Toxicology and Other Data to Support

Clinical Development of Botanical Drugs*

Jinhui Dou, Ph.D. Expert Pharmacologist and Team Leader

Botanical Review Team, OPQ,CDER

April 19, 2017

2017 Spring Symposium, NCAC-SOT

*Opinions expressed in this presentation are those of the presenter’s and

do not necessarily reflect the views or policies of the FDA

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• “Plants that Heal”: Plant derived drugs • Botanical Drug Guidance

– Guidance for Industry - Botanical drug Products (Draft, 2000) – Finalized botanical drug Guidance (2004) Principles of the Guidance

• CDER Botanical drug review experience – Investigational New Drug review (IND) – Veregen NDA (October, 2006) Toxicology studies

– Fulyzaq NDA (December, 2012) • Revised Guidance (December 2016)

– Quality and therapeutic consistency – Proposed rule for combination drugs

Botanical drug from multiple botanical raw materials (BRMs)

– Augment active ingredients (“spiking”)

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OUTLINE

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“Plants that Heal” • Plant derived drug products:

– >25% prescription drugs are derived from plants – >90% of current therapeutic classes from natural product

prototype Newman DJ, Cragg GM. J Nat Prod. 2007 Mar;70(3):461-77.

• Examples of highly purified drugs from plants

– Paclitaxel – Artemisinin

• Plant-derived mixtures as the active ingredients of botanical drugs – Psyllium, pyrethrins (OTC), Digitalis (digoxin and digitoxin) – Veregen (catechins from a partially purified green tea extract) – Fulyzaq (proanthocyanidins from Croton lechleri)

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Botanical Drug Guidance (2004 and 2016):

www.fda.gov

http://www.fda.gov/downloads/Drugs/G

uidanceComplianceRegulatoryInformati

on/Guidances/ucm070491.pdf

https://www.fda.gov/downloads/Drugs/Guidance

s/UCM458484.pdf

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Botanical Drug Product:

• Definition: A botanical mixture used as a drug

• A product that contains as ingredients: vegetable materials, which may include plant materials, algae, macroscopic fungi, or combinations thereof, that is used as a drug. It may be available as, but not limited to, a solution (e.g., tea), powder, tablet, capsule, elixir, topical or injectable.

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Botanical Drugs Excluded:

• Highly purified substance, either derived from a naturally occurring source (e.g., paclitaxel) or chemically modified (e.g., estrogens synthesized from yam extracts)

• Genetically modified botanical species intended to produce a single molecular entity (e.g., by recombinant DNA technology or cloning)

• Products produced by fermentation of yeast, bacteria, plant cells, or other microscopic organisms, including plants used as substrates – if the objective of the process is to produce a singular molecular entity (e.g.,

antibiotics, amino acids, and vitamins) or a biologic drug

• Products containing animal or animal parts (i.e., insects) and/or minerals, except when used in a traditional botanical preparation – Concepts of the Guidance may still be applicable to animal derived mixtures

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Botanical Guidance-Basic Principles (1)

• The importance of botanical raw material quality control

is emphasized

• Prior human experience may be used to support early

phase clinical trials (mostly phase 2) – Non-clinical evaluations may be reduced or delayed for initial trials

• Most of the standard animal toxicology studies are

necessary for NDA approval

– Reference the Guidance for Industry M3(R2) “Nonclinical Safety Studies for

the Conduct of Human Clinical Trials and Marketing Authorization for

Pharmaceuticals”

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Botanical Guidance-Basic Principles (2)

• Adequate and well-controlled trials are necessary for

marketing botanical drugs in the US

– Multiple-dose and multiple-batch for demonstration of

“therapeutic consistency” outlined in the revised Guidance

(2016)

• Same level of overall clinical efficacy/safety requirements

as non-botanical drugs for NDA approval

– The risk/benefit analysis approach will be the same for

botanical and non-botanical drugs

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Botanical Guidance - 2004 and 2016

• The general approach to botanical drug development (and

review) has remained unchanged since 2004

• Specific recommendations have been modified and new

sections have been added to better address late-phase

development and NDA submission for botanical drugs

– Revised Guidance are based on improved understanding of

botanical drugs and experience acquired in the reviews of

botanical NDAs and INDs.

