CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER
`
`NDA 21-574
`
`Medical Review(s)
`
`

`

`
`
`
`MEDICAL OFFICER REVIEW
`Division of Metabolic and Endocrine Drug Products (HFD—510)
`21574
`NDA ....................
`
`APPLICATION #:
`
`APPLICATION TYPE:
`
`ANDRX
`
`SPONSOR:
`
`PROPRIETARY NAME:
`
`Antidiabetic
`
`CATEGORY OF
`DRUG:
`
`USAN / Established Name:
`
`Metformin
`
`......
`
`Fortamet............‘..
`
`MEDICAL
`REVIEWER:
`
`Robert I Misbin..
`
`REVIEW DATE:
`
`Feb 20, 2004 ..........
`
`ROUTE:
`
`SUBMISSIONS REVIEWED IN THIS DOCUMENT
`
`II ocument Date: CDER Stamp Date: Submission Type:
`II ec 19, 2002
`Dec 23, 2002
`. pril 16, 2003
`April 17, 2003
`
`
`Safety update
`
`Comments:
`
`February 18, 2004
`
`Final label
`
`
`
`
`I etformin XT once daily is nearly as effective in lowering HbAlc levels as Glucophage twice daily. This
`shortcoming of Metformin XT is potentially offset by the convenience of once a day dosing. The safety
`profile of Metformin XT and Glucophage are similar. The submission of Dec 19, 2003 establishes
`equivalency (2x 500mg=lx1000mg) of the 500 mg and 1000 mg tablets. The final label, dated
`February 18, 2004 is acceptable.
`
`
`
`
`
`
`The 500 mg and 1000—mg tablets can be approved.
`
`
`
`
`Signed:
`
`
`Medical Reviewer: Robert I Misbin MD
`
`Date: Feb 20, 2004
`
`Medical Team Leader:
`
`Date:
`
`
`
`

`

`Comments on Sponsor’s Response to Approvable Letter:
`Labeling changes
`
`Original Review:
`
`Executive Summary
`
`I.
`
`II
`
`Recommendations
`
`Summary of Clinical Findings
`
`Review:
`
`I
`
`Introduction and Background
`
`II
`
`III
`
`IV
`
`Clinically relevant findings from other disciplines
`
`Pharmocokinetic and Pharmacodynamics
`
`Description of Clinical Sources
`
`V
`
`Clinical Review Methods:
`
`Debarment/financial conflict
`
`VI
`
`Review of Efficacy:
`Discussion of efficacy
`
`VII
`
`Review of Safety
`
`VIII Dosing and Administration Issues
`
`IX
`
`Use in Special Populations
`
`Conclusions and Recommendations
`
`18
`
`19
`
`19
`
`20
`
`

`

`Comments on Sponsor’s Response to Approvable Letter
`
`FDA issued an approvable letter on October 17, 2003. The major deficiency was failure
`to have demonstrated bioequivalence between the 500 mg and 1000 mg tablets. The need
`for changes in the proposed label was also cited.
`
`In the submission of Dec 19, 2003, the Sponsor submitted new data that establish
`equivalency (2x 500mg=lx1000mg) of the 500 mg and 1000 mg tablets. Appropropiate
`labeling changes were made but additional changes were still needed. The NDA could be
`approved assuming the label were revised as described below:
`
`Request for Changes to Label of Dec 19:
`
`Changes should be made to table 4 and accompanying text proposed by Dr Sahlroot. In
`addition, the following statement under Table 4
`
`should be removed entirely or revised to state:
`
`“Results ofthis study also indicated that neither Fortamet nor immediate release
`metformin were associated with weight gain or increase in body mass index”
`
`Tables 5 and _6 and accompanying text should be removed.
`
`Q4 in the PPI should be revised to read:
`
`“Fortamet, as well as otherformulations ofmetformin, lowers the amount ofsugar in
`your blood. ..etc... ”
`i
`
`The following statement under “Recommended Dosing Schedule” should be removed:
`
`E
`
`'
`
`1
`
`Regulatory statement: The final label, dated February 18, 2004, is
`acceptable. The NDA can be approved.
`'
`
`

