CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICA TI0N NUMBER:
`
`50-805
`
`MICROBIOLOGY REVIEW
`
`

`

`Oracea
`
`Clinical Microbiology Review
`DIVISION OF ANTI—INFECTIVE AND OPHTHALMOLOGY
`
`PRODUCTS (DAIOP)
`CLINICAL MICROBIOLOGY REVIEW
`CONSULTATION FOR HFD 540
`
`NDA 50—805
`
`Date Review Completed: May 15, 2006
`
`Date Company Submitted: 29 July 2005
`Dare Received (HFD520): 3 August 2005
`Date Assigned: 10 August 2005
`Date Completed: 13 January 2006
`Reviewer: Connie R. Mahon, MS & Avery Goodwin, Ph.D.
`
`NAME AND ADDRESS OF APPLICANT:
`
`Collagenex Pharmaceuticals, Inc.
`41 University Dr Suite 200
`Newtown, PA 18940
`215—579—7388
`
`CONTACT PERSON:
`
`Christopher Powala
`Vice President, Drug Development & Regulatory Affairs
`
`DRUG PRODUCT NAME:
`
`Established Name: Doxycycline f“ :apsules
`Proposed Name for drug product: OraceaTM
`Product Code. COL— 101
`
`Chemical Name: alpha—6—deoxy—5——oxytetracyeline
`Chemical formula: C22H24N208 H20
`
`Molecular Weight: 462.46 .
`
`PROPOSED INDICATION:
`
`T0 .4— ‘inflammatory lesions in patients with rosacea
`
`PROPOSED DOSAGE FORMl DOSAGE2 STRENGTH, ROUTE OF
`ADMINISTRATION:
`‘
`
`40 mg oral 1
`
`capsule taken once daily.
`
`
`
`DURATION OF TREATMENT:
`
`Duration of treatment: 16 weeks
`
`TYPE OF SUBMISSION:
`
`

`

`Oracea
`
`Clinical Microbiology Review
`DIVISION OF ANTI-INFECTIVE AND OPHTHALMOLOGY
`
`PRODUCTS (DAIOP)
`,,
`CLINICAL MICROBIOLOGY REVIEW
`
`CONSULTATION FOR HFD 540
`
`NDA 50—805
`
`Date Review Completed: May 15, 2006
`
`Microbiology Review Consult for HFD 540
`
`RELATED SUBMISSION:
`
`IND 67,833 8/021
`
`PURPOSE OF SUBMISSION:
`
`The Applicant, Collagenex Pharmaceuticals, Inc. submits an original new drug
`application (NDA 50—805) for OraceaTM for oral administration to
`‘.—'
`inflammatory
`lesions in patients with rosacea. OraceaTM is doxycycline
`’—-—-
`, which is
`synthetically derived from oxytetracycline. The dosage form is 40 mg
`9"“—
`capsule. OraceaTM is to be taken once daily in the morning.
`
`The Division of Dermatologic and Dental Drug Products has requested a review and
`assessment of the proposed clinical microbiology subsection of the package insert.
`
`SUMMARY AND RECOMMENDATIONS
`
`Collagenex Pharmaceutical has submitteda new drug application (NDA 50—805) for
`OraceaTM for oral administration to
`...._, inflammatory lesions in patients with rosacea.
`OraceaTM is doxycycline ‘ "f‘e‘f which is synthetically derived from
`
`oxytetracycline. The dosage form is 40 mg
`capsule.
`
`From the clinical microbiology perspective, this NDA submission may be approved
`provided that the Applicant makes the appropriate changes to the microbiology section of
`the proposed label recommended by the Agency.
`
`The Microbiology Reviewer provides the following changes regarding the Microbiology
`section of the label for OraceaTM:
`
`AGENCY PROPOSED MICROBIOLOGY SECTION OF THE LABEL
`
`MICROBIOLOGY
`
`Doxycycline is a member of the tetracycline class ofantibacterial drugs. The plasma
`concentrations ofdoxycycline achieved with this product during administration (see
`CLINICAL PHARM‘ICOLOGY AND DOSAGE AND ADMINISTRATION) is less than
`the concentration required to treat bacterial diseases. In vivo microbiological studies
`utilizing a Similar drug exposure for up to J 8 months demonstrated no detectable long—
`term eflects on bacterialflora of the oral cavity, skin, intestinal tract, and vagina.
`
`[\‘D
`
`

