Draft Guidance on Dapsone

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1 Contains Nonbinding ecommendations Draft Guidance on Dasone his draft guidance, once finalized, will reresent the Food and Drug Administration's (FDA's) current thinking on this toic. It does not create or confer any rights for or on any erson and does not oerate to bind the FDA or the ublic. You can use an alternative aroach if the aroach satisfies the requirements of the alicable statutes and regulations. If you want to discuss an alternative aroach, contact the Office of Generic Drugs. Active Ingredient: Dosage Form; oute: ecommended Studies: Dasone Gel; toical One study ye of study: Bioequivalence (BE) study with clinical endoint Design: andomized, double blind, arallel, lacebo controlled, in vivo Strength: 5% Subjects: Healthy males and nonregnant females with acne vulgaris. Additional comments: Secific recommendations are rovided below. Analytes to measure (in aroriate biological fluid): Not alicable (N/A) Bioequivalence based on (90% CI): Clinical endoint Waiver request of in vivo testing: N/A Dissolution test method and samling times: N/A Additional comments regarding the BE study with clinical endoint: 1. he Office of Generic Drugs (OGD) recommends conducting a BE study with clinical endoint in the treatment of acne vulgaris. Subjects are to be randomized to receive the test roduct, reference listed drug (LD), or lacebo (vehicle). he study treatment is to be administered twice daily, in the morning and evening, for 12 weeks. he two rimary endoints are to be evaluated at the end of treatment (study Week 12). 2. A lacebo (vehicle) control arm is recommended to demonstrate that the test roduct and LD are active and as a arameter to establish that the study is sufficiently sensitive to detect differences between roducts. 3. Inclusion Criteria (the sonsor may add additional criteria) a. Healthy male or nonregnant female aged 12 and 40 years with a clinical diagnosis of acne vulgaris. ecommended Dec 2014

2 b. On the face, 25 non-inflammatory lesions (i.e., oen and closed comedones) AND 20 inflammatory lesions (i.e., aules and ustules) AND 2 nodulocystic lesions (i.e., nodules and cysts). c. Investigator s Global Assessment (IGA) of acne severity grade 2, 3, or 4 (er able 1). able 1. Samle IGA Scale for Acne Vulgaris 1 Grade Descrition 0 Clear skin with no inflammatory or noninflammatory lesions 1 Almost clear; rare noninflammatory lesions with no more than one small inflammatory lesion 2 Mild severity; greater than Grade 1; some noninflammatory lesions with no more than a few inflammatory lesions (aules/ustules only, no nodular lesions) 3 Moderate severity; greater than Grade 2; u to many noninflammatory lesions and may have some inflammatory lesions, but no more than one small nodular lesion 4* Severe; greater than Grade 3; u to many noninflammatory lesions and may have some inflammatory lesions, but no more than a few nodular lesions * he Case eort Forms for acne studies can allow for reorting by investigators of lesion worsening beyond Grade 4 with treatment. It is recommended that enrollment of acne vulgaris subjects not include subjects with nodulocystic acne. Subjects who worsen beyond Grade 4 are to be described in the safety evaluation. d. Willing to refrain from use of all other toical acne medications or antibiotics during the 12-week treatment eriod. e. If female of childbearing otential, willing to use an accetable form of birth control during the study. 4. Exclusion Criteria (the sonsor may add additional criteria) a. Pregnant, breast feeding or lanning a regnancy. b. Presence of any skin condition that would interfere with the diagnosis or assessment of acne vulgaris (e.g., on the face: rosacea, dermatitis, soriasis, squamous cell carcinoma, eczema, acneform erutions caused by medications, steroid acne, steroid folliculitis, or bacterial folliculitis). c. Excessive facial hair (e.g. beards, sideburns, moustaches, etc.) that would interfere with diagnosis or assessment of acne vulgaris. d. History of hyersensitivity or allergy to dasone or any of the study medication ingredients. e. Use within 6 months rior to baseline of oral retinoids (e.g. Accutane ) or theraeutic vitamin A sulements of greater than 10,000 units/day (multivitamins are allowed). 1 U.S. Deartment of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and esearch. Draft Guidance for Industry: Acne Vulgaris: Develoing Drugs for reatment. Clinical/Medical. Setember Accessed at htt:// ecommended Dec

