**Sequence of Events with VIOXX, since opening of IND**

1.  **December 20, 1994 \--** Merck opens Investigational New Drug (IND)
    **46,894** for osteoarthritis and acute pain in the Division of
    Anti-inflammatory, Analgesic and Ophthalmic Drug Products. This was
    the first IND submitted for FDA review for human use.

2.  **February 13, 1998 --** IND 55,269 is submitted for the treatment
    of Alzheimer's Disease to the Division of Neuropharmacological Drug
    Products.

3.  **March 24, 1998**. Arthritis Advisory Committee meeting discussed
    safety issues surrounding COX-2 inhibitors.

4.  **November 23, 1998**, Merck submitted a New Drug Application (NDA
    21-042) for Vioxx^TM^ (rofecoxib) for the treatment of acute pain in
    adults, dysmenorrhea and osteoarthritis (data to support this NDA
    included in **IND 46,894**).

> The Vioxx^TM^ NDA included approximately 60 studies, which provided
> approximately five thousand subjects exposed to rofecoxib from one day
> to 86 weeks, of whom 371 and 381 patients received 12.5 and 25 mg
> daily (the recommended doses for chronic use) for one year or longer
> and 272 patients received ≥50 mg daily for ≥ 6 months (50 mg daily was
> the dose approved for acute pain).
>
> The NDA included two six-week placebo and ibuprofen-controlled
> studies; one six-week placebo and nabumetone controlled study in the
> elderly and one 6-week dose-ranging study. Some of the patients
> participating in these studies were involved in extension studies up
> to 86 weeks. Additionally, there were two six-month
> diclofenac-controlled studies, with extensions up to one year and two
> 6-month placebo and ibuprofen-controlled endoscopic studies (See
> Medical Officer review dated May 19, 1999).
>
> No cardiovascular signal was observed in the original NDA application.

5.  **April, 20 1999** -- Arthritis Advisory Committee (AAC) convened to
    consider the efficacy of 12.5 and 25 mg dose for osteoarthritis as
    well as gastrointestinal, renal, and hepatic safety of this new
    molecular entity. The AAC recommended approval.

6.  **May 20, 1999** -- Vioxx^TM^ (NDA 21-042) was approved for acute
    pain, dysmenorrhea and OA.

7.  **November 08, 1999** -- IND 59,222 was submitted to the Division of
    Oncology Drug Products (DODP) to pursue colon cancer prevention
    claim. This IND included Protocol 122 entitled, "A Multicenter,
    Randomized, Parallel Group, Placebo-Controlled, Double-Blind Study
    with In-House Blinding to Determine the Effect of 156 Weeks of
    Treatment with MK-0966 on the Recurrence of Neoplastic Polyps of the
    Large Bowel in Patients with a History of Colorectal Adenomas". DODP
    offered comments and requested clarification regarding the study
    design before the protocol was implemented. The original protocol
    had several deficiencies that need to be resolved before the study
    would be allowed to proceed (see FAX of December 07, 1999 and the
    follow-up ADVICE Letter of December 29, 1999).

8.  **January 05, 2000** -- An PreIND/End-of-Phase II meeting was held
    for IND 59,222 (Protocol 122 APPROVe) in response to the Agency
    comments and recommendations in the December 07, 1999 fax.

9.  **March 30, 2000** **\--** Preliminary information regarding an
    imbalance in serious cardiovascular thrombotic events had been
    submitted to the **original IND 46,894** for osteoarthritis and
    acute pain in March 30, 2000, along with analyses of serious
    cardiovascular events in all studies previously submitted to NDA
    21-042, ongoing placebo-controlled prevention of Alzheimer's
    studies, the ADVANTAGE study (which was almost completed) and
    post-marketing adverse experience surveillance, all of which did not
    show a cardiovascular signal. Merck's explanation was that naproxen
    had protective effects. A letter was sent to all investigators
    informing these results. The informed consent was amended to include
    this information. All protocols were amended to allow the use of low
    dose aspirin for those patients who may be at risk for
    cardiovascular events.

