[FDA Presentation:]{.underline}***

COX-2 CV Safety: celecoxib James Witter, M.D., Ph.D.

> Lead Medical Officer, CDER

***[NIH and Investigator Presentation:]{.underline}***

Celecoxib in Adenoma Prevention Trials:

The APC Trial Ernest Hawk, M.D., MPH

(Prevention of Sporadic Colorectal Director, Office of Centers,

Adenomas with Celecoxib) Training, & Resources

> NCI/OD/NIH

The PreSAP Trial Bernard Levin, M.D

(Prevention of Colorectal Sporadic M.D. Anderson Cancer Center

Adenomatous Polyps) The University of Texas

Committee Questions to Speakers

Break

### Bextra (valdecoxib) and parecoxib 

***[Sponsor Presentation:]{.underline}***

Cardiovascular Safety and Risk/Benefit Kenneth M. Verburg, Ph.D.

Assessment of Valdecoxib and Parecoxib

Closing Joseph M. Feczko, M.D.

***[FDA Presentation:]{.underline}***

COX-2 CV Safety: valdecoxib -- parecoxib James Witter, M.D., Ph.D.

### Naproxen

***[Sponsor Presentation:]{.underline}***

Bayer and Roche Joint Presentation on Naproxen Leonard M. Baum, R.Ph.

> Vice President, Regulatory Affairs
>
> Bayer HealthCare
>
> Consumer Care Division
>
> Martin H. Huber, M.D.
>
> Vice President, Global Head
>
> Drug Safety Risk Management,
>
> Hoffmann-La Roche, Inc.

Committee Questions to Speakers

**Thursday, February 17, 2005**

Call to Order Alastair J. J. Wood, M.D., Chair

Conflict of Interest Statement Kimberly Littleton Topper, M.S.

Interpretation of Observational Studies of Richard Platt, M.D., M.S.

Cardiovascular Risk of Non-steroidal Drugs Harvard Medical School

Review of Epidemiologic Studies on David Graham, M.D., M.P.H.

Cardiovascular Risk with Selected NSAIDs Medical Officer, CDER

Committee Questions to Speakers

**[Arcoxia (etoricoxib)]{.underline}**

***[Sponsor Presentation:]{.underline}***

Etoricoxib Sean P. Curtis, M.D.

> Senior Director, Clinical Research
>
> Merck Research Laboratories

***[FDA Presentation:]{.underline}***

Analysis of Cardiovascular Thromboembolic Joel Schiffenbauer, M.D.

Events With Etoricoxib Medical Officer, CDER

Break

**[Lumiracoxib]{.underline}**

***[Sponsor Presentation:]{.underline}***

Lumiracoxib: Introduction Mathias Hukkelhoven, Ph.D.

> Senior Vice President and Global Head, Drug Regulatory Affairs\
> Novartis Pharmaceuticals Corporation

Gastrointestinal and Cardiovascular Safety Patrice Matchaba, M.D.

of Lumiracoxib, Ibuprofen, and Naproxen Global Medical Director

> Lumiracoxib Program, Novartis Pharmaceuticals Corporation

***[FDA Presentation:]{.underline}***

Lumiracoxib Lourdes Villalba, M.D.

Medical Officer, CDER

Committee Questions to Speakers

Lunch

Open Public Hearing

Break

Committee Discussion

**Friday, February 18, 2005**

Call to Order Alastair J. J. Wood, M.D.,Chair

Conflict of Interest Statement Kimberly Littleton Topper, M.S.

**[Naproxen]{.underline}**

***[Investigator Presentation:]{.underline}***

Alzheimer's Prevention Study : ADAPT Constantine Lyketsos, M.D.

(Alzheimer's Disease Anti-Inflammatory The John Hopkins Hospital

Prevention Trial)

**[Additional Background Presentations]{.underline}**

Interpretation of Observed Differences Milton Packer, M.D.

in the Frequency of Events When the University of Texas

Number of Events is Small Southwestern Medical School

Committee Questions to Speakers

Clinical Trial Design and Patient Safety: Robert Temple, M.D.

Future Directions for COX-2 selective NSAIDs Director, Office of Medical

> Policy, CDER

Issues in Projecting Increased Risk of Robert O'Neill, Ph.D.

Cardiovascular Events to the Exposed Population Director, Office of
Biostatistics, CDER

Committee Questions to Speakers

Break

Risk Management Options for Action Anne Trontell, M.D., M.P.H.

***(added to agenda on 2/18/05)*** Deputy Director, Office of Drug
Safety

Summary of Meeting Presentations Sharon Hertz, M.D.

