Contains Nonbinding Recommendations. Draft Guidance on Benzyl Alcohol

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1 Contains Nonbinding ecommendations Draft Guidance on Benzyl Alcohol his draft guidance, once finalized, will reresent the Food and Drug Administration's (FDA's) current thinking on this toic.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: Benzyl alcohol Lotion; toical I. In Vitro otion: o qualify for the in vitro otion for this drug roduct ursuant to 21 CF (b)(6), under which [a]ny other aroach deemed adequate by FDA to measure bioavailability or establish bioequivalence may be accetable for determining the bioavailability or bioequivalence (BE) of a drug roduct, all of the following criteria must be met: i. Equivalent comarative qualitative and quantitative (Q1/Q2) characterization. ii. Equivalent comarative hysicochemical and microstructural (Q3) characterization of comarable H, secific gravity, emulsion globule size distribution (e.g., evaluated microscoically, if ossible) and viscosity rofiles with measurements made not only to determine the linear viscoelastic resonse but also to investigate any nonlinear viscosity behavior over a range of shear rates. We recommend to erform these comarative studies on at least three lots of the test roduct, and (as available) three lots of the LD roduct. iii. Equivalent comarative dosage form erformance characterization in vitro, using the USP <1724> comendial In Vitro elease est (IV) method. We recommend that the IV method be validated to demonstrate its reroducibility and discrimination sensitivity. Discrimination sensitivity may be validated by testing of the 5% benzyl alcohol lotion, comared with altered (e.g. 2.5% and 7.5%) benzyl alcohol lotions of otherwise comarable comosition, to demonstrate the sensitivity of the IV method to monitoring the roortionality of the release rates as a function of benzyl alcohol concentration, and to demonstrate the ability of the IV method to detect inequivalence of the altered formulations drug release rates to that measured for the 5% benzyl alcohol lotion, using the statistical methodology described in <1724>. iv. Equivalent comarative dosage form erformance characterization ex vivo in Pediculus humanus caitis (head lice), using an aroriate ediculicide hair tuft assay with relevant controls (e.g., similar to Strycharz et al., Journal of Medical Entomology 45(1): ). If the generic drug roduct has different inactive ingredients comared to the LD, then the Office of Generic Drugs requests a clinical endoint study to determine bioequivalence between the roducts. ecommended Dec 2014

2 II. In Vivo otion: ecommended studies: 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, aged 6 months to 60 years, with active infestation with Pediculus humanus caitis (head lice and their ova) 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 bioequivalence study with a clinical endoint in the treatment of active infestation with Pediculus humanus caitis (head lice and their ova) comaring the test roduct versus the reference listed drug (LD) and vehicle control, alied at one time at home on study Day 1 by the subject or their caregiver and one time at home again on Day 8. he rimary endoint is the roortion of subjects with treatment success, defined as absence of live head lice when examined 14 days after the last alication of study treatment (study Day 22). Four site visits, each including a visual examination for the resence of live lice by the evaluator with the aid of a 5X lighted magnifier and a wide tooth comb to art and searate the subject s hair, are recommended as follows: Visit 1 (study Day 1; before home treatment #1), Visit 2 (study Day 2; one day after home treatment #1), Visit 3 (study Day 9; one day after home treatment #2) and Visit 4 (study Day 22; 14 days after home treatment #2). 2. A lacebo control arm (vehicle of test roduct) 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 males or nonregnant females aged 6 months to 60 years, inclusive with an active infestation of Pediculus humanus caitis (human head lice) with at least three live lice (defined as live adults and/or nymhs) at baseline. ecommended Dec