10. **June 23, 2000** -- IND 59,222 Protocol 122 (APPROVe) was amended
    to allow the use of low dose aspirin for patients who might be at
    high cardiovascular risk and remove a treatment arm with the 50 mg
    dose

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11. **June 29, 2000** -- VIGOR (Vioxx Gastrointestinal Outcome studies)
    was submitted for review (NDA 21-042/supplement 007). The VIGOR
    study demonstrated significant decrease in the risk of
    gastroduodenal perforations, ulcers and bleedings (56) in Vioxx^TM^
    as compared to (121) on naproxen, but also an increased risk of
    cardiovascular thrombotic events, mostly driven heart attacks (0.5
    and 0.1% for Vioxx^TM^ and naproxen, respectively). Important
    limitations to the study included the use of Vioxx^TM^ 50 mg dose
    (twice the highest recommended dose for chronic use), the use in a
    population with rheumatoid arthritis, the exclusion of patients
    taking aspirin (which left out patients at high cardiovascular risk
    requiring low dose aspirin for cardiovascular prophylaxis) an the
    use of a single comparator with putative antiplatelet effects.

12. **February 8, 2001** -- Arthritis Advisory Committee met to discuss
    the results of VIGOR, a large (8,000-patient) post-marketing study
    designed to evaluate the gastrointestinal safety of Vioxx^TM^ as
    compared to naproxen, submitted under NDA 21-042/S-007. The study
    succeeded in demonstrating superior gastrointestinal safety but also
    showed an increased risk of cardiovascular thrombotic events for
    Vioxx^TM^ as compared to naproxen. The Advisory Committee noted that
    the VIGOR trial had limitations as to the generalizability of the
    cardiovascular findings which needed further investigation. These
    limitations included study design using one comparator and no
    placebo, a higher dose (50mg) not recommended for chronic use, a
    population limited to rheumatoid arthritis patients, and the
    exclusion of patients on low dose aspirin. The Committee agreed on
    the important benefit of reduced gastrointestinal bleeding that
    rofecoxib had demonstrated, a benefit no other NSAID had, and
    encouraged the FDA to keep that benefit in mind when evaluating the
    safety issues in the VIGOR trial (see attached FDA and Merck
    briefing documents, slide presentations, and transcripts of the
    AAC).

13. **February 28, 2001** -- Sponsor submitted supplemental application
    for the Rheumatoid Arthritis indication (NDA 21-042/S-012 supported
    studies submitted under **IND 46,894**). This submission included a
    1,100-patient database in patients with RA that involved Vioxx^TM^
    25 and 50 mg and naproxen 500 mg bid in trials of 3 months to one
    year duration.

14. **April 6, 2001** - **Approvable** action for NDA 21-042 supplement
    007 (VIGOR study). Additional information was requested before
    labeling changes could be made.

15. **April 11, 2001 --** DAAODP met with Merck to discuss the
    additional information request in the April 06, 2001 approvable
    letter.

16. **April 30, 2001** -- Merck fulfills request of February 14, 2001
    for complete case study report of ADVANTAGE study. Safety Updae
    Report still needed for complete response to approvable letter
    issued on April 06, 2001.

17. \[Redacted \]

18. **July 12, 2001 -- Sponsor submitted Complete Response** to the
    April 06, 2001 Approvable letter the VIGOR study (NDA 21-042/S-007).
    This submission included:

-   The ADVANTAGE study, a 6,000-patient study comparing Vioxx^TM^ 25 mg
    and naproxen in patients with osteoarthritis. Information from this
    study was submitted in March 30, 2001, April 13, 2001, and April 16,
    2001.

-   A Safety Update Report (SUR) which included serious adverse events
    from studies that had been submitted to the original NDA application
    and from new, ongoing studies that included preliminary information
    from studies 078 and 091 (studies for the prevention of
    Alzheimer's).

