In the Pipeline: FDA Advisory Committee Reviews - June 2004

Jane S. Ricciuti, RPh, MS; Regina M. Ballinger, RN; Walter E. Chalkley


AdComm Bulletin. 2004;2(5) 

In This Article

Arthritis Agents

Date and FDA Advisory Committee. June 2, 2004 meeting of the Arthritis Advisory Committee.

Subject. Clinical trial designs and endpoints for drugs for chronic gout, including new drug application (NDA) 21-740, Oxyprim (oxypurinol), Cardiome.

Background. During this meeting, the Arthritis Advisory Committee (AAC) reviewed clinical trial designs and endpoints for drugs for chronic gout, including new drug application (NDA) 21-740, Oxyprim (oxypurinol), sponsored by Cardiome. The summary document provided by FDA regarding the NDA for oxypurinol is part of an ongoing preliminary review of the product. FDA also convened this meeting to gather input regarding clinical trials intended to support the development and approval for drugs that treat hyperuricemia, a condition that leads to gout.

The National Institute of Arthritis and Musculoskeletal and Skin Disease (NIAMS) estimates that approximately 840 out of every 100,000 people will develop gout. Most of these cases occur in adult men, particularly between the ages of 40 and 50 years. Gout is the result of high levels of uric acid in the blood (hyperuricemia) and may be related to the intake of foods high in purines. There is some genetic predisposition to the development of gout. The increasing incidence of gout may be linked to increased obesity and longevity of the American population.

With proper treatment, most people with gout are able to control their symptoms. The most common treatments for an acute attack of gout are nonsteriodal anti-inflammatory drugs (NSAIDs) and corticosteroids. Preventative medications include allopurinol or probenecid to treat hyperuricemia (increased blood levels of uric acid). Allopurinol, the current gold standard in the treatment of gout, is associated with the development of allopurinol hypersensitivity syndrome which occurs in 2-4% of the population.

Oxypurinol is the major metabolite of allopurinol. Both allopurinol and oxypurinol inhibit the synthesis of uric acid by action on the enzyme xanthine oxidase. Oxypurinol is proposed for the treatment of allopurinol-intolerant hyperuricemia and/or gout and has been granted orphan drug status by FDA.

  • Oxypurinol is indicated for the treatment of allopurinol-intolerant hyperuricemia.

  • 300-800 mg of oxypurinol per day.

The committee supported the use of serum uric acid (SUA) as the surrogate endpoint in clinical trials for chronic gout. Clinical outcomes measures, such as reduction of tophi (collections of uric acid crystals in tissue) and/or reduction in acute attacks and pain, and quality of life were recommended to support SUA data. Disease specific and general quality of life measures are appropriate as secondary outcome measures because of the prevalence of comorbid conditions in the gout population.

Of separate concern to the committee is the lack of data between predictive value SUA and the correlation to total uric acid (the uric acid pool) and decreased prevalence of gout attacks.

The AAC recommended the use of a comparison trial with a non-inferiority design using allopurinol for new drugs for gout. The pain associated with gout raises ethical concerns and may preclude the use of placebo-controlled trials. There is not sufficient data available in the literature to establish a generally accepted response rate for allopurinol that could be used for calculating a non-inferiority margin.

Clinical Issues. The sponsor has submitted information on the efficacy and safety of oxypurinol from three main databases ( Table 1 ):

  • An open-label (OL) retrospective analysis from 533 patients enrolled in the original (1966) Compassionate Use Program (CUP); this program is ongoing.

  • A prospectively designed 14-week OL study (OXPL-213) involving 79 patients with an extension (A4) that is also ongoing.

  • A pharmacokinetic (PK) study (AAI-US-175).

The sponsor conducted several analyses from the CUP database. However, FDA noted several features of the program caused the database to be inadequate for assessing the efficacy or safety of oxypurinol in allopurinol intolerant patients:

  • The protocol for compassionate use was not originally designed to formally evaluate the safety or efficacy of oxypurinol. The CUP was open-label, uncontrolled with flexible follow-up visits. Laboratory measurements were not collected systematically and there was no central laboratory for analysis. The data analysis plan for the program was written subsequent to the 1966 origination of the CUP enrollment.

  • Inadequate documentation of allopurinol intolerance before entry and clinical response to therapy.