Deputy Director, Division of

> Anti-Inflammatory, Analgesic and Ophthalmologic Drug Products, CDER

Advisory Committee Discussion of Questions

Lunch

Advisory Committee Discussion of Questions

Break

Advisory Committee Discussion of Questions

Meeting Wrap-up Alastair J. J. Wood, M.D.

Adjourn

**Thursday, February 17, 2005:**

Discussion Points:

1.  Please discuss the available data regarding the potential
    cardiovascular (CV) risk for the non-selective and COX-2 selective
    NSAIDs. Please discuss whether the available data support a
    conclusion that increased CV risk is a class effect for all NSAIDs,
    the COX-2 selective NSAIDs only, or only for certain agents within
    the class. Also, please discuss the possible mechanism(s) of action
    for an increased cardiovascular risk with these agents.

***The Committee shared various opinions with the members agreeing, in
general, that there was inadequate data to draw a definite conclusion
regarding whether a class effect exists. However, that being said, they
agreed that it did appear likely that for at least the three approved
COX-2 products, a class effect appears to be present. They further
indicated that they believed that if sufficient drug was given in high
enough doses to high risk patients an increase incidence of
cardiovascular events would be yielded. There is a dearth of data on the
other NSAIDs and the consensus of the Committee was that each drug
should be individually evaluated for CV risk. It is unknown whether a CV
signal is present across all the products, with possible different
mechanisms of action, but each is suspect when used chronically and
until proven otherwise, patients/physicians should be warned.***

2.  Please discuss the contributions and limitations of the currently
    available observational studies to the assessment of CV risk for the
    non-selective and COX-2 selective NSAIDs. In particular, please
    discuss the role of such observational studies in informing
    regulatory decisions about post-marketing safety issues.

***While the Committee stated various opinions, most agreed that
observational studies do provide useful, although limited, information.
In general, observational studies are supplementary to randomized,
controlled, clinical trials (RCT) since selection bias is likely
present. Additional comments provided by the committee were:***

-   **Observational studies are supplementary to Randomized Control
    Trials (RCT)**

```{=html}
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```
-   **With COX-2 products, there is good correlation between
    observational and RCT trials**

-   **Long term follow up after drop out from RCT is necessary**

-   **More observational studies on older drugs are needed**

-   **FDA review of observational studies does not follow the same
    process standards used by FDA in reviewing RCTs**

-   **Observational studies are most helpful if they find a strong and
    consistent association across studies, with a hazard ratio greater
    than 2 or 3; Observational studies with hazard ratios under 2, even
    if statistically significant, are difficult to interpret since low
    but precise estimates of risk may be due to residual confounding or
    biases**

-   **Observational studies can be classified as "hypothesis
    generating"; they provide clues as to whether and if to conduct RCTs
    but observational studies do not establish casuality**

    3.  Please discuss the available data regarding the potential
        benefits of COX-2 selective NSAIDs versus non-selective NSAIDs
        and how any such benefits should be weighed in assessing the
        potential benefits versus the potential risks of COX-2 selective
        agents from a regulatory perspective.

***Overall the committee felt that the GI benefits should not be
minimized, however, the GI benefits of the COX-2s appear to be less than
first reported. Vioxx is the only product with GI benefit in labeling;
no clear data that show GI benefit for Celebrex and Bextra. Although not
a benign event, a GI event is in most cases not as permanently disabling
as a myocardial infarction or a stroke. The Committee members offered
the following additional considerations for weighing benefit versus
risk:***

-   ***Benefit versus risk in patients who do not tolerate nonselective
    NSAIDs should be considered***

-   ***Pain relief should be considered***

-   ***If no clear benefit, there should be an extremely low threshold
    for increased CV risk***

-   ***Pediatric issues should be considered; there are fewer choices in
    this population and only 3 NSAIDs are approved for use in pediatric
    population, only 2 liquid formulations***

-   ***Tolerability - fewer serious GI events, but a lot of symptoms
    should be considered***

**Friday, February 18, 2005**

Questions to the Committee

***[Approved products]{.underline}***

Three COX-2 selective NSAIDs are currently approved for marketing in the
United States; celecoxib (Celebrex), rofecoxib (Vioxx) and valdecoxib
(Bextra). The original approvals and subsequent supplemental approvals
were based on a determination by FDA that the potential benefits of each
product outweighed the potential risks when used for the approved
indications according to the directions included in the product
labeling. Since approval, additional data regarding the safety and
effectiveness of these products have accumulated, in particular new
information regarding the potential cardiovascular risks of these
products. FDA must consider the impact of these new data on the benefit
versus risk profile for each product in making decisions about
appropriate regulatory actions.

Although Merck voluntarily withdrew Vioxx from marketing worldwide on
September 30, 2004, questions related to Vioxx are included below since
it will be necessary for FDA to determine the appropriate regulatory
action regarding the approval status of this product.

Based on the data presented in the background package and during the
committee meeting, please address the following questions regarding the
approved COX-2 selective NSAIDS.

1.  Celecoxib

```{=html}
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```
a.  Do the available data support a conclusion that celecoxib
    significantly increases the risk of cardiovascular events?