-   Cardiovascular safety data from studies rheumatoid arthritis
    submitted in February 28, 2001, as part of an efficacy supplement to
    NDA 21-042.

-   Sponsor responses to FDA specific requests for clarification and
    information related to cardiovascular and overall safety of
    Vioxx^TM^, submitted to the FDA in July 26, and 30, August 4, and
    17, September 20, October 1, 3, 5, and 8, November 5, and 26, 2001.

19. **August 14, 2001** -- Memorandum of need to obtain a purchase order
    with Kaiser to conduct a project title: Comparison Rates of
    Myocardial Infarction (MI) between Patients Treated with
    Cyclo-Oxygenase 2 Inhibitors (COX-2) and Traditional Non-Steroidal
    Anti-Inflammatory Drugs (NSAIDs).

20. **September 01, 2001** -- IND 59,222 was transferred to the Division
    of Gastrointestinal and Coagulation Drug Products (DGCDP) following
    recommendations and comments from the Division of Oncology Drug
    Products in a letter dated December 30, 1999 and January 05, 2000
    End of Phase II meeting with (DODP).

21. **September 21, 2001 \--** FDA internal regulatory briefing on
    Vioxx^TM^. It was recommended to include balanced information
    regarding safety results of Vioxx^TM^ and de-emphasize the GI safety
    advantage in Vioxx^TM^ label.

22. **October 04, 2001 --** An urgent message was received from Bob
    Silverman of Merck. Bonnie Goldmann, (Merck) had been instructed by
    upper management to probe Dr. Woodcock about Agency thinking on
    Vioxx^TM^ label.

23. **October 15, 2001** -- Label negotiations were initiated by the FDA
    with the transmission of FDA proposed labeling for NDA 21-042/S-007
    VIGOR to Merck.

24. **November 01, 2001** -- DGCDP met with Merck to discuss the
    recommendations and comments in the April 13, 2001 advice letter for
    the prevention of colon polyps claim indication. DGCDP emphasized
    that cardiovascular safety issues needed to be addressed in this
    study. The division stated:

> "With regards to the interim safety analysis, it is understood that
> you will include an analysis of cardiovascular, edema, hypertension,
> thromboembolic, renal, hepatic and upper GI adverse events as well as
> an analysis of overall safety outcomes, SAEs and deaths. In addition
> to obtaining a recommendation from the independent safety monitoring
> board concerning continuation of the study, please clarify parameters
> that would prompt discontinuation of the study."
>
> "The agency has further concerns regarding the safety profile of
> prolonged VIOXX administration in this population, given the recent
> analysis of the cardiovascular/thrombotic/edema/hypertension and
> overall safety profiles and mortality outcomes associated with
> Rofecoxib treatment studies (VIGOR, ADVANTAGE, database of
> investigator reported events of study subjects with rheumatoid
> arthritis, and Alzheimer\'s studies)."

25. **November 06, 2001** -- Merck provides a response to FDA label
    proposal of October 15, 2001. The sponsor rejected FDA proposed
    labeling. There was little change from the original proposed label
    that accompanied NDA 21-042/S-007. In view of the extent of the lack
    of agreement a telecom was arranged with the sponsor and the
    division (DAAODP) explained our position regarding the sponsor's
    annotations to their counterproposal of November 06, 2001. This
    telecom took place on November 21, 2001. The division (DAAODP)
    requested that the sponsors reconsider their proposal in light of
    our comments and resubmit a new proposal.

26. **November 21, 2001** -- DAAODP initiated a telecom with Merck. Bob
    Silverman was present for Merck. DAAODP discussed issued raised in
    November 06, 2001 cover letter. The DAAODP requested tht the sponsor
    reconsider their proposal in the light of our comments and resubmit
    a new proposed label. It was also suggested that Merck meet with the
    DAAODP prior to the holiday break to discuss the label.

