01 PQRI Lee Botanicals 20151

8/15/2019 01 PQRI Lee Botanicals 20151

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Botanical Drug Development

and Quality Standards

Sau (Larry) Lee, Ph.D.Acting Associate Director for ScienceBotanical Review Team Leaer

!ffice of Pharmaceutical "uality, #D$R, %DA

%DA&P"R' #onference on Avancing Prouct "uality

!ctoer , *+-


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Disclaimer

!inions e/resse in this resentation are those of the

resenter an o not necessarily reflect the views or

olicies of the %DA.

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Outline

0 1hat are otanical rugs2

0 Scientific challenges in otanical rug eveloment anevaluation

0 %DA aroach for evaluating otanical rug alications

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What are the botanical drugs?

0 The term botanical means rouctsthat inclue lant materials, algae,

macroscoic fungi, or cominationsthereof.3 't e/clues highly urifie rug

sustances, roucts containinganimals or animal arts an orminerals, materials erive fromgenetically moifie otanical secies,an fermentation roucts

0 Botanical rugs may e availale invarious forms, incluing solutions,owers, talets, casules, toicals,or in4ectales.

0 Two %DA5arove otanical 6DAs73 8eregen an %uly9a:

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Botanical Drug Characteristics

0 Botanical rugs are heterogeneous mi/tures that contain7

3 ;ultile chemical comonents3 Potentially more than one chemical comonent that contriutes

meaningfully to the mi/ture


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Unique Characteristics ofBotanical Drugs

0 Botanical rugs e/hiit atch5to5atch variations in

roerties (e.g., chemical comosition).3 6atural variaility at the lant an raw material levels

3 =reater than the variaility tyically oserve in non5otanical

rugs (e.g., chemically synthesi9e an urifie rug molecules)

0 ;any otanical rug caniates have revious human5use

e/erience.

3 Dietary sulements in the >.S.

3 ?eral meicines (e.g., $uroe)3 Traitional meicines (e.g., #hina)

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Challenges0 Botanical rugs are comle/

3 ;ultile chemical comonents

3 6ot well5efine active comonent(s)

3 6atural variations0 #D$R generally consiers the entire mi/ture as the active

ingreient (AP') for otanical rugs3 Regulations on fi/e comination rugs o not aly to the otanical

mi/ture erive from a single otanical raw material

0 Botanical roucts intene to e mar@ete as rugs in the >niteStates are e/ecte to meet the same stanars as non5otanicalrugs for :uality, safety, an efficacy.

3 A conventional #;# aroach for small5molecule rugs (mainly ase onchemical testing) is generally insufficient for :uality control of otanical

roucts.3 'nformation on rior human use may rovie some inication of the

safety rofile of otanical roucts.

3 Level of clinical efficacy an safety re:uirements is the same forotanical an non5otanical rugs.

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D! approach toevaluation of botanical drugs

0 $ncourage research an eveloment of otanicals as new

rugs0 #D$R Botanical Review Team

0 *++ %DA =uiance for 'nustry7 Botanical Drug Proucts

0 *+- %DA Draft =uiance for 'nustry7 Botanical DrugDeveloment

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CD"# Botanical #evie$ %eam

0 $stalishe in *++

3 Previously uner the !ffice of 6ew Drugs3 Transferre to the !ffice of Pharmaceutical "uality in *+

0 Provies scientific e/ertise on otanical issues to the

review staff

0 $nsures consistent interretation an imlementation ofthe Botanical =uiance an relate olicies

0 #onsoliates e/eriences in regulatory review of otanical

alications an comiles information on the status ofotanical rug sumissions for agency management

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&harmacognosy #evie$ byCD"# Botanical #evie$ %eam

0 ;eicinal lant iology

3 'entification, otential misuses of relate secies0 Prior human e/eriences

3 ;ostly in traitional meicine&comlementary an alternativemeicine (#A;) systems, such as traitional #hinese meicines

3 $vience of rior an current uses

0 $/tensive review of ast e/eriences an current uses0 Documentation of mar@eting history (volume of sales, averse events, etc.)

0 All tyes of ol ata e consiere an reviewe to etermine relevance

0 Pharmacology of otanical rugs3 !l theories an ractices an new testing

0 Prouct :uality3 $nsuring :uality an theraeutic consistency ase on integrate

totality-of-evidence aroach

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B#% Current 'embers

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Sau (Larry) Lee, Ph.D. ,Associate Dir. C Team Leaer

Sau.Leefa.hhs.gov

Einhui Dou, Ph.D.,Pharmacologist CPharmacognosist

4inhui.oufa.hhs.gov #assie Taylor, Ph.D.,

#hemist

#assanra.Taylorfa.hhs.gov

#harles 1u, Ph.D.,

Senior Pharmacologistcharles.wufa.hhs.gov


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())* D! Botanical +uidance,-ey &rinciples0 'nformation on rior human use may sustitute for animal

to/icology stuies3 6on5clinical evaluation may e reuce or elaye for certainotanical roucts entering hase an * trials

0 %le/ile #;# aroach is emhasi9e

3 'entification of active comonents in a otanical mi/ture may note necessary

0 But relevant chemical mar@er(s) neee for :uality control

3 %urther urification generally not neee

0 But aitional control of otanical raw material neee

0 The level of overall clinical efficacy&safety re:uirements isthe same for otanical an non5otanical rugs for 6DAaroval

3 The ris@&enefit analysis aroach will e the same

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Botanical !pplications in CD"#