`

`Oracea
`
`Clinical Microbiology Review
`DIVISION OF ANTI-INFECTIVE AND OPHTHALMOLOGY
`
`PRODUCTS (DAIOP)
`CLINICAL MICROBIOLOGY REVIEW
`CONSULTATION FOR HFD 540
`
`NDA 50-805
`
`.
`
`Date Review Completed: May 15, 2006
`
`TRADENAAAE should not be usedfor treating bacterial infections, providing
`antibacterial prophylaxis, or reducing the numbers or eliminating microorganisms
`associated with any bacterial disease.
`
`Under precautions it is suggested that the following be added:
`
`Bacterial resistance to the tetracyclines may develop in patients using TRADE NAME;
`
`
`WW
`
`Because ofthe potentialfor tetracycline—
`resistant bacteria to develop during the use of TRADE NAME, it should be used only as
`indicated.
`
`BACKGROUND INFORMATION
`
`Collagenex Pharmaceutical submits a new drug application that references NDA 50~744
`for Periostat (doxycycline hyclate) 20 mg capsules and NDA 50-783 for Periostat 20 mg
`tablets to demonstrate that doxycycline hyclate does not induce recognizable effect on the
`composition of the gingival flora or result in an increase in antibiotic resistance.
`.
`
`The Applicant proposes the name Oracea for the drug product (doxycycline __._’—
`capsules). Doxycycline x is synthetically derived from oxytetracycline. The
`proposed indication is to (a inflammatory lesions in patients with rosacea.
`
`
`
`is the International non—proprietary name (INN), US Adopted
`Doxycycline
`Name (USAN) and the British Approved Name (BAN) for the drug substance used1n
`
`OraceaTM doxycycline ...—--—~ V
`40 mg
`capsule. Thecapsule
`consists of instantaneous—release (IR) beads containing a total of 30 mg doxycycline and
`controlled release (CR) beads containing a total of 10 mg. The beads are filled into a hard
`gelatin capsule shell. (Section 27.241 page 194 NDA 50-805).
`
`With regard to clinical microbiology, the Applicant intends to use cross—study reports
`from previously submitted NDAs. The Applicant submits two microbiology studies that
`have assessed the effects of doxycycline hyclate 20mg BID dose regimen on microflora
`of the skin for review.
`
`The Sponsor plans to cross—reference previous studies that evaluated Periostat
`(doxycycline hyclate) 20 mg BID and demonstrated that a 9—18 month regimen of
`Periostat did not exert a discemable effect on the composition of the subgingival flora or
`resultin an increase in antibiotic resistance. The three microbiology studies to be cited by
`reference to NDA 50- 744 include:
`
`0
`
`Study 5732.11A: A 3 month, randomized, placebo-controlled clinical study to
`
`

`

`Oracea
`Clinical Microbiology Review
`DIVISION OF ANTI-INFECTIVE AND OPHTHALMOLOGY
`PRODUCTS (DAIOP)
`CLINICAL MICROBIOLOGY REVIEW
`,7
`CONSULTATION FOR HFD 540
`Date Review Completed: May 15, 2006
`
`NDA 50—805
`
`-
`
`evaluate the microbial effects of five dose regimens of doxycycline hyclate on
`
`a
`
`0
`
`,
`the oral cavity
`Study 5732.11 E&F: A 12 month, randomized, double—blind, placebo—
`controlled study to evaluate the microbial effects of 10 mg QD, 20 mg QD,
`and 20 mg BID of doxycycline hyclate on the oral cavity
`Study 5732.11 H: A 9 month, randomized, double-blind, placebo—controlled
`study to evaluate the microbial effects 20 mg BID of doxycycline hyclate on
`the oral cavity
`'
`
`For the COL— 101 NDA, the Sponsor plans to submit two microbioldgy studies for
`review:
`
`0
`
`a
`
`Study 5732.11 J2 A 9 month, randomized, double—blind, placebo—controlled
`study to evaluate the microbial effects 20 mg BID of doxycycline hyclate on
`the intestinal and vaginal flora
`Study DERM—301: A 6 month, randomized, double—blind, placebo—controlled
`study to determine the microbial effects 20 mg bid of doxycycline hyclate on
`the skin microflora
`
`In the draft product labeling, the Spenser proposes the following in the microbiology
`subsection and asks if the Agency agrees.
`‘
`
`”Microbiology: Doxycycline is a member ofthe tetracycline class ofantibiotics. The
`plasma concentration ofdoxycycline achieved With this product during administration is
`
`The Sponsor also proposes to include the following statements regarding the mechanism
`of action:
`
`\.
`
`INTRODUCTION
`
`