3 b. Subject and/or arent/guardian agree that the subject will not use any other form of lice treatment during the duration of the study. 4. Exclusion Criteria (the sonsor may add additional criteria): a. Females who are regnant, breast feeding, or who wish to become regnant during the study eriod. b. Known allergy or hyersensitivity to benzyl alcohol or any comonent of the test roduct or LD. c. Scal condition that could make it difficult to evaluate the extent and severity of an infestation or that would resent a roblem in the evaluation of resonse to theray (e.g. soriatic scal lesions, extensive seborrheic dermatitis). d. Known history of irritation or sensitivity to ediculicides or hair care roducts. e. Within 4 weeks of randomization treatment with a ediculicide. f. Subject with very short (shaved) hair, subject who lans to shave head during the study, and/or subject who used any hair dye, bleaches, hair straightening or ermanent wave solution on the hair within 14 days of randomization. 5. he rimary endoint is the roortion of subjects in the Per Protocol (PP) oulation in each treatment grou with treatment success (i.e., absence of live head lice) when examined 14 days after the last alication of study treatment (study Day 22; 14 days after home treatment #2). 6. Subjects who do not resond to theray (i.e., if any live head lice are noted during Visit 2, 3, or 4) will receive standard theray (i.e., early escae clause). Such subjects will be treated as failures of theray in the final analysis. Subjects with no live lice should be rovided with sufficient study drug for the second treatment (e.g. 7 days after the first treatment.) 7. Provide oral and written instructions to the subject and/or arent/guardian as follows: a. Cover face and eyes with a towel and kee eyes closed tightly. Aly the lotion directly to the dry scal and rub into hair to comletely cover the entire scal and all scal hair. When alying the lotion, ay articular attention to the back of the neck and behind the ears. Follow the Usage Guideline in able 1 for the amount of lotion needed er alication: able 1: Benzyl Alcohol Lotion, 5% Usage Guideline Hair Length Amount of ULESFIA Lotion er Alication Ounces 8 oz bottle Short 0-2 inches 4-6 oz ½-¾ bottle 2-4 inches 6-8 oz ¾-1 bottle Medium 4-8 inches 8-12 oz 1-1½ bottles 8-16 inches oz 1½-3 bottles Long inches oz 3-4 bottles ecommended Dec

4 Hair Length Amount of ULESFIA Lotion er Alication Ounces 8 oz bottle Over 22 inches oz 4-6 bottles b. Massage the lotion into hair and scal. Leave the lotion on for 10 minutes; then thoroughly rinse off with water. c. eeat alication after 7 days after the first alication. d. Avoid eye exosure. If lotion comes in contact with the eyes, flush them immediately with water. If irritation ersists, consult a hysician. e. Anyone alying the lotion should wash their hands immediately after the alication rocess is comlete. f. Kee out of reach of children. 8. Provide details in the rotocol regarding the rocedures to be taken to decrease reinfestation, such as the examination of household members of the enrolled subjects for head lice (and treatment of such household members found to be infested), decontamination of clothing and bed linen that may have been contaminated by the infested individual rior to treatment and disinfection of combs and brushed used by the infected atient. 9. he rotocol should clearly define the er-rotocol (PP), modified intent-to-treat (mi) and safety oulations. a. he PP oulation includes all randomized subjects who met all inclusion/exclusion criteria, alied the assigned roduct as instructed and comleted the evaluation within the designated visit window (+/- 2 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, and the rotocol violations that would affect the treatment evaluation. b. he mi oulation includes all randomized subjects who met all inclusion/exclusion criteria, received the assigned study roduct and returned for at least one ost-baseline evaluation visit. c. he safety oulation includes all randomized subjects who received study roduct. 10. It is imortant to ensure that evaluators (exerienced rofessionals) conduct a thorough and consistent evaluation for the resence of lice. his information could be catured as the time sent by the evaluator to assess for the resence of lice. 11. Subjects with live lice noted at Visits 2, 3, or 4 and any subjects whose condition worsens and require alternate or sulemental theray for the treatment of their Pediculus humanus caitis during the study should be discontinued, included in the PP oulation analysis as treatment failures, 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). ecommended Dec

5 12. 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. 13. 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. 14. Alication site reactions such as irritation, erythema, yoderma, excoriation, edema, anesthesia, ain, and ocular irritation are to be recorded at each visit to allow a comarison between treatment grous. Local safety evaluation should be erformed on a four-oint scale (0 (absent), 1 (mild), 2 (moderate), and 3 (severe)) for five categories: ruritus, erythema, yoderma, and excoriation. 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. 15. If the inactive ingredients are different than those contained in the LD or resent 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. 16. he quantitative information of inactive ingredients of the vehicle/lacebo control should be rovided. 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 ecommended Dec

6 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 difference between roducts for the rimary endoint (success roortion) must be contained within [-0.20, +0.20] for dichotomous variables (success versus failure), 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 control ( < 0.05, two-sided) for the rimary endoint using the mi oulation and LOCF. 23. 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 treatment. = success rate of reference 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 ecommended Dec

