Draft Guidance on Dapsone

Transcription

1 Contains Nonbinding ecommendations Draft Guidance on Dasone his draft guidance, when finalized, will reresent the current thinking of the Food and Drug Administration (FDA, or the Agency) on this toic. It does not establish any rights for any erson and is not binding on FDA or the ublic. You can use an alternative aroach if it satisfies the requirements of the alicable statutes and regulations. o discuss an alternative aroach, contact the Office of Generic Drugs. Active Ingredient: Dosage Form; oute: ecommended Studies: Dasone Gel; toical wo otions: (1) a combination of in vitro and in vivo studies with harmacokinetic (PK) endoints, or (2) an in vivo study with clinical endoints. 1. Otion 1: In vitro and in vivo studies with PK endoints o demonstrate bioequivalence (BE) for this drug roduct using studies with PK endoints, including one in vitro study evaluating local (cutaneous) PK and one in vivo study evaluating systemic (lasma) PK, all of the following criteria should be met: A. he test and eference Listed Drug (LD) roducts are qualitatively (Q1) and quantitatively (Q2) the same as defined in the Guidance for Industry: ANDA Submissions efuse-to-eceive Standards. B. he test and LD roducts are hysically and structurally similar based uon an accetable comarative hysicochemical characterization of a minimum of three lots of the test and a minimum of three lots (as available) of the LD roduct. he influence of any differences in the container closure systems between the test and LD roducts, which may influence the hysicochemical roerties of the gel when disensed, should be considered in the design of the hysical and structural characterization studies and discussed in the associated reorts. Comarison of hysical and structural similarity for the test and LD roducts should include the following hysicochemical characterizations for each lot of test and LD roducts: a. Assessment of aearance b. Analysis of the dasone olymorhic form in the drug roduct c. Analysis of article size distribution and crystal habit with reresentative microscoic images at multile magnifications. d. Analysis of the rheological behavior which may be characterized using a rheometer that is aroriate for monitoring the non-newtonian flow behavior of semi-solid dosage forms. he following evaluations are recommended: ecommended Dec 2014; evised Oct 2017

2 A comlete flow curve of shear stress (or viscosity) vs. shear rate should consist of multile data oints across the range of attainable shear rates, until low or high shear lateaus are identified. Yield stress values should be reorted if the material tested exhibits lastic flow behavior. e. Analysis of secific gravity, H and any other otentially relevant hysical and structural similarity characterizations. C. he test and LD roducts have an equivalent rate of dasone release based uon an accetable in vitro release test (IV) comaring a minimum of one lot each of the test and LD roducts using an aroriately validated IV method. efer to the Draft Guidance on Acyclovir oical Cream for additional information regarding the develoment, validation, conduct and analysis of accetable IV studies. D. he test and LD roducts are bioequivalent based uon an accetable in vitro ermeation test (IVP) comaring the rate and extent of dasone ermeation through excised human skin from a minimum of one lot each of the test and LD roducts using an aroriately validated IVP method. ye of study: IVP study Design: Parallel, single-dose, multile-relicate er treatment grou study design Strength: 5% Skin: Barrier-cometent skin from male and/or female donors of at least 18 years of age, general oulation Additional comments: he lots of test and LD roducts evaluated in the IVP study should be the same as those evaluated in the IV study, and that these lots should be included among those for which the hysical and structural similarity is characterized and comared. efer to the Draft Guidance on Acyclovir oical Cream for additional information regarding the develoment, validation, conduct and analysis of accetable IVP studies. E. he test and LD roducts are bioequivalent based uon an accetable in vivo harmacokinetic (PK) study with one lot each of the test and LD roducts. ye of study: Fasting, in vivo PK study Design: Single-alication, two-way crossover study design Strength: 5% Subjects: Males and non-regnant, non-lactating females, general oulation Additional comments: he lots of test and LD roducts evaluated in the in vivo PK study should be the same as those evaluated in the IVP study. ecommended Dec 2014; evised Oct

3 Analytes to measure (in aroriate biological fluid): Dasone in lasma (in vivo) or in recetor solution (in vitro) Bioequivalence based on (90% CI): Dasone Waiver request of in vivo testing: Not alicable (N/A) Dissolution test method and samling times: N/A 2. Otion 2: In vivo study with clinical endoints ye of study: BE study with clinical endoints Design: andomized, double blind, arallel, lacebo controlled, in vivo Strength: 5% Subjects: Males and non-regnant, non-lactating females with acne vulgaris. Additional comments: Secific recommendations are rovided below. Analytes to measure (in aroriate biological fluid): N/A Bioequivalence based on (90% CI): Clinical endoints Waiver request of in vivo testing: N/A Dissolution test method and samling times: N/A Additional comments regarding the BE study with clinical endoints: 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. Male or non-regnant, non-lactating female aged 12 and 40 years with a clinical diagnosis of acne vulgaris. 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). ecommended Dec 2014; evised Oct