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CDER Botanical Review Team

• Establishment of BRT publically announced in 2003 – Team existed since 2001 – Previously under the Office of New Drugs (OND) – Reassigned to the Office of Pharmaceutical Quality (OPQ) in

2013

• Provides scientific expertise on botanical issues to the review staff – Pharmacognosy review of INDs and NDAs

• Complementary to CMC and pharmacology/toxicology reviews

– Consultation on botanicals not related to INDs/NDAs

• Ensures consistent interpretation and implementation of the Botanical Guidance and related policies

• Provides consultations on botanical related issues (e.g., safety and compliance) to other offices in CDER and FDA

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Pharmacognosy Review of Botanical Drugs

• Prior human experiences in herbal medicine systems to support the safety of the proposed study – e.g., Ayurveda, traditional Chinese medicine (TCM)

• Medicinal plant biology and chemistry – Identification of the original plant – Raw material quality control

• Pharmacology and toxicology information of the botanical products in literature

• Active or toxic marker compounds • Quality and therapeutic consistency

– Good agricultural and collection practice and other raw material control to minimize variations at the source

– Selection of representative nonclinical and clinical batches – Overall control strategy to ensure batch-to-batch

consistency (e.g., the need of bioassay for certain products)

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Botanical INDs in CDER (2002-2015)

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Botanical INDs by Therapeutic Areas

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Veregen (Sinecatechins, NDA 021902)

• Sponsor: MediGene, Inc. (Germany) • Drug substance: Sinecatechins (aka PolyPhenon

E, Partially purified green tea extract (Japan)

• BRM: Green tea, the dried leaves of Camellia sinensis (China)

• Formulation: 15% Ointment • Routine: Topical • Indication: Genital/perianal warts • Approval Date: October 31, 2006

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NDA 021902: Botanical Raw Material

• “Green tea” – Non-fermented leaves of Camellia sinensis

• Botanical raw material from numerous cultivars were collected on farms – Source of the variations in components

• Specify all the cultivars and use the same cultivars/farms for marketing batches – Good Agricultural and Collection Practice (GACP)

• Traceability

• Minimize natural variability and improve raw material quality control

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Veregen NDA: Safety Pharmacology

• Two safety pharmacology studies were performed in rats with Sinecatechins

• No significant behavioral and physiological changes or

changes on respiration rate and tidal volume were observed in rats treated orally with up to 1000 mg/kg drug substance

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Veregen NDA: Toxicokinetics

•EGCg, the main catechin in the drug substance, was used to as an indicator of exposure levels

•Evaluated in rats and mini-pigs by oral, topical, or intravaginal routes

•Catechins were absorbed and systemically available only minimally in minipigs following topical application

•No significant accumulation of plasma EGCg concentrations following repeated topical or intravaginal applications in mini-pigs, rabbits, or rats

•EGCg and its metabolites tended to concentrated in the liver after intravenous administration and in the GI after oral administration in dogs

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Veregen NDA: General Toxicology Studies

•3 Months orally or topically in rats and 9 Months topically in minipigs

•Target organs in rats: GI, liver, pancreas, and lymphoid tissues

•Minimal to severe local irritation including erythema, edema, and inflammatory reactions when topically applied to rats, rabbits, and mini-pigs (consistent with clinical observations)

•No systemic toxicity seen after topical treatment – Relatively low doses comparing to catechins consumed orally in the forms of beverages or capsules (up to 2 g)

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Veregen NDA: GeneTox and Carcinogenicity Studies

• Genetic Toxicology Studies (Drug Substance)

– Ames (-), In Vivo Rat MN (-)

– MLA (+)

– UDS (-), 28-Day Transgenic Mouse Mutation Assay (-)

• Carcinogenicity Studies (Drug Substance)

– p53 Transgenic mouse model (-)

– No 2-year carcinogenicity study

• Reported chemopreventive and anti-tumor effects of tea

catechins

• Extensive human experience of green tea

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Veregen NDA: Reproductive and Developmental Toxicology Studies

•Tested in rats and/or rabbits via oral,

subcutaneous, and intravaginal administration

•Drug Substance

–Not teratogenic in rats and rabbits

–Reduced fetal weights and delayed skeletal

ossification in rabbits

–Increased incidence of stillbirths in rats

•Pregnancy Category C

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Veregen NDA: Local Tolerance Studies

•Drug Product

–Tested in rats, rabbits, and mini-pigs

–Topical or vaginal administration.

–Topical treatment caused minimal to severe local

irritation in animals

–Strong local irritation to vaginal mucosa after

vaginal application in female rats and mini-pigs

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Veregen NDA: Special Toxicology Studies

•Drug Product -Sensitizer

–LLNA (+): Both drug product and substance

–Tested in guinea-pig (+)

•No Photoirritation Studies

– Green tea extracts have been used in cosmetic

products

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Green catechins: Severe Toxicity under Fasting

• Severe toxicity in dogs when given high oral doses ( 150 mg/kg/day EGCg) after fasting (Data from NCI studies)

• Much less toxicity seen in dogs in fed state

• Not a safety concern for Veregen because of very low human systemic exposure: – Low clinical daily dose of the drug product

• (~2 mg/kg/day sinecatechins)