  • Missing data included:

    • Baseline data in a substantial number of patients: SUA levels missing in 172 patients (32%); age and ethnicity are missing in 41% and 31% of patients, respectively.

    • Post-baseline SUA levels missing in 127 (24%) of patients.

    • The final dose level was not documented in 126 (24%) of patients. For analyses, they were assigned a dose category of 300 mg.

    • 148 patients (28%) that were lost to follow up.

Safety. Outcome measures for safety in OXPL-213 and A4 included clinical and laboratory evaluations at baseline, 6 weeks and end of study. There was 1 death during study OXPL-213 and 4 during the extension phase. Deaths did not appear to be related to oxypurinol. Additional data regarding some deaths is pending.

Most of the serious adverse events appeared unrelated to oxypurinol. Of note were 3 myocardial infarctions (MIs) in the base study and 1 MI and 1 unstable angina during A4. It is likely these events were not drug related but reflect associated comorbid conditions. The lack of a placebo arm precludes more definitive conclusions regarding the safety of oxypurinol.

There were 23 patients that discontinued the OXPL-213 trial due to non-fatal adverse events such as skin reactions. The hypersensitivity reactions attributed to oxypurinol are similar to those attributed to allopurinol. In Study OXPL-213, up to one-third of patients developed intolerance to oxypurinol. Liver function test elevation was seen in 6 patients, 4 of whom had prior hepatic reaction to allopurinol, and 1 patient developed thrombocytopenia.

FDA noted several unanswered questions related to safety of products for chronic gout that include effects of life-long use, both daily and intermittent, co-medications, and special populations, such as renal-insufficiency. Phase 4 studies have been designed with input from the sponsor and from FDA to address some of the deficiencies in the OXPL-213 clinical trial.

The sponsor has also proposed an internet based risk management program to manage risk-benefit considerations and provide information to both healthcare providers and patients. The plan would also address issues related to defining and confirming an "allopurinol-intolerant" patient population.

The committee indicated that the sponsor must determine safe effective doses during drug development and in subsequent clinical trials. Dose escalation studies are designed to identify the highest effective and safe dose.

Efficacy. Serum uric acid (SUA) levels were used as a surrogate endpoint for efficacy. SUA levels were measured at entry, 6 weeks, 9 weeks (only for those who had not achieved 2 mg/dL at 6 weeks), and at the end of study (weeks 12, 13, and 14). Oxypurinol treatment was associated with a modest reduction in SUA levels in 79 patients with hyperuricemia after 14 weeks of treatment. The mean change was 1.78 mg/dL (95% CI 1.47, 2.08, p=<0.001) in those 79 patients. The completer analysis at week 14 included 54 patients with the mean change from baseline of 2.32 mg/dL (95%CI 2.07, 2.57). The final mean SUA in the ITT population was 8.0 mg/dL.

FDA concluded that there was no evidence of dose-response, although the committee noted that the sample size may not have been adequate to address dose-response and recommended clarification of this issue in order to determine the appropriateness of SUA as a surrogate endpoint.

Fourteen patients (18%) had gout flares during these combined studies as follows:

  • 7 had flares during OXPL-213,

  • 6 had flares during the extension study (A4), and

  • 1 had flares during both the base and extension phase.

All of these patients experienced a decrease in SUA during the study; two achieved levels ≤ 6 mg/dL. None of these patients discontinued from the study due to their gouty flares. This was influenced by the fact that they were treated with local or systemic corticosteroids and/or NSAIDs, or colchicine as needed. Additionally, 3 patients (with no gouty attacks) had tophi complications such as draining, pain, and infection. FDA noted that the lack of placebo control or an allopurinol comparator arm hampers an adequate interpretation of these findings.

The AAC made several recommendations regarding the design of clinical trials for chronic gout. The committee agreed that the use of SUA as a surrogate endpoint was an appropriate measure of efficacy. The committee recommended the absolute value of 6.0 mg/dL as the measure. Although individuals demonstrate a broad range of uric acid levels, the committee did not recommend inclusion/exclusion criteria based on this measure citing randomization as the control.

Clinical outcomes measures, such as reduction of tophi and/or reduction in acute attacks and pain, and quality of life were also recommended to support SUA data. A larger study may be necessary to validate results and may require the inclusion of patients other than those who are allopurinol-intolerant patients. A study would also involve an extended follow up period in order to validate the accuracy of such clinical markers. Measures of clinical outcomes need to be standardized and methods validated. Patient self-evaluation of gout attack may be subjective and specific definitions of what constitutes a gout attack need to be defined.