`

`Oracea
`Clinical Microbiology Review
`DIVISION OF ANTI—INFECTIVE AND OPHTHALMOLOGY
`PRODUCTS (D‘AIOP)
`CLINICAL MICROBIOLOGY REVIEW
`CONSULTATION FOR HFD 540
`
`NBA 50—805
`
`Date Review Completed: May 15, 2006
`
`ROSACEA
`
`Rosacea is a chronic condition characterized by transient or persistent central facial
`erythema, Visible blood vessels, and often papules and pustules. The principal subtypes
`of rosacea include erythematotelangiectatic rosacea, papulopustular rosacea, phymatous
`rosacea, and ocular rosacea]. Rosacea is a disease for which there is no laboratory
`benchmark test. Therefore, the diagnosis of rosacea is a clinical one; defined by
`recognizable morphologic characteristics (vascular in origin) which may lead to
`difficulties in interpretation. Despite an incomplete understanding of the pathogenesis of
`rosacea, therapeutic modality continues to expand. However, the exact causes of these
`manifestations are unknown.
`
`Rosacea usually occurs between the ages of 30 and 50 years and the disease is
`accompanied by chronic episodes with remissions and relapses2. The prevalence of
`rosacea was reported to be 14% in women and 5% in men. Exacerbating factors such as
`heat, alcohol, stress, certain medications, certain foods and sunlight has been identified
`by some individuals: Rosacea has also been anecdotally reported to be associated with
`Helicobacter pylori4 and DemodexS ,a common inhabitant of the normal human skin.
`
`Published studies have addressed the possible role of H. pylori as a causative agent for
`rosacea. However, there is no statisticallyisi6gnificant association between infection and
`acne rosacea. A study by Argenziano et al. evaluated patients with acne rosacea and
`found anti— H. pylori IgG antibodies1n 81% of the acne rosacea patients with dyspepsia
`and 16% of those without dyspeptic symptoms. Anti-CagA IgG, a marker for H. pylori
`infection, was found in 75% of the dyspeptic patients but in none of those without gastric
`symptoms. A correlation was proposed between the severity of rosacea and the presence
`of these antibodies, but the subgroup included only 18 patients and no statistical analysis
`was provided.
`
`The mite Demodexfolliculorum, part of the skin' 5 normal flora, has also been examined
`as a potential contributing factor to rosacea, but study results have been inconclusive?
`The mite Demoa’ex spp., belonging to the Class Arachnida, Order Acarina, lives around
`hair follicles (Demodexfolliculorum hominis) or in the secretory ducts of sebaceous (fat)
`glands connected to the hair follicles (Demodex brevis) of humans. The preferred sites are
`facial skin, forehead, cheeks, eyelashes and external ear channels. The size of demodices
`varies from 0.1 mm to 0.4 mm. Adult parasites have four pairs of short legs. They can
`slowly move on the skin especially during the night. In humans, the infestation is known
`as demodicosis‘ and occurs world—wide. The tendency for the clinical manifestations of
`rosacea to appear later in life parallels the increase Demodex mite density that occurs
`with age7. The infestation may be frequently free of symptoms. Inflammation in acute
`and chronic fonns may occur due to demodicosis in humans. Therapeutic agents that may
`
`

`

`Oracea
`Clinical Microbiology Review
`DIVISION OF ANTI-INFECTIVE AND OPHTHALMOLOGY
`
`PRODUCTS (DAIOP)
`CLINICAL MICROBIOLOGY REVIEW
`CONSULTATION FOR HFD 540
`
`NDA 50—805
`
`Date Review Completed: May 15, 2006
`
`be active against the organism include metronidazole, sulfur preparations, sulfacetamide
`sodium, and tetracycline7.
`
`MICROBIOLOGY STUDIES
`
`Study DERNI 301
`
`DERM 301 was a 6 month, randomized, double—blind placebo controlled study to
`determine the microbial effects of 20 mg BID of doxycycline hyclate on the skin
`microflora. The twice daily dosage at 20 mg was chosen since it resulted in a mean
`maximum and average steady—state plasma concentration of 0.79 ug/ml and 0.48 ug/ml
`respectively, after 1.5 hours. The study DERM 310 attempted to assess if treatment with
`subantimicrobial—dose (SD) doxycycline (20 mg tablets twice daily) improved clinical
`outcome but led to overgrowth or colonization of skin by opportunistic pathogens or
`resulted in an increase inantibiotic resistance by the surface skin microflora in patients
`with moderate acne compared with placebo.
`
`The study involved 51(N) adults with moderate facial acne. The patients were
`randomized to receive SD doxycycline or placebo twice daily for 6 months. The primary
`efficacy outcome measure was changes from baseline in numbers of inflammatory, non—
`inflammatory, and total lesions. Secondary efficacy outcome was changes from baseline
`of individual counts of papules, pustules and modules, and global assessments of clinical
`improvement by patient and physician.
`
`The microbiological objectives of the study were to determine whether twice daily SD
`doxycycline therapy 1) had any detectable antimicrobial effect on the normal flora 2) led
`to overgrowth or colonization of the skin by opportunistic pathogens 3) resulted in an
`increase in resistance in the predominant skin microflora.
`
`Microbiology Procedures
`
`The microbiology objectives of the study were to determine whether twice—daily
`doxycycline therapy had any detectable antimicrobial effect on the normal skin flora that
`led to overgrowth or colonization of the skin by opportunistic pathogens; or resulted in an
`increase in antibiotic resistance in the predominant skin microflora. ,Microbial samples of
`the surface of the skin were collected from a 2 cm2 area in the center of the brow at .
`
`baseline and after six (6) months of treatment. The sample was collected by placing a 2
`cm2 template, and gently rubbing a sterile cotton swab over the area. The swab was
`placed in a tube containing 1.0 mL of pre~reduced, anaerobically—sterilized Ringer
`solution and immediately transported to the laboratory for processing.
`
`Samples were plated on non—selective media to determine the total number of anaerobic
`
`