`

`Review of Original NDA (review date October 14, 2003)
`
`Executive Summary
`
`I
`
`Recommendations:
`
`The efficacy of Metformin XT given once daily is close enough to that of Glucophage
`twice daily, that the two treatment regimens can probably be used interchangeably in
`most patients. This shortcoming of Metformin XT is potentially offset by the
`convenience of once a‘day dosing. The safety profile of Metformin XT and Glucophage
`are similar. Because dose equivalency (2x 500mg=1x1000mg) has not been established,
`only the 1000 mg tablet should be approved at present
`
`II
`
`I Summary of Clinical Findings
`
`, Metformin XT is a long acting preparation of metformin to be marketed under the trade
`name, Fortamet. It was designed to be given once daily and achieve the same glucose
`control as immediate release Metfonnin given twice daily. The Sponsor performed three
`phase 3 trials. Two of these were comparisons to immediate release Metformin
`(Glucophage) and the third was a placebo—controlled study.
`
`Study 301 was designed to demonstrate the non—inferiority of Fortamet given once daily
`at dinner to Glucophage give twice daily in patient who had been taking Glucophage for
`at least 12 weeks. As shown in the table, mean HbAlc rose in both groups. Using a non—
`inferiority margin of 0.4% units for change in HbAlc,_ Fortamet was non—inferior to
`Glucophage with respect to maintaining glucose control. The safety/tolerability profile of
`Fortamet and Glucophage were similar.
`
`'
`Mean HbAlc study 301.
`
`Change
`N (ITT)
`Baseline
`Endpoint
`313
`7.02
`7.42
`0.40
`322
`7.08 ———
`
`Met XT
`Glucophage
`
`'
`
`Difference
`
`' Study 302 was done to study safety. Its design was similar to study 301 except that there
`was a forced to titration to 2000 mg or 2500 mg (the maximal labeled dose of
`metformin). As was the case with trial 301, mean HbAlc levels rose somewhat but the
`rise was similar on both drugs (see table below).
`
` Metfonnin XT Glucophage N=
`
`Mean
`7.51
`7.70
`0.19
`7.351
`7.385
`0.33
`
`49
`
`49
`
`49
`
`53
`
`

`

`The Sponsor was asked to perform an analysis of change in HbAlc in the subset of
`patients who were naive to treatment. The purpose of this analysis was to isolate the
`glucose-lowering affect of study drug from changes in dosing of concomitant antidiabetic
`medications. As shown in the table below, Metformin XT was about as effective as
`Glucophage in reducing HbAlc.
`
`HbAlc:
`
`Treatment—naive Patients, ITT
`
`Metformin XT n=11 Glucophage n=11
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Study 303 was a four month, double—blind, placebo—controlled trial in patients who were
`na‘1‘ve to pharmacologic treatment or had been off antidiabetic medication at least 8
`weeks. As shown in the table below, the placebo subtracted LS mean change for HbAlc
`in the ITT population was —0.78 (p=0.028).
`
`
`Change in HbAlc baseline to endpoint ITT
`
`
`Treatment
`N
`Baseline, mean
`Endpoint, mean
`
`
`—1.26
`Metformin XT
`19
`8.54
`7.28
`
`—O.43
`Placebo
`I
`33
`8.65
`8.23
`
`
`
`
`
`
`
`The safety/tolerability profile of Metformin XT was similar to what has been found with
`immediate release metformin.
`
`

`

`I
`
`Introduction and Background
`
`Metformin (Glucophage) has been available in the USA since 1995 and is generally
`considered the treatment of choice for obese patients with type 2 diabetes. It can be used
`as monotherapy or in combination with other antidiabetic agents including insulin.
`
`Metformin (Glucophage) is given twice or three times per day in doses ranging from 500
`mg bid to 850 mg tid. Gastrointestinal discomfort occurs early in treatment and is the
`major limiting factor in dose escalation. Most patients can tolerate or become tolerant to
`the gastrointestinal AE’s of metformin. A regimen of 1000 mg bid is common.
`Glucophage is marketed as 500 mg, 850 mg and 1000 mg tablets. Generic metformin is
`also available.
`
`Glucophage XR is a once a day preparation of metformin. It is marketed as 500 mg and
`750 mg tablets. The maximum recommended dose of Glucopage XR is 2000 mg once
`daily with the evening meal.
`
`Metformin XT is a long acting preparation of metformin to be marketed under the trade
`name, Fortamet. It was designed to be given once daily and achieve the same glucose
`control as immediate release Metformin given twice daily. The Sponsor performed three
`phase 3 trials. Two of these Were comparisonsto immediate release Metformin
`(Glucophage) and the third was a placebo-controlled study.
`
`II
`
`Clinically relevant findings from review from other disciplines
`
`Commenting on the efficacy results (HbAlc reduction) from trial 303, the statistical
`reviewer, Dr Todd Sahlroot, notes:
`
`“Because the lower bound of the CI for the mean difference excluded zero, XT was also
`statistically inferior to Glucophage (p<0.0001) in addition to being clinically non—
`- inferior”.
`
`This result arises from the use of a non—inferiority margin of 0.4%-for the change in
`HbAlc.
`
`Dr Sahlroot noted that dropouts due to “lack of efficacy” were 5% of XT patients
`compared to 2% of Glucophage patients (p=0.047)
`
`Dr Sahlroot also questions the “assay sensitivity” of the trial, noting that mean HbAlc
`levels rose from baseline to endpoint in both treatment arms.
`
`These issues are dealt with in the “Discussion of efficacy” section of this review.
`
`