27. **November 28, 2001 \--** Except for studies 078 and 091 -- was
    completed on November 28, 2001 (see November 28, 2001, Medical
    Officer's review of the Complete Response to the April 06, 2001
    Approvable letter) and showed a trend for increased risk of
    myocardial infarctions for Vioxx^TM^ as compared to naproxen.
    However no such difference was noted in clinical trial data
    submitted with Vioxx^TM^ compared placebo or other NSAIDs

28. **December 05, 2001** -- Merck submitted a revised label proposal
    for VIGOR as suggested in the November 21, 2001.

29. **December 12, 2001** -- Regulatory briefing was held to update Drs.
    Woodcock and Temple on the labeling negotiation.

30. **December 19, 2001** -- A face-to-face meeting was scheduled and
    confirmed to continue discussion of Vioxx^TM^ proposed label for
    January 09, 2002.

31. **December 21, 2001** -- Approvable action for NDA 21-042/S-012
    (rheumatoid arthritis) pending additional cardiovascular safety
    information.

32. **January 03, 2002** -- Bob Silverman requested confirmation of Dr.
    Temple's attendance for the scheduled January 09, 2002 meeting. He
    was informed that Dr. Temple would not be available.

33. **January 07, 2002** -- Merck cancelled the January 09. 2002
    meeting. Merck requested the meeting to be rescheduled with Dr.
    Temple attending. Merck submitted revised labeling which now
    included NDA 21-042/S-007 VIGOR and S-012 RA. There was still
    substantial distance between the sponsor and DAAODP.

34. **January 11, 2002** \-- Approvable action for NDA 21-042/S-007,
    pending labeling negotiations regarding the cardiovascular safety of
    Vioxx^TM^.

35. **January 25, 2002** \-- As there was substantial distance between
    the sponsor's and the division's (DAAODP) positions, the division
    presented an update of labeling negotiations at a pre-decisional
    meeting at the Center level. This venue allowed for open discussion
    for difficult issues with experienced leaders in the Center. There
    was a consensus that the data from the various large databases was
    of concern and that labeling should include information related to
    cardiovascular findings associated with Vioxx^TM^. This was similar
    to comments make by multiple advisory committee members at the
    February 2001 meeting.

36. **January 30, 2002** -- A telecom with the sponsor was held on
    January 30, 2002 for NDA 21-042/S-007 VIGOR and S-012 RA. Labeling
    negotiations continued with teleconferences being held on February
    08, and 20, and March 07, and 20, 2002 until a final label was
    issued (see attached MINUTES and proposed FDA label).

37. **March 12, 2002** -- A detailed review of cardiovascular thrombotic
    events in ongoing studies 078 and 091for the prevention of
    Alzheimer's disease was conducted separately. These studies provided
    a 2,800-patient placebo-controlled database for Vioxx^TM^ 25 mg as
    compared to placebo, with a median exposure of 14 months. Analyses
    of cardiovascular thrombotic events in these studies showed no
    difference in the risk of myocardial infarctions or stroke between
    Vioxx^TM^ 25 mg and placebo (see MO review dated [March 12, 2002
    under NDA 21-042/S-007).]{.underline}

> "The Alzheimer's studies described in this memo were not specifically
> designed or powered to address CV outcomes. However, they provide a
> relatively large placebo-controlled database (rofecoxib N= 1267,
> placebo N= 1464), with a median exposure of 14 months and a
> substantial number of MI and cerebrovascular events for analysis. In
> this database, there was no excess for *all* cardiovascular thrombotic
> events (cardiac, cerebrovascular and peripheral together) and
> particularly, no excess of MI in the rofecoxib 25 mg group, as
> compared to placebo. However, total cause mortality (29 vs. 15) and
> cardiovascular thrombotic deaths (8 and 3) trended against rofecoxib.
>
> These data support the hypothesis that the excess of MI found with
> rofecoxib 50 mg in the VIGOR study - as well as the trends observed in
> the ADVANTAGE and the RA databases with the 25 mg dose relative to
> naproxen - may in part be explained by the lack of an anti-platelet
> effect of rofecoxib relative to naproxen. However, in addition, the
> biologically plausible pro-thrombotic effect and the known effects on
> fluid retention, edema and hypertension may play a role in the
> different cardiovascular safety profile of rofecoxib as compared to
> naproxen.
>
> Adequately powered and prospectively designed studies are necessary to
> definitively address cardiovascular safety issues with VIOXX."