`

`Oracea
`
`Clinical Microbiology Review
`DIVISION OF ANTI-INFECTIVE AND OPHTHALMOLOGY
`
`PRODUCTS (DAIOP)
`CLINICAL MICROBIOLOGY REVIEW
`CONSULTATION FOR HFD 540
`
`NDA 50—805
`
`.
`
`Date Review Completed: May 15, 2006
`
`and facultative organisms were-determined from the plate dilutions that gave rise to 30 to
`300 colony forming units (CFUs). The fewer than 30 colonies on the most diluted plate,
`the actual number of colonies was counted.
`
`Doxycycline-resistant bacteria were detected by placing the sample on non-selective
`medium containing 4 ug/mL of doxycycline. The number of anaerobic bacteria and
`facultative bacteria resistant to at least 4 ug of doxycycline were determined and
`expressed as percentage of the total for each organism. Isolates were identified by genus
`and species whenever possible. Isolates were tested for susceptibility to determine the
`MIC required to inhibit visible growth on the agar medium. The MICSO and MICgo were
`calculated for all bacterial organisms for each group at each sample period. Susceptibility
`testing was performed on media containing doxycycline, minocycline, tetracycline,
`erythromycin, clindamycin, and vancomycin by agar dilution method.
`
`Microbiological data were analyzed using the unpaired t test. If the data did not follow a
`normal distribution, the non—parametric Mann—Whitney test was used to avoid bias of
`outliers. Differences within groups were evaluated using a paired t test or rank sum test.
`
`Microbiology Findings
`
`The results of the study indicate that the differences in microbial colony counts between
`or within the groups from baseline were not statistically significant. These findings
`appear to also indicate that no significant changein the composition of the normal skin
`flora was observed.
`
`Additionally, the report also indicated that antibiotic susceptibility testing showed no
`differences between or within the study groups in the MICs obtained from doxycycline.
`The report also indicated that there were no strong correlations between resistance to
`doxycycline and resistance to any of the five (5) other antibiotics tested. However,
`moderate correlations (r: 0.5) were detected between doxycycline and both tetracycline
`and minocycline. Bacteria resistant to one tetracycline class are often resistant to others;
`therefore, cross— resistance between doxycycline and other tetracyclines was not
`unexpected. No differences between the correlation coefficients for cross—resistance in
`the doxycycline 6—month samples and either placebo 6 month samples or the doxycycline
`baseline samples were observed.
`
`Conclusions
`
`In Study DERM—30l, the Applicant reports that a 6—month regimen of 20 mg BID
`resulted in 1) no effect on the cultivable microflora of the skin, 2) no emergence of
`resistant microorganisms; and 3) no development of multi—antibiotic resistance, including
`Vancomycin.
`
`

