Draft Guidance on Methylphenidate Hydrochloride

Transcription

1 Cota Nobdg ecommedato raft Gudace o Methylphedate ydrochlorde h draft gudace, oce falzed, wll repreet the Food ad rug Admtrato' (FA') curret thkg o th topc. t doe ot create or cofer ay rght for or o ay pero ad doe ot operate to bd FA or the publc. ou ca ue a alteratve approach f the approach atfe the requremet of the applcable tatute ad regulato. f you wat to dcu a alteratve approach, cotact the Offce of Geerc rug. Actve gredet: Form/oute: ecommeded tude: Methylphedate ydrochlorde Exteded eleae ablet/oral tude. ype of tudy: Fatg eg: Sgle-doe, two-treatmet, four-perod, two-equece, fully replcated croover vvo Stregth: 54 mg Subject: ealthy male ad opregat female, geeral populato.. ype of tudy: Fed eg: Sgle-doe, two-treatmet, four-perod, two-equece, fully replcated croover vvo Stregth: 54 mg Subject: ealthy male ad opregat female, geeral populato. Addtoal Commet: Pleae refer to the Amatade ydrochlorde ablet raft Gudace for addtoal formato regardg fed tude. Aalyte to meaure ( approprate bologcal flud): Methylphedate plama Boequvalece baed o (90% C): Methylphedate Pleae refer to Addtoal Commet below for more gudace regardg boequvalece. Waver requet of vvo tetg: 8 mg, 7 mg, ad 36 mg baed o () acceptable boequvalece tude o the 54 mg tregth, () acceptable -vtro doluto tetg of all tregth, ad () proportoal mlarty of the formulato acro all tregth. Pleae refer to the Mrtazape ablet raft Gudace for addtoal formato regardg waver of vvo tetg. oluto tet method ad amplg tme: Pleae ote that a oluto Method atabae avalable to the publc at the OG webte at Pleae fd the doluto formato for th product at th webte. Pleae coduct comparatve doluto tetg o doage ut each of all tregth of the tet ad referece product. Specfcato wll be determed upo revew of the applcato. ecommeded Sep 0; eved Nov 04

2 addto to the method above, for modfed releae product, doluto profle o doage ut each of tet ad referece product geerated ug USP Apparatu at 00 rpm ad/or Apparatu at 50 rpm at leat three doluto meda (p., 4.5 ad 6.8 buffer) hould be ubmtted the applcato. Agtato peed may have to be creaed f approprate. t acceptable to add a mall amout of urfactat, f eceary. Pleae clude early amplg tme of,, ad 4 hour ad cotue every hour utl at leat 80% of the drug releaed, to provde aurace agat premature releae of drug (doe dumpg) from the formulato. Specfcato wll be determed upo revew of the data ubmtted the applcato. ue to a cocer of doe dumpg of drug from th drug product whe take wth alcohol, the Agecy curretly requet that addtoal doluto tetg be coducted ug varou cocetrato of ethaol the doluto medum, a follow: etg Codto: 900 ml, 0. N Cl, USP apparatu rpm, wth or wthout alcohol; et : ut teted accordg to the propoed method (wth 0.N Cl), wth data collected every 5 mute for a total of hour et : ut aalyzed by ubttutg 5% (v/v) of tet medum wth Alcohol USP ad data collecto every 5 mute for a total of hour et 3: ut aalyzed by ubttutg 0% (v/v) of tet medum wth Alcohol USP ad data collecto every 5 mute for a total of hour et 4: ut aalyzed by ubttutg 40% (v/v) of tet medum wth Alcohol USP ad data collecto every 5 mute for a total of hour Both tet ad L product mut be teted accordgly ad data mut be provded o dvdual ut, mea, rage ad %CV o both tregth. Addtoal commet regardg the boequvalece tudy:. Addtoal Boequvalece Metrc Partal AUC he Cocerta ablet labelg dcate that Cocerta (methylphedate hydrochlorde) exteded-releae tablet a exteded-releae formulato of methylphedate wth a b-modal releae profle. Each Cocerta tablet compred of a mmedate-releae compoet ad a exteded-releae compoet, thu provdg a mmedate releae of methylphedate ad a ecod exteded releae of methylphedate. hu, Cocerta a multphac modfed-releae formulato deged to releae a bolu of methylphedate followed by lower delvery later the day. Accordg to the FA-approved labelg for th product, clcal tude howed tattcally gfcat mprovemet behavoral aemet core throughout hour, relatve to placebo, followg admtrato ecommeded Sep 0; eved Nov 04