> ***Yes- 32 No- 0 Abstain - 0***

b.  Does the overall risk versus benefit profile for celecoxib support
    marketing in the US?

> ***Yes - 31 No - 1 Abstain - 0***

c.  If yes, please describe the patient population(s) in which the
    potential benefits of celecoxib outweigh the potential risks and
    what actions you recommend that FDA consider implementing to ensure
    safe use of celecoxib.

-   ***The Committee agreed that osteoarthritis and rheumatoid arthritis
    patients, in addition to patients being treated for pain were
    populations where the benefits of celecoxib could outweigh potential
    risks. They agreed that there appeared to be no evidence of CV risk
    at the 200 mg dose and marginally positive evidence at the 400 mg
    dose. No signal was seen in the epidemiologic studies. With regard
    to the colon polyp study, 400 and 800 mg doses were studied. An
    excess CV risk would likely be seen with the 800 mg dose, probable
    at the 400 mg dose and possibly no evidence with the 200 mg dose.***

***The following were suggested as potential actions for the FDA to
take:***

-   ***Black Box Warning (BBW) (24)***

-   ***Remove BBW if clinical trial results demonstrate safety (4)***

-   ***Restrict Direct to Consumer Advertising (22)***

-   ***Provide both known and unknown information to patients and
    health***

> ***practitioners (22)***

-   ***Develop Patient Guide or Med-guides (25)***

-   ***Provide Dear Health Care Provider Letter (2)***

-   ***Restrict patient population (7)***

-   ***Restrict dose (5)***

2.  Valdecoxib

```{=html}
<!-- -->
```
a.  Do the available data support a conclusion that valdecoxib
    significantly increases the risk of cardiovascular events?

> ***Yes - 32 No -- 0 Abstain - 0***

b.  Does the overall risk versus benefit profile for valdecoxib support
    marketing in the US?

> ***Yes - 17 No - 13 Abstain - 2***

c.  If yes, please describe the patient population(s) in which the
    potential benefits of valdecoxib outweigh the potential risks and
    what actions you recommend that FDA consider implementing to ensure
    safe use of valdecoxib.

***In general, the Committee felt that the evidence was very limited and
it is difficult to extrapolate to a real life setting.***

***The following were suggested as potential actions for the FDA to
take.***

-   ***Black Box Warning (22)***

-   ***Remove BBW if clinical trial results demonstrate safety (2)***

-   ***Restrict Direct to Consumer Advertising (19)***

-   ***Provide known and unknown information to patients and health
    practitioners (19)***

-   ***Develop Patient Guide or Medguide (17)***

-   ***Dear Health Care Provider Letter (2)***

-   ***Restrict population (6)***

-   ***Restrict dose (3)***

-   ***Restrict duration (6)***

-   ***Contraindications in the post CABG setting***

3.  Rofecoxib

```{=html}
<!-- -->
```
a.  Do the available data support a conclusion that rofecoxib
    significantly increases the risk of cardiovascular events?

> **Yes - 32 No - 0 Abstain - 0**

b.  Does the overall risk versus benefit profile for rofecoxib support
    marketing in the US?

> ***Yes - 17 No - 15 Abstain - 0***

***The Committee had the following comments:***

-   ***The blood pressure effects seen with the product are clearly
    outside the norm and are undesirable; a mechanism other than a
    prostacyclin mechanism could be at play since the other COX-2s do
    not appear to have such a large blood pressure effect***

-   ***A signal for heart failure is present and the other NSAIDs have
    not exhibited this same signal***

-   ***The blood pressure and the heart failure data is compelling
    indicating it is substantially worse than other COX-2s***

-   ***A strong dose relationship is very apparent***

-   ***Rofecoxib is the only COX-2 selective product approved for
    pediatric patients however, there are minimal data to support safe
    long-term use in pediatrics***

c.  If yes, please describe the patient population(s) in which the
    potential benefits of rofecoxib outweigh the potential risks and
    what actions you recommend that FDA consider implementing to ensure
    safe use of rofecoxib.