`

`Oracea
`
`Clinical Microbiology Review
`'
`DIVISION OF ANTI-INFECTIVE AND OPHTHALMOLOGY
`'
`PRODUCTS (DAIOP)
`CLINICAL MICROBIOLOGY REVIEW
`.
`CONSULTATION FOR HFD 540
`Date Review Completed: May 15, 2006
`
`NDA 50—805
`
`The results presented in the report provided by the Applicant indicated that treatment
`with SD doxycycline twice daily had no effect on skin microflora including
`Propiom'bacterium acnes. There was also no observed change in the composition of the
`normal skin flora. The report indicated that the treatment did not result in the emergence
`of organisms resistant to doxycycline or cross— resistance to other antimicrobial agents.
`Increase in the proportion of flora resistant to doxycycline or increase in MIC values for
`bacteria resistant to 4 ug/mL of doxycycline was not observed. Evidence of development
`of cross-resistance between doxycycline and related or un-related antibiotics was not
`reported.
`
`Study 5732.1 1 J
`
`A 9 month, randomized, double-blind, placebo—controlled study to evaluate the microbial
`effects 20 mg BID of doxycyc‘line hyclate on the intestinal and vaginal flora
`
`vaginal microflora. Sixty-nine (69) periodontal diseased subjects (30—75 years of age)
`were randomized to receive drug or placebo Control for a 9 month period. Stool samples
`and vaginal swabs were collected at baseline and after three (3) and 9 months of therapy.
`Samples were examined for tOtal anaerobic counts, opportunistic pathogens and
`doxycycline-resistant (3 4 ug/mL) bacteria. All recovered isolates were identified and
`susceptibility tests to five additional antimicrobials were determined.
`
`Microbiology Procedures
`
`Fecal Samples
`
`Fecal sample collection kits that included all materials needed to collect the sample and
`written instructions for collection and handling were provided for each subject. Once
`received at the clinical site, samples were shipped to the microbiology testing laboratory.
`Samples were weighed, placed into anaerobically—sterilized, pre-reduced (PRAS) Ringers
`solution. The samples were sonicated briefly to disperse the organisms and then serial 10—
`fold dilutions were made in Ringers solution. The samples were place in culture media
`appropriate for the target microorganisms and incubated in the incubation conditions
`required by the target organisms.
`‘
`
`Cultures were examined for growth following the indicated incubation period. Colony—
`forming units (CFUs) of anaerobic and aerobic organisms were determined from the plate-
`dilution that gave rise to 30—300 CFUs if available. If less than 30 colonies were present
`on the most diluted plate, the number of colonies were counted, provided that more than a
`
`

`

`Oracea
`
`Clinical Microbiology Review
`DIVISION OF ANTI-INFECTIVE AND OPHTHALMOLOGY
`PRODUCTS (DAIOP)
`CLINICAL MICROBIOLOGY REVIEW
`CONSULTATION FOR HFD 540
`
`.NDA 50~805 .
`Date Review Completed: May 15, 2006
`
`
`
`Bacteroides
`22.97
`20.00
`15.15
`| 10.00
`27.63
`{32.73
`
`10.53
`Bifidobacterium
`6.76
`12.31
`19.70
`I 18.00
`.
`3.64
`
`
`Clostridium
`2.70
`1.54
`4.55
`‘ 0.00
`1.32
`5.45
`
`Eubacterium
`12.16
`r1385
`3.03
`6.00
`.
`5.45
`
`
`
`0.00
`3.64
`Fusobacterium
`14.86
`97.23
`6.06
`I 10.00
`
`
`
`
`
`Prevotella
`‘341
`13.54
`6.06
`‘F00
`10.53
`$.27
`inegativerods
`J
`
`
`Unidentified Gram
`
`13.51
`
`10.77
`
`22.73
`
`22. 00
`
`23.68
`
`18.18
`
`The median counts, 1og10 (wet-weight-adjusted) for sub-therapeutic doxycycline dose
`(SDD) or placebo treatments in the microbial groups examined from the fecal flora are
`shown in Table 2.
`
`Microbial Group
`
`B as eline
`
`9—Month
`3—Month
`
`
`SDD
`
`Placebo
`
`7.16
`
`7.03
`
`p-
`value
`0.999
`
`Placebo
`
`7.59
`
`p-
`value
`0.8129
`
`
`
`Table 2: Median logm wet—weight—adjusted counts and two—sample median test analysis for differences
`between SDD and placebo treatments for the fecal flora
`
`
`
`
`
`
`
`
`Total Anaerobic
`
`
`counts
`
`Doxycycline-resistant
`
`
`counts
`
`Candida
`2.88
`3.45
`
`Total Enterics
`4.02
`3.91
`Staphylococcus
`3 .38
`4.42
`
`aureus
`
`Change from baseline
`
`Doxycycline—resistant
`
` counts
`
`
`7.19
`
`5.80
`
`2.24
`
`
`
`1.71
`0.15
`2.99
`
`Between the two treatment groups statistically significant difference Q3: < 0 05) was
`detected1n the doxycycline resistant counts present at the baseline sampling period. At
`this sampling period, prior to the administration of study drug, the CFUs of doxycycline—
`resistant organisms detected from the SDD treatment group were significantly higher
`than the placebo control At the 3 month or the 9 month sample periods, however, there
`was no between——samp1e differenceIn doxycycline-resistant counts detected.
`
`The M'IC50, MICgo and range for doxycycline—resistant organisms are shown in Table 3
`There were no differences in the values obtained within the SDD treatment groups or
`between SDD and placebo treatment groups. The values obtained for the doxycycline—
`resistant bacteria recovered from the SDD group appeared comparable to those of the
`placebo group
`
`10
`
`