3 f. Use for less than 3 months rior to baseline of estrogens or oral contracetives; use of such theray must remain constant throughout the study. g. Use on the face within 1 month rior to baseline of 1) cryodestruction or chemodestruction, 2) dermabrasion, 3) hotodynamic theray, 4) acne surgery, 5) intralesional steroids, or 6) x-ray theray. h. Use within 1 month rior to baseline of 1) sironolactone, 2) systemic steroids, 3) systemic antibiotics, 4) systemic treatment for acne vulgaris (other than oral retinoids, which require a 6-month washout), or 5) systemic anti-inflammatory agents i. Use within 2 weeks rior to baseline of 1) toical steroids, 2) toical retinoids, 3) toical acne treatments including over-the-counter rearations, 4) toical anti-inflammatory agents, or 5) toical antibiotics. 5. One scientific ublication has reorted greater efficacy in females (comared to males) with facial acne vulgaris treated with dasone toical gel, 5%; thus, consider randomizing aroximately equal numbers of male and female subjects to each of the three arms in the study wice daily, once in the morning and once in the evening, subjects should wash their face with a mild or soaless, non-medicated cleanser, gently at skin dry with a clean towel, and then aly a thin layer of study medication, aroximately a ea-sized amount, to cover the entire affected skin areas of the face. he subject should be instructed to avoid contact of the study roduct with the mouth, eyes and oen wounds, and to wash their hands after alication. 7. Subjects should not aly moisturizers, new brands of make-u, creams, lotions, owders or any toical roduct other than the assigned treatment to the treatment area. Subjects should minimize exosure to sunlight, including sunlams, while using the roduct. Use of sunscreen roducts and rotective clothing over treated areas is recommended when sun exosure cannot be avoided. 8. he rotocol should include a list of the rescrition and over-the-counter drug roducts, rocedures, and activities that are rohibited during the study, such as: a. Any other toical roducts alied to face. b. Medicated soas used on face. c. Sironolactone. d. Oral retinoids, theraeutic vitamin A sulements of greater than 10,000 units/day (multivitamins are allowed) or other systemic treatment for acne vulgaris. e. Systemic (e.g., oral or injectable) antibiotics. f. Systemic steroids, systemic anti-inflammatory agents or immunosuressive drugs. g. Antiruritics, including antihistamines, within 24 hours of study visits. h. Use on the face of 1) cryodestruction or chemodestruction, 2) dermabrasion, 3) hotodynamic theray, 4) acne surgery, 5) intralesional steroids, or 6) x-ray theray. i. Use of hormonal contracetives should not be initiated or changed during the study. j. Use of tanning booths, sunbathing, or excessive exosure to the sun. 2 anghetti E et al. he efficacy and tolerability of dasone 5% gel in female vs. male atient with facial acne vulgaris: gender as a clinically relevant outcome variable. J Drugs Dermatol Dec; 11 (12): ecommended Dec