***The following were suggested as potential actions for the FDA to
take:***

-   ***Black Box Warning***

-   ***Remove BBW only if future clinical trial results demonstrate
    safety***

-   ***Restrict Direct to Consumer Advertising (DTC)***

-   ***Provide known and unknown information to patients and health
    practitioners***

-   ***Patient Guide or Med-Guides Development***

-   ***Dear Health Care Provider Letter***

-   ***Require strong Post Marketing follow-up***

-   ***Restrict dose to 12.5 mg, 25 mg and remove 50 mg from the
    market***

-   ***Require informed consent***

-   ***Provide patient reminders about risk 1 year after starting the
    drug***

-   ***Require clinical trial using 12.5 mg. dose***

-   ***Consider restricted access to the drug***

-   ***Be aware that the pediatric patient could increase their risk of
    CV events earlier - but keep for use in pediatric patients because
    pain is not always adequately controlled***

-   ***Institute a patient registry***

-   ***Restrict patient population***

4.  If the available data support a conclusion that one or more COX-2
    selective agents increase the risk of cardiovascular events, please
    comment on the role, if any, of concomitant use of low-dose aspirin
    in reducing cardiovascular risk in patients treated with COX-2
    selective NSAIDs.

***No vote was offered for this question; some of the Committee comments
were as follows:***

-   ***There is insufficient evidence to make a conclusion***

-   ***There is no compelling evidence that concomitant low dose aspirin
    is effective in preventing CV disease when used in "normals"***

-   ***Must be careful - ASA is not a panacea for CV disease***

-   ***There is no compelling evidence that ASA will reverse CV toxicity
    based on available studies, but data is limited***

-   ***Aspirin appears to "undo" any possible GI benefit of the
    COX-2s***

-   ***If ASA is needed for CV prophylaxis, then patients should not be
    on a COX-2 inhibitor***

    5.  What additional clinical trials or observational studies, if
        any, do you recommend as [essential]{.underline} to further
        evaluate the potential cardiovascular risk of celecoxib,
        rofecoxib, and valdecoxib? What additional clinical trials or
        observational studies, if any, do you recommend as
        [essential]{.underline} to further evaluate the potential
        benefits (e.g., reduced gastrointestinal risk) of celecoxib,
        rofecoxib, and valdecoxib? Please be specific with regard to
        which COX-2 selective agent to study, trial design, patient
        populations, control groups, endpoints, duration, sample size,
        etc.

***No vote was offered for this question; some of the Committee comments
were as follows:***

-   ***Across all products and to rule out the risk of excess
    cardiovascular events, additional randomized clinical trials (RCT)
    should be conducted at doses to be marketed; blood pressure
    measurements should be included in these trials***

-   ***Comparator drug used in the trials should not be limited to
    naproxen; placebo as the comparator should be used in trials
    designed to determine the absolute risk of CV events***

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-   ***Choice of comparator would also depend on the
    population/indication being studied; for example, arthritis trials
    would not utilize placebo, however pain trials might***

-   ***Follow-up of all patients is critical - especially the RCT drop
    out patients***

-   ***It is important that we not ignore the need for additional safety
    trials with the nonselective NSAIDs***

There are more than 20 non-selective NSAIDs currently approved for
marketing in the United States. Unlike the situation with the COX-2
selective agents, large, long-term, placebo-controlled clinical trials
have not been conducted to evaluate long-term risks, including
cardiovascular risks. Based on the data presented in the background
package and during the committee meeting, please address the following
questions regarding the approved non-selective NSAIDs:

5.  Do you recommend that the labeling for these products include
    information regarding the absence of long-term controlled clinical
    trial data to assess the potential cardiovascular effects of these
    drugs? If so, please describe how you recommend that information be
    conveyed (e.g., warning, precaution).

> ***Yes - 28 No -- 0 Abstain - 0***

***(The following members were not present and therefore did not did not
offer a vote for question 6: Paganini, Shapiro, Gibofsky, Hoffman)***

***Committee comments included:***

-   ***Taking a blanket approach with these drugs is not recommended***

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-   ***Providing observational data is important with the absence of
    clinical trial data***

-   ***Provide all data so both patients and prescribers are informed on
    our knowledge level on these drugs***

-   ***Although it appears that the CV risk applies to the class as a
    whole, any BBW should be modified to reflect what we know about each
    individual product***

-   ***Rather than a BBW, some suggest that text be added to the warning
    section of the label while additional data is collected***

-   ***Concern was raised that a BBW may shift patients to meloxicam or
    other products with even less available risk data; there is no
    assurance that these products don't have the same risks***

-   ***Some indicated that they felt that the available data on naproxen
    would justify a decreased warning requirement***