7 = 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. 24. he Case eort Form (CF) should clearly document the secific reason for use of this roduct, e.g. new infestation of lice or failure to resond adequately to other toical rescrition or over-the counter treatments. 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. 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, disease severity (IGA), vital signs, adverse events, disosition (including reason for discontinuation of treatment,) concomitant medications, medical history, comliance and comments, etc. 25. 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 b. Subject identifier ecommended Dec

8 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 i. Date of reatment One j. Date of reatment wo k. Comleted the study (yes/no) l. eason for remature discontinuation of subject m. Subject required additional treatment for Pediculus humanus caitis 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. Final designation of treatment outcome (success/failure) on study Day 15 u. Comliance (i.e., was lotion alied and removed as instructed?) (yes/no) v. Concomitant medication (yes/no) w. 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 trt1_date trt2_date comletd disc_rs add_tx _rs mitt mitt_rs safety safe_rs tx_out comlian CM AE YEAS F 1 A Y N Y Y Y S 0 Y Y YEAS F 1 B Y N 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: Study Identifier SUBJID: Subject Identifier for the Study SIEID: Study Site Identifier AGE: Age AGEU: Age units (years) ecommended Dec

9 SEX: Sex, e.g., M=Male, F=Female, U=Unknown ACE: 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 EX: Name of Actual reatment (exosure), e.g., A=test roduct, B= LD, C=lacebo trt1_date: Date of reatment #1 (ex. November 5, 2014 would be dislayed as ) trt2_date: Date of reatment #2 (ex. November 12, 2014 would be dislayed as ) comletd: Subject comleted the study, e.g., Y=Yes, N=No disc_rs: 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, L=live lice noted at Visits 2, 3, or 4 add_trt: Subject required additional treatment for Pediculus humanus caitis due to unsatisfactory treatment resonse, e.g., Y=Yes, N=No : Per Protocol (PP) oulation inclusion, e.g., Y=Yes, N=No _rs: 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. mitt: Modified Intent to reat (mi) oulation inclusion, e.g., Y=Yes, N=No mitt_rs: eason for exclusion from mi oulation, e.g., A=never treated, etc. safety: Safety oulation inclusion, e.g., Y=Yes, N=No safe_rs: eason for exclusion from Safety oulation, e.g., A=never treated, etc. tx_out: Final designation of treatment outcome based of live head lice on study Day 15, e.g., A=success, B=failure comlian: reatment comliance (was lotion alied and removed as instructed?), e.g., Y=Yes, N=No CM: Concomitant medication, e.g., Y=Yes, N=No AE: Adverse event(s) reorted, e.g., Y=Yes, N=No 26. Please rovide a dataset containing a searate line listing for each 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 d. Visit number e. Visit date f. Number of days since baseline visit g. Evaluator: identity of evaluator h. Number of live head lice i. Skin reaction score\s for each sign and symtom evaluated (e.g., erythema, yoderma, excoriation, edema, and ain) ecommended Dec

10 j. Concomitant medication reorted during this visit (yes/no) k. Adverse event reorted during this visit (yes/no) l. 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 VISINUM SVSDC ELMBS EVAL live_lic sr_eryth sr_yod sr_excor sr_edema sr_ain CMrt AErt LBtest A Y N Y 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 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 live_lic: Number of live head lice sr_eryth: Skin reaction erythema score, e.g. 0=absent, 1=mild (slight, barely ercetible), 2=moderate (distinct resence), 3=severe (marked, intense) sr_yod: Skin reaction yoderma score, e.g. 0=absent, 1=mild (slight, barely ercetible), 2=moderate (distinct resence), 3-severe (marked, intense) sr_excor: Skin reaction excoriation score, e.g. 0=absent, 1=mild (slight, barely ercetible), 2=moderate (distinct resence), 3=severe (marked, intense) sr_edema: Skin reaction edema score, e.g. 0=absent, 1=mild (slight, barely ercetible), 2=moderate (distinct resence), 3=severe (marked, intense) sr_ain: Skin reaction ain 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 ecommended Dec

11 AErt: LBtest: Adverse Event reorted during this visit, e.g., Y=Yes, N=No Laboratory esting erformed during this visit, e.g., Y=Yes, N=No 27. 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 benzyl alcohol. ecommended Dec