`

`Oracea
`Clinical Microbiology Review
`DIVISION OF ANTI—IN
`
`FECTIVE AND OPHTHALMOLOGY
`
`g
`PRODUCTS (DAIOP)
`CLINICAL MICROBIOLOGY REVIEW
`CONSULTATION FOR HFD 540
`
`NDA 50—805
`
`Date Review Completed: May 15, 2006
`
`Table 3: Susceptibilities to doxycycline (pg/mL) of predominant bacteria recovered on medium containing
`4 uglmL doxycycline from each treatment group and sample period.
`
`MICs in
`SDD
`Placebo
`
`
`ug/mL
`.
`Baseline
`months
`9 months
`Baseline
`3 months
`9 months
`
`
`MICso
`16
`16
`32
`'
`
`MIng
`32
`>32
`32
`>32
`>32
`Range
`0.06->32
`0.06—>32
`O.25->32
`0.06->32
`0.06->32
`O.25—>32
`
`
`
`MICs to doxycycline and 5 other antibiotics were determined for all isolates recovered
`from doxycycline—containing culture media. The data were analyzed to show changes in
`the resistance of these organisms. Correlation coefficients values were calculated
`between the MICs obtained for doxycycline and the 5 other antibiotics tested against
`predominant organisms recovered on medium containing 4 pg of doxycycline per ml.
`Table 4 shows the result of the correlation coefficient analysis. The data indicate that
`there was no consistently strong correlation between doxycycline and any of the three
`non—tetracycline antibiotic tested. However, a strong correlation between doxycycline and
`minocycline, and doxycycline and tetracycline was observed.
`
`Table 4: Correlations between MICs obtained for doxycycline with each of the other 5 antimicrobials tested
`against predominant bacteria recovered from medium containing 4 ug/mL doxycycline at each sample
`period fro each treatment.
`
`
`
`Sample Period and
`Minocycline
`Tetracycline Amoxicillin
`Erythromycin
`Clindamycin
`
`
`Treatment Group
`
`
`
`Baseline SDD
`0.497
`0.589
`0.178
`0.283
`0.272
`_:|
`
`0.546
`0.268
`Baseline Placebo
`0.495
`0.474
`0.335
`
`
`
`3 month SDD
`0.616
`0.592
`0.099
`0.124
`0.420
`1
`
`3 month Placebo
`0.618
`0.653
`0.083
`0.195
`0.628
`_
`
`9 month SDD
`0.683
`0.364
`0.266
`0.415
`0.114
`
`
`0.435
`
`i
`
`9 month Placebo
`
`0.500
`
`0.393
`
`0.069
`
`0.510
`
`These results indicate that treatment with‘SDD does not tend to promote a greater chance
`for the development of cross—resistance with any of the non—tetracycline antibiotics tested.
`However, as can be expected, because of the close molecular and pharrnacodynamic
`similarities between doxycycline and minocycline and doxycycline and tetracycline, it is
`conceivable that prolonged use of SDD may promote the emergence of resistance to
`tetracycline and its derivatives.
`
`