38. **March 14, 2002** -- FDA does an additional statistical analysis of
    cardiovascular thrombotic events in VIGOR. This analysis suggested
    there was an increase with Vioxx^TM^ 50 mg compared to naproxen over
    time.

39. **March 19, 2002** -- The Gastrointestinal Drugs Advisory Committee
    met to discuss study design issues for chemopreventive agents
    studied for the prevention for sporadic adenomatous polyposis. On
    June 7, 2002 Merck submitted an amendment to IND 59,222 containing a
    review of the advisory committee meeting and a proposal to resolve
    outstanding issues regarding Protocol 122.

40. **April 11, 2002**, The Agency approved the rheumatoid arthritis
    indication along with labeling changes that included the results of
    the VIGOR study and changes to the PRECAUTIONS, Drug Interactions,
    and Dosage and Administration sections of the label to reflect all
    that was known at that time about potential risk for cardiovascular
    thrombotic evetns with Vioxx^TM^.

Excerpts from the April 2002 label are as follows:

Special Studies

The following special studies were conducted to evaluate the comparative
safety of VIOXX.

VIOXX GI Clinical Outcomes Research (VIGOR Study)

Study Design

The VIGOR study was designed to evaluate the comparative GI safety of
VIOXX 50 mg once daily (twice the highest dose recommended for chronic
use in OA and RA) versus naproxen 500 mg twice daily (common therapeutic
dose). The general safety and tolerability of VIOXX 50 mg once daily
versus naproxen 500 mg twice daily was also studied. VIGOR was a
randomized, double-blind study (median duration of 9 months) in 8076
patients with rheumatoid arthritis (RA) requiring chronic NSAID therapy
(mean age 58 years). Patients were not permitted to use concomitant
aspirin or other antiplatelet drugs. Patients with a recent history of
myocardial infarction or stroke and patients deemed to require low-dose
aspirin for cardiovascular prophylaxis were to be excluded from the
study. Fifty-six percent of patients used concomitant oral
corticosteroids. The GI safety endpoints (confirmed by a blinded
adjudication committee) included: PUBs-symptomatic ulcers, upper GI
perforation, obstruction, major or minor upper GI bleeding.

Study Results

Gastrointestinal Safety in VIGOR

The VIGOR study showed a significant reduction in the risk of
development of PUBs, including complicated PUBs in patients taking VIOXX
compared to naproxen (see Table 2).

\[Table 2. VIGOR-Summary of Patients with Gastrointestinal Safety
Events1 COMPARISON TO NAPROXEN\]

Other Safety Findings: Cardiovascular Safety

The VIGOR study showed a higher incidence of adjudicated serious
cardiovascular thrombotic events in patients treated with VIOXX 50 mg
once daily as compared to patients treated with naproxen 500 mg twice
daily (see Table 3). This finding was largely due to a difference in the
incidence of myocardial infarctionbetween the groups. (See Table 4.)
(See PRECAUTIONS, Cardiovascular Effects.) Adjudicated serious

cardiovascular events (confirmed by a blinded adjudication committee)
included: sudden death, myocardial infarction, unstable angina, ischemic
stroke, transient ischemic attack and peripheral venous and arterial
thromboses.

![](media/image1.png){width="5.75in" height="4.010416666666667in"}

![](media/image2.png){width="5.677083333333333in" height="4.28125in"}

For cardiovascular data from 2 long-term placebo-controlled studies, see
PRECAUTIONS, CardiovascularEffects.

PRECAUTIONS

Cardiovascular Effects

The information below should be taken into consideration and caution
should be exercised when VIOXX is used in patients with a medical
history of ischemic heart disease.