Disease specific and general quality of life measures are appropriate as secondary outcome measures because of the prevalence of comorbid conditions in the gout population. The duration of clinical trials would depend upon the clinical outcome and should range from 1-2 years.

The committee discussed a variety of issues related to inclusion and exclusion criteria. Considering the prevalence of comorbid conditions, such as renal insufficiency, in gout patients, these patients should be included in clinical trials in order to gain appropriate representation of the diseased population; however, stratification may be required in these populations. Additional recommendations include:

  • Exclusion of dialysis and end stage renal patients. Creatinine clearance should be the measure of renal status.

  • Patients on colchicines, NSAIDs, and low dose aspirin be included in the clinical trials. Other medications, such as diuretics, should be considered individually.

  • Dietary considerations should not be of major consideration in the clinical trials.

  • Patients with kidney stones should be included.

  • Renal/heart transplant patients, including those on cyclosporine, should be studied separately.

Date and FDA Advisory Committee. June 3, 2004 meeting of the Arthritis Advisory Committee.

Subject. Clinical trial design and endpoints for drugs for acute gout, including a review of NDA 21-389, Arcoxia (etoricoxib), Merck.

Background. The AAC reviewed clinical trial designs and endpoints for drugs for acute gout, including NDA 21-389, Arcoxia (etoricoxib [ATC:M1A]), sponsored by Merck. Etoricoxib is a NSAID, cyclo-oxygenase-2 (COX-2) inhibitor for the treatment of arthritic gout.

Acute gouty arthritis affects approximately 2.2 million people in the US annually. It is one of the most common forms of inflammatory joint disease in men over the age of 40. Acute gouty arthritis is characterized by painful joint inflammation caused by metabolic imbalances that result in the overproduction or under excretion of uric acid leading to deposits of uric acid crystals in the joints, especially in the lower extremities. Acute gouty arthritis is associated with intense pain and inflammation that can reach peak levels within a few hours and remain at that level for several days.

The presence of gout is confirmed by the presence of polymorphonuclear leukocytes and intracellular monosodium urate crystals in synovial fluid aspirated from an inflamed joint. Monosodium urate crystals observed using polarized light microscopy are needle-shaped and negatively birefringent (refracting light). Examination of aspirated joint fluid can also rule out other disorders, such as septic arthritis and pseudogout. Occasionally, patients with gout may present without uric acid crystals in the synovial fluid aspirate. However, aspiration repeated five hours to one day later shows crystals in the synovial fluid of most of these patients. The American Rheumatism Association (ARA) outlined more specific criteria for the diagnosis of gout.

Currently, acute gout is managed by NSAIDs, colchicine, and corticosteroid therapy. The FDA is seeking information from experts in research and industry in order to develop guidance on the clinical development of new therapies for gout.

  • Etoricoxib is .indicated for the pain and signs of inflammations associated with acute gouty arthritis.

  • 120 mg of etoricoxib once daily

The committee was generally supportive of the clinical trial design used for etoricoxib and agreed that placebo-controlled trials would be difficult in acute gout due to the ethical considerations of withholding effective treatment.

While acknowledging considerations related to enrollment difficulties, such as limited disease population, the committee recommended increasing the length of clinical trials from 8 days to several weeks in order to better demonstrate efficacy.

The committee indicated that pain as a primary endpoint in acute gout trials is appropriate and recommended the use of patient-determined pain scales. The committee also recommended using time to pain relief over a set period of time, inflammatory measures and/or quality of life measures as secondary endpoints.

Clinical Issues. Merck conducted an analysis of 2 studies in over 40 sites worldwide comparing the effectiveness of etoricoxib to indomethacin. The purpose of the combined analysis was to evaluate the response to etoricoxib and indomethacin by analyzing the subgroups of patients with moderate or severe/extreme baseline pain. The patients met the Wallace Criteria for diagnosis for acute gout and had moderate, severe or extreme pain. Patients with stable baseline gout medications such as colchicine and allopurinol were included but patients who took other NSAIDs or corticosteriods were excluded. Table 2 further summarizes the study design.