`

`Oracea
`Clinical Microbiology Review
`DIVISION OF ANTI-INFECTIVE AND OPHTHALMOLOGY
`PRODUCTS (DAIOP)
`'
`CLINICAL MICROBIOLOGY REVIEW
`CONSULTATION FOR HFD 540
`‘
`.
`Date Review Completed: May 15, 2006
`
`NDA 50—805
`
`Vaginal Sample Flora Analyses
`
`The number of vaginal samples received was less than initially projected and was further
`reduced when several samples failed to produce growth on preliminary culture. The
`numbers of isolates recovered were too low to allow for any meaningful analysis in
`regard to the particular bacterial species present. Although the Applicant reported results
`of the unpaired t—test to analyze the culture counts in an attempt to determine if
`significant changes occurred between treatments, interpretation of the analysis is difficult.
`The Applicant reported that the distribution of the data was not normal which could have
`led to false positives (Type I error), and therefore, the reported p—values <‘0.050 should
`be interpreted with caution. Nevertheless, the Applicant indicated that no apparent
`statistically significant differences were detected between SDD and placebo treatments at
`any time.
`
`Conclusions
`
`This investigation made an attempt to determine if SDD exerted any detectable effect on
`the intestinal flora that could be attributed to antimicrobial activity. The levels of
`doxycycline used was below the reported MIC, however, at this level, the possibility exist
`that this concentration may be inhibitory for certain organisms that are ubiquitously
`sensitive to tetracyclines. Based on the data ppesented in this study, there appear to be no
`significant differences between treatment groups in terms of MIC. The levels of
`doxycycline present in the intestine appeared lower than that required for stimulating any
`significant change in MIC. There were no observable changes in the MIC50 or MICgO
`values. Please note that longer treatment duration or results obtained from a larger
`patient sample may show a trend towards the development of doxycycline resistance.
`However, such a test was not performed.
`
`Thenumber of vaginal samples obtained was lower than what was initially expected.
`This was attributed to inadequate sample collection, storage, and transport. Therefore, the
`samples were not enough to draw any significant conclusion. However, from the limited
`samples that were available, the data indicate that low dose doxycycline did not appear to
`have an effect on vaginal candidiasis since yeast was only recovered from one subject.
`Please note that the clinical data indicated that there were 3 incidences of vaginitis (2 in
`the SDD group and 1 in the placebo group) over the 9 month course of treatment.
`However, the significance of this finding is not known.
`
`SYNOPSES OF CLINICAL PROTOCOLS: COL 101—ROSE—301 AND COLL 101-
`ROSE 302
`
`The Applicant conducted two, (COL—101 ROSE—301 and COL-101 ROSE-302), multi—
`center, randomized, double—blind, placebo—controlled, parallel—group, outpatient, phase 3
`
`12
`
`

`

`Oracea
`Clinical Microbiology Review
`DIVISION OF ANTI-INFECTIVE AND OPHTHALMOLOGY
`
`PRODUCTS (DAIOP)
`CLINICAL MICROBIOLOGY REVIEW
`CONSULTATION FOR HFD 540
`
`NDA 50—805
`
`Date Review Completed: May 15, 2006
`
`trials to evaluate the safety and efficacy of doxycycline for reducing total inflammatory
`lesions associated with rosacea. A total of 537 patients (142 COL— 101, 144 placebo
`patients for ROSE 302 with a total of 286 patients; 127 COL101, 124 placebopatients for
`ROSE 301 with a total of 251 patients) were included in the study. Patients visited the
`clinics for evaluations at baseline and at Weeks 3, 6, 12, 16, and 20. Patients were
`evaluated at each visit for the number and types of lesions, and other assessments
`including adverse events. The Investigator’s Global Assessment (IGA) and the
`Clinician’s Erythema Assessment (CEA) Scale scores were obtained at each visit. Study
`drug treatment ceased at Week 16 and patients returned for follow—up clinical and safety
`evaluations at Week 20.
`
`This study did not include any microbiological studies for evaluation. The primary
`efficacy variable during the double—blind treatment period was change in total
`inflammatory lesion count (papules + pustules + nodules) from baseline to Week 16.
`Secondary efficacy parameters included the change from baseline to Week 16 in the CEA
`scale score, change from baseline to week 16 in the IGA score, and the proportion of
`treatment responders at Week 16 based on the IGA.
`
`Criteria for evaluation
`
`Maintenance of response after 4 weeks post—treatment was assessed using the following
`parameters: change in total inflammatory lesion count (papules + pustules + nodules)
`from Week 16 to Week 20; change from Week 16 to Week 20 in the CEA scale score;
`change from Week 16 to Week 20 in the IGA score; and the proportion of treatment
`responders at week 20 based on the IGA. The investigator’s global assessment scale is
`depicted in Table 5.
`
`Table 5: Investigators Global Assessment (IGA) Scale.
`
` Grade Definition , l Guideline 1
`
`
`
`
`0 Clear
`No signs or symptoms present
`Skin is completely clear of inflammatory
`
`lesions
`
`One or two papules1 Near clear l 1 or 2 small, non—inflammatory papules
`
`
`
`
`2 Mild
`| Some papules/pustules
`3 to 10 papules/pustules
`3 Moderate
`Moderate number of
`11 to 19 papules/pustules
`
`papules/pustules
`>20 papules/pustules and nodules
`Numerous papules/pustules;
`nodules
`
`
`
`
`
`
`
`Patients with a score of 0 or 1 were categorized as treatment “successes” regardless of
`their baseline IGA Values or baseline lesion counts, and patients who did not meet this
`criterion were categorized as treatment ‘failures”. The change in the CEA total score
`
`18
`
`