`

`III
`
`Pharmocokinetic and Pharmacodynamics Issues:
`
`There are two major PK issues:
`
`The dosage equivalence between the 500 mg and 1000 mg tablets has not been
`established for the phase 3 and commercial formulations. Indeed, the dose equivalence
`study of the pilot lot failed.
`
`The PK/relative bioavailability information in the proposed label was derived from
`studies using the pilot lot and the pilot lots and phase 3 lots were not bioequivalent.
`
`These problems are discussed in Dr Wei’s review. From a clinical perspective, I offer the
`following comments:
`
`Fortamet given once daily is nearly as effective as Glucophage given twice daily. Both
`preparations of Metformin (Glucophage and Fortamet) show decreasing absorption with
`increasing dose. This explains, in my judgment, why 1000 mg of Glucophage given
`twice daily is somewhat more effective than 2000 mg of Fortamet given once daily.
`
`The efficacy of the 1000 mg dose of Fortamet has been established by the clinical trials.
`But the efficacy of the 500 mg dose of Fortamet has not established by the clinical trials.
`The 500 mg tablet was always given along with one or two 1000 mg tablets. Given the
`size of the trials, and variability of response, one cannot expect to distinguish 1000 mg
`from 1500 mg or 2000 mg from 2500 mg. The 500 mg tablet was never used alone.
`Therefore, its efficacy has not been established.
`
`Appears This Way
`On Original
`
`

`

`I IV
`
`Description of Clinical Sources
`(See clinical review)
`
`V
`
`Clinical Review Methods:
`
`The review was conducted of the hard copy of the summary of the NDA with reference to
`other documents that had been submitted electronically No routine inspections of the
`sites were performed. Although the consent documents were not reviewed, the trials
`appears to have been conducted in accordance with acceptable ethical standards. The
`escape criteria for lack of efficacy are praiseworthy. The financial disclosure
`documentation appears adequate.
`
`Regulatory statements regarding documents reviewed:
`
`The Sponsor, Andrx Labs submitted debarrnent and financial disclosure documents. The
`documents are signed by Nicholas Farina, Vice President of Andrx Labs on 11/20/02. I
`have examined these documents and found them to be acceptable. The debarment
`statement indicated that the Andrx Labs did not and will use the services of any
`individual or organization that had been debarred.
`
`The Sponsor makes reference to FDA form 3455. The following financial disclosure
`information has been submitted:
`
`Form OMB No. 0910-0396. The applicant certifies that Andrx Labs has not
`1
`entered into any financial arrangement with the clinical investigators named in the lists
`included in the NDA whereby the value of compensation to the investigator could be
`affected by the outcome of the study.
`2
`The applicant furthers certifies that none of the listed clinical investigators
`disclosed a proprietagl interest in the product or an equity interest in Andrx Labs
`3
`The applicant certifies that no listed investigator was the recipient of other
`payments such as honoraria, consultation fees, research grants, or compensation in the .
`form of equipment from Andrx Labs.
`4
`List of investigators from whom completed financial disclosure forms were
`received.
`
`Appears This WGY
`On Original
`
`