-   ***It was stated that based on the committee discussions at the AC
    meeting, a shift in prescribing practice could occur. It is
    important to send the message that the current state of information
    is insufficient to state that any of the products are absolutely
    safe.***

-   ***It is important to require that sponsor marketing materials
    provide the information that is known about their products while at
    the same time providing adequate information as to what is as of yet
    unknown about product risk (describe the absence of data)***

-   ***The committee advised that caution be used such that revisions
    regarding long-term use risks to the OTC product labeling does not
    cause \"hysteria"***

    7.  What additional clinical trials or observational studies, if
        any, do you recommend as [essential]{.underline} to further
        evaluate the potential cardiovascular risk of the non-selective
        NSAIDs? Please be specific with regard to which non-selective
        NSAIDs (i.e., all or only selected agents), trial design,
        patient populations, control groups, endpoints, duration, sample
        size, study drug etc.

***The Committee comments included:***

-   ***Randomized Clinical Trials (RCTs) are likely impossible for these
    products; as an alternative, it was suggested that sponsors conduct
    large scale, cluster, randomized trials; Randomization to drug would
    be an important feature to include***

-   ***The committee suggested that sponsor incentives could be
    proposed; These might include deletion of a BBW or warning text
    should a sponsor design and complete adequate trials.***

-   ***The committee agreed that in the absence of "good" safety data,
    no additional NSAIDs be switched to OTC status***

**[Standards for approval of new NSAIDs (non-selective and COX-2
selective agents)]{.underline}**

The information that has accumulated about the safety and effectiveness
of COX-2 selective NSAIDs since their approval, including the potential
for increased cardiovascular risk, must be considered as FDA determines
the standards for data to be submitted in support of approval of new
non-selective and COX-2 selective NSAIDs. In addition, the experience
with the approved COX-2 selective agents will help inform benefit versus
risk assessments that will need to be made by FDA in evaluating pending
and future applications for new NSAIDs.

Based on the data presented in the background package and during the
committee meeting, please address the following questions regarding the
approval of new non-selective and COX-2 selective NSAIDs.

7.  With regard to evaluation of cardiovascular risk, what studies do
    you recommend as [essential]{.underline} to be completed and
    reviewed prior to approval of new NSAIDs? With regard to the
    evaluation of the potential benefits (e.g., reduced gastrointestinal
    risk), what studies do you recommend as [essential]{.underline} to
    be completed and reviewed prior to approval of new NSAIDs? Please be
    specific with regard to trial design, patient population, control
    groups, endpoints, duration, sample size, safety monitoring and
    patient protections, etc.

-   ***It is important to be practical for new drugs to enter the market
    and they must undertake an APPROVE type of trial in low risk
    populations and in the active control group - trials must be 1-2
    years in length***

-   ***The Committee recommended that future studies include primarily
    naproxen as a comparator. Ibuprofen and diclofenac should also be
    studied as comparators for different purposes, ibuprofen as a
    typical NSAID while diclofenac may be a model of a relatively
    selective traditional NSAID.***

-   ***Need a neutral or better than neutral, upper confidence boundary
    against naproxen; the standard/bar needs to be high enough in order
    to protect the public***

-   ***Suggested populations likely to use the products include those
    that are older and with a mild CV risk***

-   ***Regarding GI benefit, it would be appropriate to compare new
    products versus naproxen or another NSAID combined with a PPI***

-   ***The Committee cautioned that recommendations must be practical;
    trials such as the APPROVe and CABG 2 studies should be conducted in
    indications sought for marketing, i.e., OA, RA, and low risk
    individuals (not high risk individuals). The duration of the trials
    should preferably run two years and include an active control.***

9.  If the pre-approval studies recommended as essential in question 8
    do not demonstrate an increased risk of cardiovascular events for a
    new NSAID, please comment on how FDA should handle the issue of
    cardiovascular risk in labeling. For example, would the absence of a
    cardiovascular risk signal in the pre-approval database preclude the
    need for any warnings or precautions in the labeling for the new
    product? Alternatively, should all future NSAIDs carry a "class"
    warning or precaution about cardiovascular risk even in the absence
    of a signal of increased risk in the pre-approval database? If yes,
    please describe your recommendations for the "class" labeling
    regarding cardiovascular risk with particular attention to whether
    you recommend it apply to all NSAIDs or only COX-2 selective NSAIDs.

***No vote was offered for this question; The Committee made the
following comments:***

-   ***The absence of establishing an increase risk is not the same as
    no increase; evidence sufficiently powered and controlled to rule
    out an increase in incidence is needed***

-   ***The Committee consensus was that for new products, the standard
    for demonstrating safety should be higher***

The meeting was adjourned at 5:15 p.m.