4 9. he two rimary endoints of the study are: 1) mean ercent change from baseline to week 12 (study Day 84) in the inflammatory (aules and ustules) lesion count and 2) mean ercent change from baseline to week 12 in the non-inflammatory (oen and closed comedones) lesion count. he rotocol should clearly define aules, ustules, oen comedones, closed comedones, nodules and cysts. When counting facial acne lesions, it is imortant that all lesions be counted, including those resent on the nose. Counts of nodules and cysts should be reorted searately and not included in the inflammatory or noninflammatory lesion counts. 10. he dichotomized IGA severity scale should be treated as a secondary endoint for suortive evidence. his secondary endoint for bioequivalence should be evaluated as the roortion of subjects with a clinical resonse of success at week 12. Success should be defined as an IGA score that is at least 2 grades less than the baseline assessment. Failure should be defined as an IGA score that is the same, higher or one grade lower than the baseline assessment. 11. he rotocol should clearly define the er-rotocol (PP), modified intent-to-treat (mi) and safety oulations in the rotocol. a. he acceted PP oulation used for bioequivalence evaluation includes all randomized subjects who meet the inclusion/exclusion criteria, aly a resecified roortion of the scheduled alications (e.g., 75% to 125%) of the assigned roduct for the secified duration of the study, do not miss the scheduled alications for more than 3 consecutive days, and comlete the evaluation within the designated visit window (+/- 4 days) with no rotocol violations that would affect the treatment evaluation. he rotocol should secify how comliance will be verified, e.g., by the use of subject diaries. b. he mi oulation includes all randomized subjects who meet the inclusion/exclusion criteria, aly at least one dose of assigned roduct, and return for at least one ostbaseline evaluation visit. c. he safety oulation includes all randomized subjects who receive study roduct. 12. Subjects who are discontinued rematurely from the study due to lack of treatment effect after comleting 4 weeks of treatment should be included in the PP oulation as treatment failures. Subjects whose condition worsens and require alternate or sulemental theray for the treatment of acne vulgaris during the study should be discontinued, included in the PP oulation analysis, and rovided with effective treatment. Subjects discontinued early for other reasons should be excluded from the PP oulation, but included in the mi oulation, using Last Observation Carried Forward (LOCF). 13. he start and sto date of concomitant medication use during the study should be rovided in the data set in addition to the reason for the medication use. 14. All adverse events (AEs) should be reorted, whether or not they are considered to be related to the treatment. he reort of AEs should include date of onset, descrition of the AE, severity, relation to study medication, action taken, outcome and date of resolution. his ecommended Dec

5 information is needed to determine if the incidence and severity of adverse reactions is different between the test roduct and LD. 15. Alication site reactions such as erythema, dryness, burning/stinging, erosion, edema, ain and itching are to be recorded at each visit to allow a comarison between treatment grous. A descritive analysis comaring the alication site reactions for each treatment grou is recommended. It is imortant to ensure that the test roduct is not worse than the reference roduct with regard to the exected and unexected alication site reactions. 16. If the inactive ingredients are different than those contained in the LD or in significantly different amounts, then the sonsor is to clearly describe the differences and rovide information to show that the differences will not affect the safety, efficacy and/or systemic or local availability of the drug. 17. he method of randomization should be described in the rotocol. It is recommended that an indeendent third arty generate and hold the randomization code throughout the conduct of the study in order to minimize bias. he sonsor may generate the randomization code if not involved in the ackaging and labeling of the study medication. A sealed coy of the randomization scheme should be retained at the study site and should be available to FDA investigators at the time of site insection to allow for verification of the treatment identity of each subject. 18. A detailed descrition of the blinding rocedure is to be rovided in the rotocol. he ackaging of the test, reference and lacebo roducts should be similar in aearance to make differences in treatment less obvious to the subjects and to maintain adequate blinding of evaluators. When ossible, neither the subject nor the investigator should be able to identify the treatment. he containers should not be oened by the subject at the study center. 19. Please refer to 21 CF , and the Guidance for Industry, Handling and etention of BA and BE esting Samles, regarding retention of study drug samles and 21 CF for requirements for maintenance of records of bioequivalence testing. In addition, the investigators should follow the rocedures of ICH E6, Good Clinical Practice: Consolidated Guideline, for retention of study records and data in order to conduct their studies in comliance with Good Laboratory Practices (GLP) and Good Clinical Practices (GCP). etention samles should be randomly selected from the drug sulies received rior to disensing to subjects. etention samles should not be returned to the sonsor at any time. 20. It is the sonsor's resonsibility to enroll sufficient subjects for the study to demonstrate bioequivalence between the roducts. 21. o establish bioequivalence, the 90% confidence interval of the test/reference ratio of the mean ercent change from baseline to week 12 in the inflammatory (aules and ustules) lesion counts and in the non-inflammatory (comedones) lesion counts should be contained within [0.80, 1.25], using the PP oulation. ecommended Dec