In VIGOR, a study in 8076 patients (mean age 58; VIOXX n=4047, naproxen
n=4029) with a median duration of exposure of 9 months, the risk of
developing a serious cardiovascular thrombotic event was significantly
higher in patients treated with VIOXX 50 mg once daily (n=45) as
compared to patients treated with naproxen 500 mg twice daily (n=19). In
VIGOR, mortality due to cardiovascular thrombotic events (7 vs 6, VIOXX
vs naproxen, respectively) was similar between the treatment groups.
(See CLINICAL STUDIES, Special Studies, VIGOR, Other Safety Findings:
Cardiovascular Safety.) In a placebo-controlled database derived from 2
studies with a total of 2142 elderly patients (mean age 75; VIOXX
n=1067, placebo n=1075) with a median duration of exposure of
approximately 14 months, the number of patients with serious
cardiovascular thrombotic events was 21 vs. 35 for patients treated with
VIOXX 25 mg once daily versus placebo, respectively. In these same 2
placebo-controlled studies, mortality due to cardiovascular thrombotic
events was 8 vs. 3 for VIOXX versus placebo, respectively. The
significance of the cardiovascular findings from these 3 studies (VIGOR
and 2 placebo-controlled studies) is unknown. Prospective studies
specifically designed to compare the incidence of serious CV events in
patients taking VIOXX versus NSAID comparators or placebo have not been
performed.

**Because of its lack of platelet effects, VIOXX is not a substitute for
aspirin for cardiovascular prophylaxis.** Therefore, in patients taking
VIOXX, antiplatelet therapies should not be discontinued and should be
considered in patients with an indication for cardiovascular
prophylaxis. (See CLINICAL STUDIES, Special Studies, Platelets;
PRECAUTIONS, Drug Interactions, Aspirin.) Prospective, long-term studies
on concomitant administration of VIOXX and aspirin evaluating
cardiovascular outcomes have not been conducted.

Drug Interactions:

Aspirin: Concomitant administration of low-dose aspirin with VIOXX may
result in an increased rate of GI ulceration or other complications,
compared to use of VIOXX alone. In a 12-week endoscopy study conducted
in OA patients there was no difference in the cumulative incidence of
endoscopic gastroduodenal ulcers in patients taking low-dose (81 mg)
enteric coated aspirin plus VIOXX 25 mg daily, as compared to those
taking ibuprofen 2400 mg daily alone. Patients taking low-dose aspirin
plus ibuprofen were not studied. (See CLINICAL STUDIES, Special Studies,
Upper Endoscopy in Patients with Osteoarthritis and Rheumatoid
Arthritis.)

At steady state, VIOXX 50 mg once daily had no effect on the
anti-platelet activity of low-dose (81 mg once daily) aspirin, as
assessed by ex vivo platelet aggregation and serum TXB2 generation in
clotting blood. Because of its lack of platelet effects, VIOXX is not a
substitute for aspirin for cardiovascular prophylaxis. Therefore, in
patients taking VIOXX, antiplatelet therapies should not be discontinued
and should be considered in patients with an indication for
cardiovascular prophylaxis. (See CLINICAL STUDIES, Special Studies,
Platelets and PRECAUTIONS, Cardiovascular Effects.) Prospective,
long-term studies on concomitant administration of VIOXX and aspirin
have not been conducted.

41. **August 13, 2002** -- MON -- Request for purchase order to fund
    Kaiser for a project titled: Design of a Survey Questionnaire to be
    Used in the Study of Comparision Rates of Myocardial Infarction (MI)
    between Patients Treated with Cyclo-Oxygenase-2 Inhibitors (COX-2)
    and Traditional Non-Steroidal Anti-Inflammatory Drugs (NSAIDs).