`

`Oracea
`"Clinical Microbiology Review
`DIVISION OF ANTI-INFECTIVE AND OPHTHALMOLOGY
`
`PRODUCTS (DAIOP)
`CLINICAL MICROBIOLOGY REVIEW
`\ CONSULTATION FOR HFD 540
`
`NDA 50—805
`
`Date Review Completed: May 15, 2006
`
`from baseline to endpoint (Week 16) was also evaluated as secondary efficacy parameter.
`The clinician used the scale shown below (Table 6) to evaluate five facial areas:
`forehead, chin, nose, right cheek, and left cheek. The CEA total score was the sum of the
`scores from the five facial areas.
`
`Table 6: Clinician’s Erythema Assessment (CEA) Scale
`
`
`
`
`
`
`1 Mild
`Slight pinkness
`
`2 Moderate
`Definite redness
`
`
`3 Significant
`Marked erythema
`
`
`Fiery redness
`
`
`
`
`
`
`
`
`
`Summary of Efficacy Findings
`
`The Applicant chose the change if total inflammatory lesion count from baseline to Week
`16 (end of treatment) as the sole primary endpoint in these studies. Counts of papules,
`pustules, and nodules represented a standard and objective measurement for evaluating
`the effects of a study medication on rosacea, and was the most directly relevant measure
`to support the proposed indication for Oracea, “to A, inflammatory lesions in patients
`with rosacea”, according to the Applicant (Section 2.5.4.2 pg 90, NDA 50—805)._
`
`The result in Table 7 shows the total inflammatory lesion count for studies 301, 302, and
`combined studies demonstrating the mean change that occurred from baseline to Week
`16. In this table, it shows that in all studies (301, 302, and combined) statistically
`significant (p=<0.001) reduction in total inflammatory count from baseline to Week 16 in
`patients treated with Oracea compared with placebo treatment groups. From baseline .
`counts of 20 in the Oracea group and 20.8 in the placebo group in the combined analysis,
`the mean change at Week 16 was —10.6 in the Oracea group versus —5.1 in the placebo
`group. In Study 301, the mean change was -1 1.8 in the Oracea group while the placebo
`group showed -5.9; Study 302, Oracea group shows -9.5 while placebo, —4.3 (p <0.001).
`
`’
`
`Baseline Mean
`
`Median (range)
`
`17(10—39)
`
`Placebo
`n=124
`20.3
`
`17.0(10—
`63)
`
`Placebo
`(n=144)
`21.2
`
`18 (10—
`100)
`
`17.0(10-
`105)
`
`1700-
`105)
`
`175(10—
`100)
`
`Table 7: Total Inflammatory Lesion Count: Mean Change from Baseline and Week 16 (ITT population).
`
`
`| Visit
`| Study 301
`Study 302
`_ Combined studies
`
`Oracea,m
`Oracea
`OraceaTM Placebo
`
`(n=127)
`. (n=l42)
`(n=169)
`(11:268)
`19.5
`20.5
`20.0
`20.8
`
`
`Week 168 Mean
`I 7.7
`14.4
`11.0
`16.9
`9.4
`15.7
`
`Median (range)
`
`5.0(0-38)
`
`9.0 (0—
`
`8(0-105)
`
`13.0(1—78)
`
`7(0—105)
`
`11.0(0-
`
`l4,
`
`

`

`‘
`Oracea
`Clinical Microbiology Review
`DIVISION OF ANTI-INFECTIVE AND OPHTHALMOLOGY
`
`PRODUCTS (DAIOP)
`CLINICAL MICROBIOLOGY REVIEW
`CONSULTATION FOR HFD 540 ,
`
`.
`
`Change from Baseline to
`Week 16 Mean
`
`—11.8
`
`—5.9
`
`—9.5
`
`-4.3
`
`NDA 50-805
`Date Review Completed: May 15, 2006
`
`
`T
`|
`111.)
`-10.6
`-5.1
`
`6.0 (-34 to —9.0(-4l to
`-7(—46—89)
`
`38)
`28)
`| <0.001
`<0.001
`p values
`Source: Table 9.1 (NDA 50—805; Module 5, 301- vol 1.9 pp 118; 302— vol 1.32, p 134; combined vol 1.56, p 10)
`a: Week 16 was the last valid observation available on treatment.
`b: p-value for treatment difference on change from baseline, using a Van Elteren test stratified by pooled center
`
`Median
`(range)
`
`—10(-38 to
`11)
`
`-..8.0 (-46—
`89)
`
`-8.0 (—41
`to 28)
`
`In the Clinician’s Erythema-Assessment (CEA) total score, the results of the combined
`analysis (Table 8) show a significaht reduction in the Oracea group than in the placebo
`group at Week 16, with a change in baseline of—2.0 in the Oracea group versus —1 .5 in the
`placebo group (p=0.024). In study 301, the change from baseline was ~2.7 in the Oracea
`group versus —1.8 in the pla