Secondary endpoints included patient's global assessment of response to therapy, investigator's global assessment of response to therapy, and assessment of study joint tenderness. The sponsor noted the difficulty of recruitment despite the active comparator design. The sponsor also outlined some other potential considerations for future clinical trials for acute gout:

  • Collect additional onset data such as the use of pain measurement over multiple, early, and specific time points.

  • Alternative scales to enhance precision, i.e., a 0-10 point Numeric Rating Scale or 10 cm Visual Analog Scale.

  • Include the use of a function outcome measure.

In both Studies 049 and 040, etoricoxib was generally well tolerated. The most common drug-related adverse events included dizziness (2.8 % for etoricoxib, 14.3% for indomethacin), hypertension (5.6% for etoricoxib, 8.7% for indomethacin), diarrhea (2.8% for etoricoxib, 4.3% for indomethacin), nausea (1.7% for etoricoxib, 5.6% for indomethacin) and headache (1.1% for etoricoxib, 6.2% for indomethacin).

Eight patients discontinued etoricoxib for adverse events compared to 13 patients on indomethacin.

The analysis combined the results of two identically designed, published studies that demonstrated comparable efficacy of etoricoxib and indomethacin in acute gouty arthritis. Patients completed pain assessments at baseline and on each day of the study 4 hours after their daily dose of study medication. Patients were seen in the clinic for office visits on Days 1, 2, 5, 8 and 22 (14 days after the last dose of the study medication on Day 8).

The efficacy of etoricoxib in treating pain over Days 2 through 5 was comparable to that seen with indomethacin in patients with moderate pain and in patients with severe/extreme pain. On a scale of 0 (no pain) to 4 (extreme pain), patients with moderate pain treated with etoricoxib reported a 1.14 unit decrease in their pain level from baseline, while those receiving indomethacin reported a 0.99 unit decrease in their pain level from baseline. Patients with severe/extreme pain treated with etoricoxib reported a 2.00 unit decrease in their pain level from baseline, while those receiving indomethacin reported a 2.06 unit decrease in their pain level from baseline. Additionally, etoricoxib and indomethacin provided comparable efficacy in all secondary endpoints in both subgroups of patients (moderate or severe/extreme).

The committee was generally supportive of the clinical trial design used for etoricoxib, agreeing that placebo-controlled trials would not be feasible in an acute gout clinical trial, although some consideration was given to placebo-control for the first 8 hours using a sub-study with a limited number of patients. In consideration of the use of a non-inferiority trial, the committee noted that it was questionable whether sufficient data is available to define a margin for such a trial.

Gout represents a unique clinical entity to which acute pain is a symptom. In certain circumstances, a pain model could also be applied in the investigation of acute gout if pain resolution is the primary endpoint this may not be separable from the inflammatory symptoms. The committee indicated that pain as a primary endpoint is appropriate and recommended use of patient determined scales. Additionally, the committee noted the value of using time to pain relief over a defined period of time, inflammatory measures and/or quality of life measures as secondary endpoints.

The committee noted the high value of a demonstration of efficacy within the first 24 hours in clinical trials for acute gout. The committee also noted that the data was lacking information regarding the follow-up of patients regarding complete resolution of pain in the etoricoxib trials and recommended increasing the length of future trials to provide more detailed information on outcome. As attacks of gout may be self-limiting and resolve spontaneously over 1-2 weeks, the committee suggested following patients during an acute period of at least 1 week through a withdrawal period during week 2. Additional data could be collected during week 3 to track extended outcome, although care should be taken not to enter the realm of chronic gout.

Limitations of enrollment of patients in acute gout clinical trials may be due to the exclusion of patients who are currently on NSAIDs. The committee's recommendations on enrollment criteria for acute gout clinical trials included:

  • Patients on therapy or chronic maintenance with colchicines and allopurinol.

  • Exclusion of patients on NSAIDs, except short acting NSAIDs, and steroids.

  • Patients experiencing acute gout attacks within the 18-72 hours of enrollment.

  • Inclusion of patients on diuretics and low dose aspirin.

  • Stratification of patients with polyarticular gout.

Committee discussion regarding the documentation of the presence of gout in patients enrolled in clinical trials did not yield definitive recommendations. The committee agreed that the use of the American Rheumatism Association (ARA) criteria for diagnosis of gout were appropriate but no recommendation could be made on the requirements for crystal identification prior to enrollment.


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