0 > to *+

3 ;ore than ++ re5'6Ds&'6Ds

3 Aro/. & commercial, *& research

3 *& single otanical raw material, & multile otanical raw

materials

3 ;a4ority in hase *, an a hanful of them in hase

3 Two 6DAs arove

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Botanical !pplications in CD"#

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10%

3%

5%1%

4%

9%

7%

1%7%3%

1%

34%

1% 7%

1%4%

IND

Review Distribution

Anesthesia, Analgesia, and AddictionAnti-infective

Antiviral

Bone, Reproductive, and rologic

!ardio-Renal

"er#atological "ental

$astroenterolog

&e#atolog

'eta(olis# and )ndocrinolog

*eurolog

*onprescription !linical

+ncolog

schiatr

ul#onar Allerg

ransplant and +phthal#olog

rologic Reproductive

Oncology Dermatological Dental

Anesthesia

Analgesia

Addiction


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()./ D! Draft Botanical +uidance

0 Revises the final %DA Botanical =uiance issue in *++

3 The recommenations for early5hase trials remains the same

0 Provies aitional secific recommenations to etter

aress late5hase eveloment an 6DA sumission for

otanical rugs

3 8eregen arove in *++3 %uly9a: arove in *+*

0 Recommens an integrate (the so5calle totality of

evidence) aroach to ensure the consistency of :uality an

thus theraeutic effects of otanical rug roucts for

aroval an mar@eting

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0ntegrated !pproach toQuality Control of Botanical Drugs0 To ensure that mar@ete rouct atches eliver a theraeutic effect

consistent with that oserve for rouct atches teste in clinical

stuies (i.e., theraeutic consistency)

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'anufacturing

&rocess Control

!nalytical %esting

0 #hromatograhy

0 Sectroscoy

#a$ 'aterial

Control

0 #ultivar control0 =oo Agricultural

& #ollection

ractices (=A#P)

it1for1&urpose

Clinical Design

0 ;ultile

atches

0 Dose resonse

Bioassay


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Case Study, uly2aq0 The *n otanical 6DA (arove on Decemer , *+*)

0 Delaye5release oral talet containing *- mg crofelemer

0 #rofelemer, a otanical rug sustance erive from the cruelant late/ of Croton lechleri (Dragon’s Blood )

0 st %DA arove rug for symtomatic relief of noninfectious

iarrhea in atients with ?'8&A'DS on antiretroviral theray

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Crofelemer Structure0 An oligomeric roanthocyaniin mi/ture rimarily comose of (F)5

catechin, (5)5eicatechin, (F)5gallocatechin, an (5)5eigallocatechin

monomer units lin@e in ranom se:uence

0 ;ultile analytical methos collectively rovie e/tensive information

on the structural signatures of crofelemer (e.g., the comosition of

roanthocyaniin oligomers)

0 These analytical methos were ultimately consiere insufficient to

suort the characteri9ation of :uality control of this comle/ mi/ture

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Latex from Croton Lechleri


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!dditional Data to Support %herapeutic Consistency of uly2aq

0 Botanical raw material control

3 'mlementation of =oo Agricultural an #ollection Practices(=A#P)

3 Restriction of harvesting otanical raw material to secific eco5geograhic regions ($=Rs)

3 Reuces the variaility at the lant an raw material levels

0 Bioassay3 Base on well5@nown mechanism of action (i.e., crofelemer targets

an controls ual intestinal chlorie channels7 cA;P5stimulatecystic firosis transmemrane conuctance regulator #l5 channel

an the calcium5activate #l5 channel)3 Potentially rovies more fle/iility for the manufacturer to ma@e

ostaroval changes (e.g., e/ansion of $=Rs to increase aniversify the otanical raw material suly)

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!dditional Data to Support %herapeutic Consistency of uly2aq

0 Dose5resonse clinical ata generate ase on multile

atches3 The rug


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3esson 3earned fromBotanical 4D!s

0 Aroval of otanical 6DAs is ossile

0 Practical aroach for :uality control of otanicalroucts can e eveloe

3 Raw material controls re:uire

3 #linical relevant secifications for rug sustance&rouct can

e estalishe if multile atches are use in the ivotal clinical

trials

3 !ther ata, e.g., from ioassay an&or multile5atch, ose

resonse clinical trials, may e neee, in con4unction with

conventional #;# ata, to hel ensure theraeutic consistency

0 #linical trials of otanical rugs are no more ifficult

than non5otanical rugs

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3esson 3earned from

Botanical 4D!s

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htt7&&www.sciencemag.org&site&roucts&collectio

noo@s&T#;KEanKK*+-Khigh*+res.f


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Challenges of Developing &roductsfrom 'ultiple Botanical #a$ 'aterials

0 A otanical mi/ture from one lant secies is not

consiere as a fi/e comination rug3 The mi/ture as a whole is consiere as the active ingreient

0 6umer of '6Ds for otanical roucts erive frommultile otanical raw materials is increasing

0 %DA currently consiers otanical roucts erive frommultile otanical raw materials as fi/e5comination rugs

3 ?owever, %DA recogni9es that emonstrating each otanical rawmaterial

01 PQRI Lee Botanicals 20151

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