`

`VI
`
`Review of Efficacy
`
`Study 301
`
`This wasa double-blind study to evaluate Metformin XT once daily vs Glucophage twice
`daily in patients with type 2 diabetes who had previously been taking Metformin. A
`double-dummy design was used to maintain the blind so that each patient received both
`active drug and placebo for the alternative medication. Metformin XT (or placebo) was
`given once daily at about 6:00 PM before dinner. Glucophage (or placebo) was given at
`about 8:00 am before breakfast and 6:00 pm. Eligible patients were to have been on a
`stable dose of Metformin for at least 12 weeks. For the first 6 weeks, the dose of study
`medication was titrated to achieve a FPG of 140 mg/dl. For the last 20 weeks the dose
`was kept constant. Other antidiabetic medications could be continued during the trial at
`their pre—trial dose.
`
`Inclusion criteria: Patients had type 2 diabetes, 30—70 years of age on a fixed dose of
`Glucophage 850 to 2550 mg/d for at least 12 weeks. At visit 1 (screening), HbAlc was
`9% or less, FPG< 230 mg/dl. Difference in FPG between visits 1 and 2 could not exceed
`20% of the higher value. In addition to the standard exclusion criteria, patients could not
`be using a glitazone in combination with metformin.
`
`Dosing: Randomization and dosing began at visit 3 (2 weeks after screening). Dosing was
`initiated based on the previous dose of metformin and the FPG. The dose was titrated in
`an attempt to achieve a FPG of 140 mg/dl. The minimal dose was 1000 mg/d and the
`maximal dose was 2500. Study medications were administered as 500 mg or 1000 mg
`tablets or matching placebos. Doses of 1000 mg and 2000 mg were given as 1x or 2x
`1000 mg tablets. The dose of 1500 mg or 2500 mg were achieved by adding a single 500
`mg tablet. No change in study medication dose was allowed beyond week 6.
`
`Hypothesis and level of significance: The study was designed to support approval for
`Metformin XT with the same indications as Glucophage. Metformin XT was required to
`pass a non—inferiority test vs Glucophage using HbAlc,with a non-inferiority margin or
`0.4 and 80% power.
`
`Disposition:
`
`680 patients were randomized. 263/339 (77.6%) of patients randomized to Metformin XT
`completed the trial compared to 292/341 (84.2%) of patients randomized to Glucophage.
`18/339 (5.3%) of patients randomized to Metformin XT withdrew because of “lack of
`efficacy” Compared to 8/341 (2.3%) of patients randomized to Glucophage.
`
`

`

`Demography:
`
`Patients were 59% male, 75% white, 14% Hispanic and 9% black. The mean age was
`about 57 years. The mean weight was about 95kg, mean BMI 31.4 The distribution of
`metformin dose at randomization was < 1500 mg (33%), 1500—<2000mg (19%), 2000 mg
`or more (48%). Approximately 50% of patients were using insulin secretagogues(mainly
`Glyburide and Glipizide). Approximate 7% were using insulin. Approximately 40% were
`using lipid-lowering drugs or ACE inhibitors. About 16 % were using beta blockers.
`The two arms appeared to be well matched with respect to demographic characteristics.
`
`The dose of study medication at the end of the titration period is in the following table:
`% of all randomized patients
`Metformin XT
`Glucophage
`
`Final dose
`
`
`
`
`
`
`
`The average final dose was 2119 for Met XT and 2126 for Glucophage. The mean change
`from baseline was 443 for Metformin XT and 467 for Glucophage.
`
`Result:
`
`Mean HbAlc
`
`Difference
`N (ITT)
`Baseline
`Endpoint
`Change
`
`3—13
`742
`0.40
`Met XT
`
`_lucophage_22 7. 08 0.13 721 .
`
`
`From the table shown above, it appears that Met XT and Glucophage were approximate
`the same in maintaining HbAlc levels. Values rose slightly in both groups. Based on a
`non—inferiority margin of 0.4%, Met XT passed a test of non—inferiority but only barely.
`- The upper limit of the 97.5% CI for the difference in HbAlc at endpoint is 0.385.
`
`The change in HbAlc based on baseline dose is displayed in the follOwing table. Not
`unexpectedly,patients taking larger doses of drug at baseline had higher HbAlc levels
`and the increase at endpoint tended to be greater as well. One notes however, that the rise
`in HbAlc in patients on Glucophage did not occur in patients taking less than 2000mg
`per day. By contrast, the rise in HbAlc occurred at all dose levels for patients taking
`Metformin XT, although it was greatest at the highest dose level.
`
`Metformin XT
`Glucophage
`7.14
`0.29
`
`6.95
`
`
`7.47
`
`7.07
`0.26
`7.09
`
`7.57
`0.45
`7.08
`
`8.09
`0.70
`
`10
`
`