3 of a gle morg doe. A th multphac modfed-releae doage form deged to acheve both rapd oet of actvty ad utaed actvty wth a durato of hour, FA ugget that addtoal boequvalece metrc may be approprate to eure that a geerc (tet) vero therapeutcally equvalet to the correpodg referece product. hu, for Cocerta the followg three partal AUC (pauc) metrc are propoed addto to the tradtoal (AUC 0- ad C max ) metrc: AUC 0- hould compare tet & referece ytemc expoure repoble for early oet of repoe durg the early part of the oce-daly dog terval; AUC - hould compare tet & referece ytemc expoure repoble for utag the repoe the mddle of the oce-daly dog terval. For the chldre takg th medcato, th would correpod to the early afteroo tme to eure the completo of the chool day after luch; ad AUC -3 hould compare tet & referece ytemc expoure repoble for mateace of the repoe late tage of the oce-daly dog terval. For the chldre takg th medcato, th would correpod to the late afteroo tme to eure the completo of homework ad other after-chool actvte. he 90% cofdece terval of the geometrc mea tet/referece (/) rato for the above fve C max ad AUC metrc (C max, AUC 0-, AUC -, AUC -3, AUC 0- ) hould fall wth the lmt of 80-5%. he amplg tme () for the frt pauc baed o tme at whch 90-95% of ubject are lkely to acheve optmal early oet of repoe. Becaue the rate of tal methylphedate aborpto aocated wth the rate of early oet of repoe, the amplg tme determed baed o max of the mmedate-releae porto of the formulato. max a pharmacoketc parameter aocated wth rate of repoe. baed o the chool hour ad max of the exteded-releae porto of the formulato. 3 baed o the effcacy durato clam of Cocerta from the pvotal clcal tude. Fatg Study: Log-traformed AUC 0-3, AUC 3-7, AUC 7-, AUC 0-, ad C max, where AUC 0-3 the area uder the plama-cocetrato v. tme curve from 0 to 3 hour, AUC 3-7 area uder the curve from 3 to 7 hour; AUC 7- area uder the curve from 7 to hour; AUC 0- area uder the curve from 0 to fty, ad C max the maxmum plama cocetrato. he pauc, AUC 0-3, AUC 3-7, ad AUC 7- have bee determed to be the mot approprate parameter for evaluato of the drug boavalablty repoble for the quck oet ad utaed mateace of the clcal repoe throughout the durato of drug effect. hee three pauc replace the uual AUC 0-t, ad together wth the other boequvalece parameter, AUC 0- ad C max, wll eure that the pharmacoketc profle ad clcal effect of tet ad referece product are uffcetly mlar. Fed Study: Log-traformed AUC 0-4, AUC 4-8, AUC 8-, AUC 0-, ad C max, where AUC 0-4 the area uder the plama-cocetrato v. tme curve from 0 to 4 hour, AUC 4-8 area uder the curve from 4 to 8 hour; AUC 8- area uder the curve from 8 to hour; AUC 0- area uder the curve from 0 to fty, ad C max the maxmum plama cocetrato. he pauc, AUC 0-4, AUC 4-8, ad AUC 8- have bee determed to be the mot approprate parameter for evaluato of the drug boavalablty repoble for the quck oet ad utaed mateace ecommeded Sep 0; eved Nov 04 3