6 22. As a arameter for determining adequate study sensitivity, the test roduct and LD should both be statistically suerior to lacebo (<0.05) with regard to 1) mean ercent change from baseline to week 12 in the inflammatory lesion count and 2) mean ercent change from baseline to week 12 in the non-inflammatory lesion count, both using the mi study oulation and LOCF. 23. he following Statistical Analysis Method is recommended for equivalence testing for a continuous variable: Equivalence Analysis he comound hyothesis to be tested is: H 0 : µ / µ θ 1 or µ / µ θ 2 versus H A : θ 1 < µ / µ < θ 2 Where µ = mean of test treatment, and µ = mean of reference treatment yically, we reject H 0 with a tye I error α = 0.05 (two 1-sided tests), if the 90% confidence interval for the ratio of means between test and reference roducts (µ / µ ) is contained within the interval [θ 1, θ 2 ], where θ 1 = 0.80 and θ 2 = ejection of the null hyothesis H 0 suorts the conclusion of equivalence of the two roducts. 24. he following Statistical Analysis Method is recommended for equivalence testing for a dichotomous variable (success/failure): Equivalence Analysis Based on the usual method used in OGD for binary outcomes, the 90% confidence interval for the difference in success roortions between test and reference treatment must be contained within [-0.20, +0.20] in order to establish equivalence. he comound hyothesis to be tested is: H 0 : - < or - > 0.20 versus H A : where = success rate of test treatment and = success rate of reference treatment. Let n = samle size of test treatment grou c n = number of successes in test treatment grou n = samle size of reference treatment grou ecommended Dec

7 c n = number of successes in reference treatment grou = c n / n, = c n / n, and se = ( (1 - )/ n + (1 - )/ n ) ½. he 90% confidence interval for the difference in roortions between test and reference was calculated as follows, using Yates correction: L = ( - ) se (1/ n + 1/ n )/2 U = ( - ) se + (1/ n + 1/ n )/2 We reject H 0 if L and U 0.20 ejection of the null hyothesis H 0 suorts the conclusion of equivalence of the two roducts. 25. ank transformation of the data may be needed if the data is significantly skewed such that analysis of the raw data would not be valid. 26. Study data should be submitted to the OGD in electronic format. a. A list of file names, with a simle descrition of the content of each file, should be included. Such a list should include an exlanation of the variables included in each of the data sets. b. Please rovide a df document with a detailed descrition of the codes that are used for each variable in each of the SAS datasets (for examle, Y=yes, N=no for analysis oulation). c. All SAS transort files, covering all variables collected in the Case eort Forms (CFs) er subject, should include.xt as the file extension and should not be comressed. A simle SAS rogram to oen the data transort files and SAS files should be included. d. Primary data sets should consist of two data sets: No Last Observation Carried Forward (NO-LOCF-ure data set) and Last Observation Carried Forward (LOCF-modified data set). e. Please rovide a searate dataset for variables such as demograhics, lesion counts, vital signs, adverse events, disosition (including reason for discontinuation of treatment), concomitant medications, medical history, comliance and comments, etc. 27. Please rovide a summary dataset containing a searate line listing for each subject (if data exist) using the following headings, if alicable: a. Study identifier ecommended Dec