`

`As shown in the table that follows the result using the per protocol population was largely
`the same as with the ITT population. For the per protocol population, the upper limit of
`the 97.5% CI for the difference in HbAlc at endpoint is 0.300
`
`
`EndpointN(per protocol) Baseline Difference . Change
`
`
`
` Glucophage
`
`Mean HbAlc
`
`In the ITT population, the mean FPG at baseline was about 146 mg/dl in both groups. It
`rose at endpoint by 10.0 mg/dl with Metformin XT and 4.2 mg/dl with Glucophage. The
`difference of the LS mean increase wass 6.43 mg/dl ( 95% CI 06—122). The p value for
`this difference is 0.03
`
`In the ITT population, the mean fructosamine at baseline was about 290 umol/L in both
`groups.
`It rose at endpoint by 16.9 with Metformin XT and 2.3 with Glucophage. The
`difference of the LS mean increase was 15.5 ( 95% CI 9.6—21 .4). The p value for this
`difference is 0.0001
`
`Mean fasting plasma insulin levels were about 17.5 uU/ml at baseline and fell about 3.5
`uU/ml in both groups. In the PP population, the mean FPG at baseline was about 145
`mg/dl in both groups.
`It rose at endpoint by 6.0 mg/dl with Metformin XT and 2.9 mg/dl
`with Glucophage. The difference of the LS mean increase wass 3.04 mg/dl ( 95% CI —
`2.7, 8.8).
`
`In the PP population, the mean fructosamine at baseline was about 289 umol/L in both
`groups.
`It rose at endpoint by 11.6 with Metformin XT and 2.1 with Glucophage. The
`difference ofthe LS mean increase was 15.5 (95% CI 3.8, 15.7).
`
`Mean body weight at baseline was about 94 kg. The change was +0.3 kg ( 95% CI 0.0,
`0.6) for Metformin XT and 0.0 kg for Glucophage. BMI was about 31.2. The change was
`+0.1( 95% CI 0.0, 0.2) for Metformin XT and 0.0 for Glucophage.
`
`Lipid levels changed little during the trial. The only value possibly worth noting is a rise
`in triglyceride from 199 to 246 in patients on Metformin XT. In patients on Glucophage,
`mean triglyceride levels remained unchanged at 200 mg/dl.
`
`11
`
`

`

`Study 302 — To compare the tolerability and safety of 2000 mg and 2500 mg
`Metformin XT given once daily to the same dose of Glucophage given twice daily.
`
`This was a double-blind study to evaluate Metformin XT once daily vs Glucophage twice
`daily when given in doses of 2000 mg or 2500 mg per day. A double-dummy design was
`used to maintain the blind so that each patients, received both active drug and placebo for
`the alternative medication. Metformin XT (or placebo) was given once daily at about
`6:00 pm before dinner. Glucophage (or placebo) was given at about 8:00 am before
`breakfast and 6:00 pm. “Patients were assigned to either 2000mg or 2500mg as needed
`inorder to achieve at least 100 in each of these high dose groups between the two
`protocols ( 301 and 302)”. 56 patients were randomized to Metformin XT and 59 were
`randomized to Glucophage.
`
`Patients on 1000 mg or less of metformin received 1000 mg initially which was increased
`to the assigned 2000 or 2500 mg at the rate of 500 mg per week. Patients on 2000 mg or
`more received their assigned dose of 2000 mg or 2500 mg initially and throughout.
`Patients on between 1000-2000 mg received 1500-2000mg initially which was increased
`to the assigned 2000 or 2500 mg. During the first 4 weeks, the dose of any concomitant
`antidiabetic medication was adjusted at the discretion of the investigator inorder to allow _
`for the “protocol—driven” increases to the assigned dose of either 2000 or 2500mg.
`
`Inclusion criteria: Patients had type 2 diabetes, 30—70 years of age HbAlc was 9% or less,
`FPG< 230 mg/dl.
`
`Statistics: The study was designed to compare the safety of high dose Metformin XT
`with the same dose as Glucophage. There was no power calculation
`
`Demography:
`
`Patients were about 67% male, 63% white, 23% Hispanic and 13% black. The mean age
`was about 55 years. The mean weight was about 93kg, mean BMI 31. 68% of patients
`on Metformin XT and 78% on Glucophage were using insulin secretagogs (mainly
`Glyburide and Glipizide). Approximate 15% were using insulin. 14/56 patients
`randomized to Metformin XT and 11/59 patients randomized to Glucophage were
`receiving no antidiabetic medications. 78% of patients randomized to Metformin XT and
`70% of patients randomized to Glucophage had no change in their concomitant
`antidiabetic medications during the trial (this includes the patients who were taking no
`antidiabetic medications other than study drugs). Of the patients who did have changes in
`their other medications, there appeared to be no difference between the two arms with
`respect to adding new medications, dropping old ones, or changes in dose.
`
`12
`
`