4 of the clcal repoe throughout the durato of drug effect. hee three pauc replace the uual AUC 0-t, ad together wth the other boequvalece parameter, AUC 0- ad C max, wll eure that the pharmacoketc profle ad clcal effect of tet ad referece product are uffcetly mlar. he reao for electg 3 hour ad 4 hour, repectvely, for the early oet pauc fatg ad fed tude are a follow: For the mmedate-releae porto of the formulato, max about hour fatg ubject; Food prolog the max of mmedate-releae methylphedate by about hour; he methylphedate max tadard devato about 0.5 hour; For max, two tadard devato.0; Geerally, approxmately 95% of obervato fall wth two tadard devato of the mea; hu, ce the max from the mmedate-releae porto of th formulato about hour uder fatg codto ad 3 hour uder fed codto, pauc calculated to 0-3 hour a fatg BE tudy ad 0-4 hour a fed BE tudy hould capture the repoe of 95% of the ubject. h hould provde aurace that a tet ad referece product wll be therapeutcally equvalet over the early part of the daly dog terval, correpodg to oet of repoe. he reao for electg 7 ad 8 hour for the mddle pauc the fatg ad fed tude, repectvely, are baed o the max value of exteded-releae porto of th formulato ad chool hour. h wll eure mlar drug expoure durg the remag chool hour after early oet of repoe. he reao for electg hour for the late pauc both the fatg ad fed tude due to the labelled effcacy durato (.e., hour). AUC 3-7 ad AUC 7- the fatg tate, ad AUC 4-8 ad AUC 8- the fed tate hould eure that two product are therapeutcally equvalet over the later part of the daly dog terval, correpodg to the durato of the utaed repoe.. Stattcal Aaly of Pharmacoketc ata ubject-by-formulato teracto varace o eure the wtchablty betwee Cocerta ad geerc product, a ubject-by-formulato tet for each PK metrc recommeded addto to the etablhmet of average boequvalece baed o the PK metrc detfed the prevou ecto. he procedure to calculate the pot etmate for ubject-by-formulato teracto varace ca be foud APPENX G of the FA 00 boequvalece tattcal gudace, but alo reproduced th recommedato Step -3. Step. efe ew varable ug the logarthm-traformed pharmacoketc (PK) parameter (AUC 0-3, AUC 3-7, AUC 7-, AUC 0-, ad C max for the fatg tudy; AUC 0-4, AUC 4-8, AUC 8-, AUC 0-, ad C max for the fed tudy). Gudace for dutry: Stattcal Approache to Etablhg Boequvalece, Jauary 00. Acceble from: UCM07044.pdf ecommeded Sep 0; eved Nov 04 4

5 Aumg a four-perod deg wth equal replcato of the referece () ad tet () treatmet arm each equece, each logarthm-traformed PK parameter defed a where: kl, ; dcate equece j, ; dcate ubject wth equece k,; dcate treatmet l,; dcate replcate o treatmet k for ubject wth equece he ew varable are defed a: Where: ( + ) ( + ) Step. Compute the formulato mea ad the varace of,, ad, poolg acro equece. hee varace etmate are deoted a M, M, ad M, repectvely, where ˆµ, k, ad ˆ ˆ µ ˆ µ k k k j l M ˆ M ˆ W M ˆ W kl j j j ( ) ( ( ) ) Step 3. Etmate the ubject-by-formulato teracto varace,, by: ecommeded Sep 0; eved Nov 04 5

6 ˆ σ ˆ σ ( ˆ σ + ˆ σ ) M ( M + M ) W W Step 4. eterme, the 95% upper cofdece boud for. he table below llutrate the cotructo of a (-α) level upper cofdece boud for. Ue α0.05 for a 95% upper cofdece boud. Note E q Pot Etmate q Cofdece Boud U q ( q - E q ) E M ( ) M U χ α,. E 0. 5 M 0.5 ( ) χ α, M U E M ( ) χ α, M U 3 σ ( ) / E q + U q ( ) / E q + U q the upper 95% cofdece boud for ˆ σ σ. χ α, from the cumulatve dtrbuto fucto of the ch-quare dtrbuto wth - degree of freedom,.e. Pr( χ χα, ) α. A per APPENX A the FA 00 boequvalece gudace, the recommeded allowace for ecommeded Sep 0; eved Nov 04 6