42. **October 07, 2002** -- \[Redacted\]

43. **November 01, 2002** -- Under IND 59, 222 recommendations and
    comments were provided regarding Merck's proposal to address
    outstanding issues related to Protocol 122 from the March 19, 2002
    Gastrointestinal Advisory Committee meeting. This letter emphasized
    the need for long-term clinical data to fully address cardiovascular
    safety issues with Vioxx^TM^. This letter states:

> **"**We do not agree that 3-year data are sufficient for approval of
> your drug for this indication. VIOXX has an evolving safety profile
> that is new since discussions with you on January 5, 2000. In April,
> 2001, the division IND 59,222 Page 2 recommended 8 years of follow up.
> Your label now acknowledges that a previously unanticipated risk,
> cardiac events, has been associated with rofecoxib and this is the
> subject of on-going scientific assessment. The risk of cardiac and
> other adverse events, including mortality, over time must be fully
> studied and we believe that 3 years is insufficient because it is
> likely that longer administration will occur. Given the changing
> nature of rofecoxib's safety profile, we now feel that a patient's
> duration of treatment should be 5 years. Colonoscopies should be
> performed at baseline, at year 1, at year 3, and at the end of
> treatment. In addition, a follow-up colonoscopy a minimum of 1 year
> after treatment discontinuation is needed to evaluate the potential
> for polyp rebound (i.e., a total of 6 years). Labeling recommendations
> in the Dosage and Administration section will specify a duration of
> administration based on the clinical trial data."

44. **November 13, 2002** \-- Merck proposed an analysis of CV
    thrombotic events in placebo-controlled studies (Protocol 203). The
    protocol was entitled "A prospective combined analysis of thrombotic
    cardiovascular events in three randomized, double-blind,
    placebo-controlled studies of rofecoxib in patients at risk of
    developing recurrent sporadic adenomatous colon polyps (APPROVe,
    protocol 122), recurrent colon cancer (VICTOR, protocol 145, which
    was being conducted outside the USA) or prostate cancer (Prostate
    cancer chemoprevention study, protocol 201)." The objective of
    protocol 203 was to compare the cardiovascular safety of rofecoxib
    25 mg to placebo using a combined analysis of data from the three
    studies which had been submitted to the Divisions of
    Gastro-Intestinal and Coagulation Drug Products and the Division of
    Reproductive Drug Products.

> All three studies were multi-center, double-blind, randomized,
> placebo-controlled studies. They each had their own Data Safety
> Monitoring Board and one Cardiovascular Adjudication Committee that
> determined whether the cases were in fact confirmed cardiovascular
> thrombotic events. The CV Adjudication committee had its Standard
> Operating Procedures and used the same definitions as used for the
> VIGOR study.

45. **December 09, 2002** -- Under IND 46,894 FDA asked Merck to provide
    a follow up safety update analysis of cardiovascular thrombotic
    events in the placebo-controlled Alzheimer's studies that had been
    included in the April 11, 2002 label.

46. **December 19, 2002** -- Under IND 46,894 the FDA sent an advice
    letter to Merck acknowledging that Protocol 203 (the pooled analysis
    of cardiovascular events) would provide substantial clinical
    information greatly needed for Vioxx^TM^, but emphasized that it
    might not be sufficient to address the ongoing cardiovascular safety
    concerns surrounding Vioxx^TM^.

> Subsequently, several teleconferences took place between FDA and Merck
> to further discuss this pooled analysis (see MINUTES dated February
> 04, and March 09, 2004, and an ADVICE Letter dated August 16, 2004).
> Of note to date we had not reached agreement on this pooled analysis,
> and no results from this have been made available to the FDA.

47. **February 28, 2003** -- A meeting was held with Merck to further
    discuss the proposed safety database in support of the colon polyp
    prevention (see MINUTES). The FDA reiterated the risk of cardiac and
    other adverse events, including mortality, overtime must be fully
    studied, and that three years was insufficient because it was likely
    that longer administration would occur. The FDA was also concerned
    about possibility of rebound of polyps after stopping the drug.

48. **December 5, 2003 --** Sponsor submitted supplemental application
    for the treatment of Juvenile Rheumatoid Arthritis (NDA
    21-042/S-026). This filing was preceded by extensive discussion
    about design/duration of pediatric studies.