`

`Results:
`
`As shown in the table below, HbAlc values tended to rise over the study but there was no
`difference between Metformin XT and Glucophage. This result was mirrored in change
`in FPG, which rose 14 mg/dl in both groups, 152 mg/dl to 166 mg/dl for Metforrnin XT
`(p=0.02), and 150 to 164 (p=0.02) for Glucophage.
`
`Metforrnin XT
`Glucophage
`
`
`19
`19
`29
`29
`29
`
`7.78
`0.52
`7.57
`7.67
`0.10
`
`
`
`
`
`
`30
`30
`24
`24
`24
`
`
`7.33
`-0.02
`7.45
`8.06
`0.61
`
`49
`49
`53
`53
`53
`7.51
`0.19*
`7.51
`7.85
`0.33**
`
`**p=0.02
`
`Mean body weight rose 0.5 kg with metformin XT (NS) and 1.3kg (p=0.007) for
`Glucophage. Mean BMI rose 0.2 with metformin XT (NS) and 0.5 (p=0.002) for
`Glucophage. Changes in serum lipids were small and there were no differences between
`the two arms.
`
`The Sponsor was asked to perform an analysis of change in HbAlc in the subset of
`patients who were naive to treatment. The purpose of this analysis was to isolate the
`glucose-lowering affect of study drug from changes in dosing of concomitant antidiabetic
`medications. As shown in the table below, Metformin XT was at least as effective as
`Glucophage in reducing HbAlc.
`
`Treatment-naive Patients, ITT
`
`Metformin XT n=11
`Glucophage n=11
`
`
`4
`4
`6
`6
`
`8.30
`7.60
`7.92
`7.40
`
`
`
`7
`7
`5
`5
`
`6.83
`6 36
`7.36
`7.28
`
`
`
`
`
`
`
`
`
`11
`11
`11
`11
`
`7.36
`6 81
`7.66
`7.35
`
`l3
`
`

`

`Study 303 — Placebo-controlled trial
`
`This was a 4 month trial to compare maximum dose Metformin XT to placebo in patients
`with type 2 diabetes who were naive to treatment or had been off antidiabetic mediations
`at least 8 weeks. To be randomized, eligible patients had to have HbAlc at visit 1 of
`7.5% or greater and FPG 150-240 mg/dl. Dosing began with one 1000—mg tablet given
`with the evening meal. The dose was increased by 500 mg weekly until the maximal dose
`of 2500mg (2x 1000 mg tablet plus 500mg tablet) was achieved. Patients who could not
`tolerate 2500 mg were allowed to drop back to 2000 mg and then to 1500 mg. Patients
`who could not tolerate 1500 mg by week four were withdrawn. Study drugs were 500 mg
`and 1000mg tablets of metformin XR or matching placebo, all doses given once daily
`Immediately after the evening meal.
`‘
`
`At week 8 and beyond patients were withdrawn if:
`
`FPG>200 mg/dl with <20mg/dl fall from baseline
`
`or if HbAlc>1 1% at any time.
`
`Of randomized patients, 55% were male, 64% white, 18% black and 18% Hispanic. The
`mean age was 56 years, mean weight 87 kg, mean BMI 30%. The maximum tolerated
`dose was 2500 mg for 64% of Metformin XR patients and 94% of placebo patients, 2000
`mg and 1500 mg for 9% and 14% of Metformin XR patients. Missing information
`accounted for 14% of Metformin XR patients and 6% of placebo patients.
`
`Results
`
`Change inéHbAlc:
`
`As shown in the table below, the placebo subtracted LS mean change for HbAlc in the
`ITT population was —0.78 (p=0.028).
`
`.
`
`
`
`Change in HbAlc baseline to endpoint ITT
`I Treatment
`N
`Baseline, mean
`
`
`Endpoint, mean Change
`
`Metformin XT
`l9
`8.54
`,
`
`Placebo
`33
`8.65
`
`
`
`For the per protocol population, the placebo subtracted LS mean change for HbAlc was
`—0.76 (p=0.028).
`
`Change in HbAlc baseline to endpoint per—protocol
`
`Treatment
`N
`Baseline, mean
`Endpoint, mean Change
`Metformin XT
`16
`8.41
`7.24
`—1.17
`
`
`
`
`
`27 8.66 8.23Placebo —0.43
`
`14
`
`