8 b. Subject identifier c. Site identifier: study center d. Age e. Age units (years) f. Sex g. ace h. Name of Actual reatment (exosure): test roduct, LD, lacebo control i. Location of reatment Area j. Duration of reatment (total exosure in days) k. Comleted the study (yes/no) l. eason for remature discontinuation of subject m. Subject required additional treatment for acne vulgaris due to unsatisfactory treatment resonse (yes/no) n. Per Protocol (PP) oulation inclusion (yes/no) o. eason for exclusion from PP oulation. Modified Intent to reat (mi) oulation inclusion (yes/no) q. eason for exclusion from mi oulation r. Safety oulation inclusion (yes/no) s. eason for exclusion from Safety oulation t. otal number of inflammatory lesions on the face at baseline u. otal number of non-inflammatory lesions on the face at baseline v. otal number of nodules/cysts on the face at baseline w. IGA score at baseline x. otal number of inflammatory lesions on the face at week 12 y. otal number of non-inflammatory lesions on the face at week 12 z. otal number of nodules/cysts on the face at week 12 aa. IGA score at week 12 bb. Final designation for IGA (success/failure) cc. reatment comliance : number of missed doses er subject dd. Concomitant medication (yes/no) ee. Adverse event(s) reorted (yes/no) Please refer to able 2 as an examle. his samle table may contain additional information not alicable to your study and/or it may not contain all information alicable to your study. able 2: Examle of a summary dataset containing one line listing for each subject SUDYID SUBJID SIEID AGE AGEU SEX ACE EX YEAS F 1 A Face 84 Y N Y Y YEAS F 1 B Face 84 Y N Y Y EXLOC EXDU comletd disc_rs add_trt _rs mitt mitt_rs ecommended Dec

9 safety Y F 0 Y Y Y S 0 N N Note: Caitalized headings are from Clinical Data Interchange Standards Consortium (CDISC) Study Data abulation Model (SDM) Imlementation Guide (IG) for Human Clinical rials V3.1.2 Final dated 11/12/08. SUDYID: SUBJID: SIEID: AGE: AGEU: SEX: ACE: EX: EXLOC: EXDU: comletd: disc_rs: add_trt: : _rs: mitt: mitt_rs: safety: safe_rs: numinfb: numnonb: numnodb: iga_b: safe_rs numinfb numnonb numnodb iga_b numinf12 Study Identifier Subject Identifier for the Study Study Site Identifier Age Age units (years) Sex, e.g., M=Male, F=Female, U=Unknown ace, e.g., 1=White, 2=Black or African American, 3=Asian, 4=American Indian or Alaska Native, 5=Native Hawaiian or Other Pacific Islanders Name of Actual reatment (exosure), e.g., A=test roduct, B= LD, C=lacebo control Location of reatment Area, e.g. F=face, etc. Duration of reatment (total exosure in days) Subject comleted the study, e.g., Y=Yes, N=No eason for remature discontinuation from the study, e.g., A=adverse event, B=death, C=lost to follow-u, D=non-comliance with treatment, E=treatment unblinded, F=subject moved out of area, G=unsatisfactory treatment resonse, H=withdrew consent, I=rotocol violation, K=other event Subject required additional treatment for acne due to unsatisfactory treatment resonse, e.g., Y=Yes, N=No Per Protocol (PP) oulation inclusion, e.g., Y=Yes, N=No eason for exclusion from PP oulation, e.g., A=rematurely discontinued, B=lost to follow-u, C=subject moved out of the area, D=noncomliant, etc. Modified Intent to reat (mi) oulation inclusion, e.g., Y=Yes, N=No eason for exclusion from mi oulation, e.g., A=never treated, etc. Safety oulation inclusion, e.g., Y=Yes, N=No eason for exclusion from Safety oulation, e.g., A=never treated, etc. otal number of inflammatory lesions on face at baseline otal number of noninflammatory lesions on face at baseline otal number of nodular/cystic lesions on face at baseline IGA score at baseline, e.g., 0=Clear; 1=Almost clear, 2=Mild, 3=Moderate, 4=Severe numinf12: otal number of inflammatory lesions on face at week 12 numnon12: otal number of noninflammatory lesions on face at week 12 numnon12 numnod12 iga_12 iga_f comlian CM AE ecommended Dec