4 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 non-inflammatory lesions 1 Almost clear; rare non-inflammatory lesions with no more than one small inflammatory lesion 2 Mild severity; greater than Grade 1; some non-inflammatory 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 non-inflammatory lesions and may have some inflammatory lesions, but no more than one small nodular lesion 4* Severe; greater than Grade 3; u to many non-inflammatory 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). 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. 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 Available at htt:// ecommended Dec 2014; evised Oct

5 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. j. Case reorts 2,3 have described cases of methemoglobinemia following toical dasone (5%) alication. Consider excluding subjects with known G6PD deficiency, or congenital or idioathic methemoglobinemia. All enrolled subjects should be monitored for adverse effects consistent with hemolysis or methemoglobinemia. 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. 2 Graff DM, Bosse GM, Sullivan J. Case reort of methemoglobinemia in a toddler secondary to toical dasone exosure. Pediatrics. 2016;138(2):e Swartzentruber GS, Yanta JH, Pizon AF. Methemoglobinemia as a comlication of toical dasone. N Engl J Med. 2015;372(5): 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 2014; evised Oct

6 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. 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 re-secified 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 using Last Observation Carried Forward (LOCF). 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 using LOCF, 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 LOCF. sonsors should rovide a re-secified definition of lack of treatment effect. ecommended Dec 2014; evised Oct

7 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. he sonsor should clearly exlain whether the medication was used rior to baseline visit, during the study or both. 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 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. Inactive ingredients used should rovide adequate margins of safety for the roosed clinical exosure in the target oulation. 17. he method of randomization should be described in the rotocol and the randomization schedule should be rovided. 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. efer 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. ecommended Dec 2014; evised Oct

8 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. 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 : versus - < or - > 0.20 H A : ecommended Dec 2014; evised Oct

9 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 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 in standardized format. efer to study data standards ublished at he rotocol should include a full detailed statistical analysis lan. 28. Provide the Subject-Level Analysis Dataset (ADSL), one record er subject, using the following headings, if alicable: a. Study identifier b. Unique subject identifier c. Subject identifier for the study 5 Study Data Standards for Submission to CDE available at: htt:// m htm ecommended Dec 2014; evised Oct

10 d. Study site identifier (if alicable) e. Age f. Age units (years) g. Sex h. ace i. Name of lanned treatment j. Name of actual treatment k. Safety oulation flag (yes/no) l. eason for exclusion from safety oulation m. Modified Intent-to-reat (mi) oulation flag (yes/no) n. eason for exclusion from mi oulation o. Per-Protocol (PP) oulation flag (yes/no). eason for exclusion from PP oulation q. Comleters oulation flag (yes/no) r. andomized oulation flag (yes/no) s. Datetime of first exosure to treatment t. Datetime of last exosure to treatment u. End of study date v. End of study status w. Subject required additional treatment due to unsatisfactory treatment resonse (yes/no) x. otal number of inflammatory lesions on the face at baseline y. otal number of non-inflammatory lesions on the face at baseline z. otal number of nodules/cysts on the face at baseline aa. IGA score at baseline bb. otal number of inflammatory lesions on the face at week 12 cc. otal number of non-inflammatory lesions on the face at week 12 dd. otal number of nodules/cysts on the face at week 12 ee. IGA score at week 12 ff. Final designation for IGA (success/failure) gg. Comliance rate (%) hh. Subject missed the scheduled alications for more than XX consecutive days (yes/no) ii. Adverse event reorted (yes/no) jj. Concomitant medication (yes/no) 29. Provide the basic data structure (BDS) dataset with records er subject, er analysis timeoint, using the following headings, if alicable: a. Study identifier b. Unique Subject identifier c. Study site identifier (if alicable) d. Name of lanned treatment e. Name of actual treatment f. Safety oulation flag (yes/no) g. Modified Intent-to-reat (mi) oulation flag (yes/no) h. Per-Protocol (PP) oulation flag (yes/no) ecommended Dec 2014; evised Oct

11 i. Comleters oulation flag (yes/no) j. Analysis date k. Analysis visit l. otal number of Inflammatory lesions m. otal number of noninflammatory lesions n. otal number of Nodules/cyst lesions o. IGA score. Study visit within the designated window (yes/no) q. Additional treatment required during the visit (yes/no) r. Adverse event reorted during the visit (yes/no) s. Concomitant medication during the visit (yes/no) 30. 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. ecommended Dec 2014; evised Oct