`

`Of 22 patients randomized to Metforrnin XR, one patient (4%) withdrew because of lack
`of efficacy. Of 34 patients randomized to placebo, 12 patients (35%) withdrew because
`of lack of efficacy. There was a statistically significant difference (p=0.0087) in the
`distribution of time to discontinuation due to lack of therapeutic respbnse between the
`two groups.
`
`Changes in other efficacy measures for the ITT population are shown in the tables below:
`
`
` Fasting Plasma
`
`
`
`Glucose, mg/dl
`
`Metformin XT
`
`-39 (p=0.026)
`Placebo
`
`
`Fasting Plasma
`
`
`Insulin uU/ml
`
`Metformin XT
`
`
`-1.1 (NS)
`13
`
` Fructosamine,
`
`
`umol/L
`
`
`
`
`
`
`—44 (p=0.036)
`
`
`
`
`
`Metformin XT
`
`Placebo
`
`Lipid Parameters
`
`
`
`353
`
`374
`
`Baseline, mean
`
`Endpoint
`
`Percent Change
`Mean
`1 Median
`
`Cholesterol,
`
`
`
`mg/dl
`Metformin XT
`
`
`
`209
`
`
`212
`
`265
`
`
`
`15
`
`116
`Metformin XT
`
`Placebo
`129
`
`
`
`HDL,
`cholesterol
`
`Metforrnin XT
`
`46
`
`
`
`Placebo
`223
`
`
`
`
`LDL,
`cholesterol
`
`
`
`Placebo
`51
`
`
`
`Triglycerode,
`mg/dl
`
`Metformin XT
`
`Placebo
`
`
`

`

`
`Change in Body Weight, baseline to endpoint ITT
`Treatment
`Baseline, mean
`Metformin XT
`
`
`
`
`
`
`-0.7
`81.0
`
`
`
`
`
`
`
`
`Appears This Way
`On Original
`
`

`

`Discussion of Efficacy:
`
`Fortamet (Metformin XT) was developed to be used in place of Glucophage with the
`advantage that it requires only once a day dosing. Given that the Sponsor proposes to
`duplicate most of the text of the Glucophage label, it is reasonable to require that
`Metforrnin XT be therapeutically equivalent to Glucophage. The pivotal trial, trial 301,
`showed that Metformin XT was non-inferior to Glucophage based on the pre—specified
`method of statistical analysis, using a non-inferiority margin of 0.4% for HbAlc
`reduction. However, a direct comparison of the mean changes showed that Metforrnin XT
`was inferior statistically to Glucophage. Thus, the choice of a nOn—inferiority margin of
`0.4% was critical.
`
`It would be incorrect to conclude that FDA considers a difference of 0.4% units in
`HbAlc to be clinically insignificant. The non—inferiority margin of 0.4% units can be
`justified as follows:
`
`1
`
`2
`
`3
`
`FDA considers two formulations of the same drug to be bioequivalent if the
`confidence intervals of the relative bioavailability falls between 80-125%. The
`relative bioequivalence need not be 100%. In other words, if B is less bioavailable
`than A, but the confidence interval of the difference does not exceed 20%, B is
`close enough to A to be considered bioequivalent.
`Use of metformin monotherapy in patients with untreated diabetes has generally
`resulted in a reduction in HbAlc of about 2% units.
`
`The non-inferiority margin of 0.4% units can arise from combining the
`information in #1 and #2:
`20% x 2% units = 0.4% units
`In other words, if
`one formulation of metformin could be expected to lower HbAlc from 9% to 7%
`(reduction of 2 % units), a second preparation would be approvable, if it were
`expected to lower HbAlc from 9% to <7.4 (reduction of >1.6% units).*
`
`* per Dr Sahlroot — The actual mean reduction would be greater than 1.6% units since the mean treatment
`difference in the change from baseline must be sufficiently smaller than 0.4% so that the upper bound of
`the 95% CI for the difference does not exceed 0.4%.
`
`Metformin XT might not be quite as efficacious as Glucophage, but it is close enough to
`be useful clinically, particularly because it requires less frequent dosing. However, this
`reasoning is open to challenge. Unlike the situation cited above (reduction by metformin
`in HbAlc from 9% to 7%), the mean HbAlc levels in trial 301 actually rose in both arms.
`This observation led Dr Sahlroot to question the assay sensitivity of the trial. His point is
`well taken. How can one be sure that the patients in this trial were responsive to
`metformin at all? What is the evidence that Metforrnin XT can actually lower HbAlc
`levels?
`
`’ This problem is solved at least partially by consideration of data from trials 302 in which
`Metformin XT lowered HbAlc levels in the treatment-naive patients to at least the same
`extent as did Glucophage. However, there were very few naive patients in this trial so the
`power to detect a difference is small.
`
`17
`
`