49. **December 17, 2003 \--** In response to the request for information
    of December 9, 2002 by the Division of Anti-inflammatory Drug
    Products, the sponsor provided a safety update analysis of
    cardiovascular thrombotic events in the placebo-controlled Alzheimer
    studies.

50. **January 28, 2004 --** Review of the December 17, 2003 submission
    is completed. At that time an excess in total cause mortality was
    noted as well as a trend towards worsening cognitive function in one
    of the Alzheimer's studies. No regulatory action was indicated at
    that time, pending complete review of the submission by the Division
    of Neuropharmacologic Drug Products and a full safety update that
    was expected for 4Q 2004.

51. **March 30, 2004 --** Merck submitted supplemental NDA 21-042/S-030
    to support change to Vioxx^TM^ label with the final thrombotic
    cardiovascular safety data from Alzheimer's protocols 078 and 091.

52. **March 26, 2004 --** NDA 21,647 approved for the treatment of
    migraine headache supported by studies conducted under IND 55,269.
    Signatory authority, Dr. Russell Katz, (Division of
    Neuropharmacological Drug Products)

53. **April 13, 2004 --** Merck is invited to give a presentation on
    their interpretation of efficacy data from studies 078 and 091
    Alzheimer's disease. Merck is also invited to present gout data from
    pending NDA 21-389 Arcoxia^TM^ (etoricoxib) Tablets at the June 2,
    and 3, 2004 Arthritis Advisory Committee meeting.

54. **June 4, 2004 --** NDA 21-042/S-026 an Approvable action was taken
    for the JRA indication. Although agreement was reached that the
    study submitted in support of efficacy demonstrated non-inferiority
    to the comparator (naproxen), agreement was not reached on the
    language to be added to the package insert describing the pediatric
    clinical trial.

55. **June 09, 2004 --** 74-Day letter for NDA 21-042/S-030 is issued
    with the following comments regarding the efficacy of Protocols 078
    and 091:

> "The results of Study 078 do appear to indicate that patients with
> Mild Cognitive Impairment, who take rofecoxib in a dose of 25 mg/day,
> have an increased risk of developing overt Alzheimer's Disease
> compared with those who receive placebo. The lack of a significant
> effect on cognition and on measures of global function in either of
> two further studies of rofecoxib in overt Alzheimer's Disease \[Study
> 091, and the study conducted by Aisen et al\] do contrast with the
> results of Study 078. The study by Aisen et al, did show a trend
> toward greater worsening on the cognitive primary efficacy measure,
> the ADAS-Cog, in patients treated with rofecoxib than in those treated
> with placebo."

56. **August 11, 2004** -- DAAODP learns that Dr. Graham is going to
    present a poster related to cardiovascular risks with Vioxx^TM^ at
    the International Conference on Pharmacoepidemiology and Therapeutic
    Risk Management. Upon review of the poster abstract, the Division
    felt that the data did not support the author's conclusions. A
    complete study report was not provided to the DAAODP until October
    7, 2004. The study is under review.

57. **August 19, 2004** -- NDA 21-042/S-026 approval of the JRA
    indication supported by studies conducted under IND 46,894.

58. **September 27, 2004 -** Merck is schedule to brief FDA on the
    cognition efficacy data from Protocols 078 and 091 submitted under
    IND 55,269 and NDA 21-042/S-030 currently under review. At 8:32 a.m.
    Merck conveys to FDA that DSMB recommended stopping APPROVe study
    under IND 59,222. The APPROVe study showed increased risk of
    myocardial infarction and stroke for the 12.5 and 25 mg dose as
    compared to placebo after 18 months of treatment.

59. **September 28, 2004** -- Merck request an emergency meeting with
    FDA upper management. At the meeting Merck shares data from the
    APPROVe trial conducted under IND 59,222 and announces the product
    withdrawal of Vioxx^TM^ from the market.

60. **September 30, 2004** -- Public announcement of worldwide product
    withdrawal of Vioxx^TM^.