10 numnod12: otal number of nodular/cystic lesions on face at week 12 iga_12: IGA score at week 12, e.g., 0=Clear; 1=Almost clear, 2=Mild, 3=Moderate, 4=Severe iga_f: Final designation for IGA, e.g., S=success, F=failure comlian: reatment comliance, e.g., number of missed doses er subject CM: Concomitant medication, e.g., Y=Yes, N=No AE: Adverse event(s) reorted, e.g., Y=Yes, N=No 28. Please rovide a dataset containing a searate line listing for visit er subject (if data exist) using the following headers, if alicable: a. Study identifier b. Subject identifier c. Name of Actual reatment (exosure): test roduct, LD, lacebo control d. Location of Dose Administration: alication site e. Visit number f. Visit date g. Number of days since baseline visit h. Evaluator: identity of evaluator i. otal number of inflammatory lesions j. otal number of noninflammatory lesions k. otal number of nodular/cystic lesions l. IGA score m. Skin reaction scores for each sign and symtom evaluated (e.g., erythema, dryness, burning/stinging, erosion, edema, ain, itching, etc.) n. Concomitant medication reorted during this visit (yes/no) o. Adverse event reorted during this visit (yes/no). Laboratory testing during this visit (yes/no) Please refer to able 3 as an examle. his samle table may contain additional information not alicable to your study and/or it may not contain all information alicable to your study. able 3: Examle of dataset containing one line listing for each visit er subject SUDYID SUBJID EX EXLOC VISINUM SVSDC ELMBS EVAL numinf numnon numnod iga A F ecommended Dec

11 erythema dryness burning erosion edema Y Y N Note: Caitalized headings are from Clinical Data Interchange Standards Consortium (CDISC) Study Data abulation Model (SDM) Imlementation Guide (IG) for Human Clinical rials V3.1.2 Final dated 11/12/08. SUDYID: Study Identifier SUBJID: Subject Identifier for the Study EX: Name of Actual reatment (exosure), e.g., A=test roduct, B=LD, C= lacebo control EXLOC: Location of reatment Area: secific anatomical site of alication, e.g., F=face etc. VISINUM: Visit Sequence Number SVSDC: Visit date: (SVSDC=Subject Visit Start Date ime-character) ELMBL: Elased ime since Baseline (days) EVAL: Evaluator: identity of the evaluator numinf: otal number of inflammatory lesions on face numnon: otal number of noninflammatory lesions on face numnod: otal number of nodular/cystic lesions on face iga: IGA score, e.g., 0=Clear; 1=Almost clear, 2=Mild, 3=Moderate, 4=Severe erythema: Skin reaction erythema score, e.g., 0=absent, 1=mild (slight, barely ercetible), 2=moderate (distinct resence), 3=severe (marked, intense) dryness: Skin reaction dryness score, e.g., 0=absent, 1=mild (slight, barely ercetible), 2=moderate (distinct resence), 3=severe (marked, intense) burning: Skin reaction burning/stinging score, e.g., 0=absent, 1=mild (slight, barely ercetible), 2=moderate (distinct resence), 3-severe (marked, intense) erosion: Skin reaction erosion score, e.g., 0=absent, 1=mild (slight, barely ercetible), 2=moderate (distinct resence), 3=severe (marked, intense) edema: Skin reaction edema score, e.g., 0=absent, 1=mild (slight, barely ercetible), 2=moderate (distinct resence), 3=severe (marked, intense) ain: Skin reaction ain score, e.g., 0=absent, 1=mild (slight, barely ercetible), 2=moderate (distinct resence), 3=severe (marked, intense) itching: Skin reaction itching score, e.g., 0=absent, 1=mild (slight, barely ercetible), 2=moderate (distinct resence), 3=severe (marked, intense) CMrt: Concomitant Medication reorted during this visit, e.g., Y=Yes, N=No AErt: Adverse Event reorted during this visit, e.g., Y=Yes, N=No LBtest: Laboratory esting erformed during this visit, e.g., Y=Yes, N=No 29. hese recommendations are secific to this roduct and may not be aroriate for bioequivalence studies of any other roduct, including any other dosage form or strength of dasone. ain itching CMrt AErt LBtest ecommended Dec