`

`Addition data comes from the four month placebo controlled trial 303. This trial showed
`that Fortamet reduced mean HbAlc levels from 8.54% to 7.28% compared to a reduction
`from 8.65 to 8.23% for placebo.
`'
`
`When all the efficacy data are taken together, I believe the Sponsor has shown that
`FOrtamet is effective in lowering HbAlc levels and that the efficacy of Fortamet given
`once daily is close enough to that of Glucophage twice daily, that the two treatment
`regimens can probably be used interchangeably in most patients. The most meaningful
`way to note the difference is that 2% of patients on Glucophage in trial 301 withdrew
`because of “lack of efficaCy” compared to 5% of Fortamet ( p=0.047).
`
`V11
`
`Review of Safety:
`
`Study 301:
`
`One patient on Metformin XT died. This patient had an incarcerated umbilical hernia on
`day 135, developed pneumonia and died. A serious AE was reported by 5.1% of patients
`on Metformin XT and 4.7% on Glucophage. Withdrawals due to AE occurred in 5.1% of
`patients on Metformin XT and 4.5% of patients on Glucophage. In 6/17 patients on
`Metformin XT and 10/15 Glucophage, the withdrawals were due to gastrointestinal
`complaints thought to be possible related to study drug.
`
`Treatment—emergent signs and symptoms were reported by 74% of patients on Metformin
`XT and 73.6% of patients on Glucophage. Complaints in the gastrointestinal system were
`33.4% (diarrhea 16.7%) on Metformin XT and 30.6 (diarrhea 13.1%) on Glucophage.
`6/335 of patients on Glucophage XT experienced hypoglycemia and 7/337 on
`Glucophage. All but one in each arm was taking other antidiabetic agents in addition to
`study drug. One patient (028—032) on Metformin XT was withdrawn because of
`hypoglycemia.
`
`Study 302:
`
`One patient on Metformin XT died. The patient had a long history of coronary artery
`disease and was found unresponsive one morning. Treatment—emergent signs and
`symptoms were reported by 80% of patients on Metformin XT and 66% on Glucophage.
`Complaints in the gastrointestinal system were reported in 17/54 (31%) with Metformin
`XT and 14/59(14%) of patients on Glucophage. Diarrhea was reported in 10/54 (19%)
`with Metformin XT and 6/59(10%) of patients on Glucophage. Complaints in the
`gastrointestinal system led to no withdrawals from Metformin XT and 3 withdrawals
`from Glucophage.
`
`18
`
`

`

`Study 303:
`
`There were no deaths or drug-realted SAE’s. About 10% of patients in each. group
`withdrew because of AE’s that were thought to be possibly drug related. There were two
`patients in each group that withdrew because of gastrointestinal complaints. Inthe two
`Metformin XT patients the complaints were diarrhea and flatulence. In the two placebo
`patients the complaints were diarrhea and “stomach” cramps. Gastrointestinal complaints
`were reported in 13/21 (62%) patients on Metformin XT compared to 9/34 (27%) patients
`on placebo. Mean hematocrit fell from 44.9 to 43.5 in patients on metformin XT and
`remained unchanged at 42.9 in patients on placebo.
`
`A 120 day safety update submitted April 16, 2003 contains no information that would
`affect the labeling or use of this product.
`
`VIII Dosing and Administration Issues
`
`The label recapitulates the safety and efficacy data from the Glucophage label. This is
`acceptable because the clinical studies have demonstrated that Fortamet and Glucophage
`are therapeutically equivalent or nearly so. Suggested changes for the label are given in
`an appendix to be communicated to the Sponsor. Of particular importance is the
`suggestion by Dr Sahlroot that the greater withdrawal rate for “lack of efficacy” be
`communicated in the label.
`
`Laura Pincock of DDMAC has suggested several changes be made in the PPI. I have
`included these in an apprendix — “To be communicated to the Sponsor”
`
`IX
`
`Use in Special Populations — No issues pertain
`
`Appears This Way
`On Original
`
`19
`
`

`

`X
`
`Conclusions and Recommendations:
`
`The efficacy of Metformin XT given once daily is close enough to that of Glucophage
`twice daily, that the two treatment regimens can probably be used interchangeably in
`most patients. To the extent that Glucophage may be slightly more effective that
`Metformin XT, patients may be able to compensate by increasing the dose of Metformin
`XT. This shortcoming of Metformin XT is potentially offset by the convenience of once a
`day dosing. The safety profile of Metformin XT and Glucophage are similar.
`
`The application contains serious deficiencies regarding biophannacy issues. Among these
`is lack of a dose—equivalency study (2x 500mg = I