– Low absorption from topical application

•Safety database for polyphenons from other human use

– PK studies were conducted using a green tea beverage

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Ensure Quality and Therapeutic Consistency for Veregen

• Quality control extended to green tea raw material

• Reasonably tight CMC control for the drug substance

– 8 catechins fully characterized and quantified

– Large portion (85-90%) of the drug substance was characterized

• “Multiple-batch” in phase 3 clinical trials

– NDA drug substance specifications were derived from data of Phase 3 clinical batches

• Flat Dose-Response

– The 10% ointment and the 15% of the Veregen product had similar response rates

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NDA 202292: The Medicinal Plant for Crofelemer

The botanical raw material (latex) is collected from Croton lechleri Müll. Arg. (Euphorbiaceae) in Peru.

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Ensure Quality and Therapeutic Consistency for Fulyzaq (1)

• Extend quality control to the botanical raw material

– Latex from a well identified single plant species

• Botanical Raw Material (BRM) tested for major classes of compounds

– GACP established for the raw material collection

• Sustainable harvest of the latex from mature trees

• Reasonable CMC for Crofelemer as a complex botanical mixture

– Further characterization and quantification of proanthocyanidin oligomers at molecular level difficult due to nature of the botanical and technical limitations

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Ensure Quality and Therapeutic Consistency for Fulyzaq (2)

• Other information to support therapeutic consistency and safety

– Bioassay to demonstrate batch consistency

– In vitro and PK data indicated that closing of chloride channels saturated at clinical doses

– Multiple-dose and multiple-batch phase 3 trials suggest clinical responses not sensitive to dose or batch variations

– Locally active with low absorption and systemic exposure

– Extensive herbal medicine use to treat diarrhea helpful

• The latex, commonly known as “Dragon’s blood”, is the number one herbal medicine for diarrhea in Peru (at relatively large doses)

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Drug Substances of Veregen and Fulyzaq

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Catechin in Sinecatechins Proanthocyanidins in Crofelemer

R = H (C and EC) or

R= OH (GC and EGC)

Average range n = 3 to 5.5

(n = 1-28 as literature reported)

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Lessons Learned from Botanical NDA Reviews

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http://www.nature.com/nbt/journal/v26/n10/pdf/nbt1008-1077.pdf

Science 2015 Jan 16;347(6219 Suppl.):S32-4 http://www.sciencemag.org/site/products/collectio

nbooks/TCM_Jan_16_2015_high%20res.pdf

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What’s New in the Guidance (2016): Augment Active Constituents (P12)

• Although generally discouraged, it may be permissible in unusual cases to augment levels of individual active constituents in a botanical drug product to achieve batch-to-batch consistency in the therapeutic effect.

• Only appropriate:

– In situations in which the active constituents in the drug substance are known

– There is a substantial natural variation in the concentrations of these active constituents in the botanical raw material (e.g., due to changes in growing conditions over time that cannot be controlled).

• when limited amounts of the purified active constituents could be added to meet the specification for a benchmark drug substance – The target levels of active constituents should not exceed levels that occur

naturally.

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Fixed-Dose Combination in the Guidance (2016):

• Proposed Rule on Fixed-Combination and Co-Packaged Drugs (https://www.gpo.gov/fdsys/pkg/FR-2015-12-23/pdf/2015-32246.pdf)

• Fixed dose drug combinations (FDCs) are combinations of two or more active drugs in a single dosage form as defined under the Fixed-Combination regulations (21 CFR 300.50 and 330.10(a)(4)(iv)).

– Current regulations require demonstration of the contribution toward overall efficacy and safety of each component of a combination drug product.

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Fixed-Dose Combination in the Botanical Guidance (2016):

• The Agency believes that it is desirable to facilitate the development of botanicals and other natural products that have been used in humans. Both the 2004 and 2016 outlined similar thinking on combination: – A botanical drug product derived from a single source (e.g., a

single botanical raw material) would not be considered a fixed combination drug product … the entire botanical mixture generally is considered to be the active ingredient.

• Agency has proposed revisions to the current Fixed-Combination regulations that would allow FDA to waive the combination rule requirements in certain situations. – Exemption (or waiver) may be given to traditional formula, like

many of those used in Ayurveda or TCM, with 4 or more BRMs (i.e., herbs)

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Consideration of Botanical Drugs (1): Following the leads of human experience

• Dragon’s blood has been commonly used for treating diarrhea in Peru

and other countries in South America

• Other herbs (e.g., TCM herbs) containing polyphenols (e.g., condensed

tannins) also used as anti-diarrhea agents

• “Polyphenols as astringent agents to stop diarrhea” (涩肠止泻)

• Artemisinin discovery initiated from Artemisia’s TCM

use for malaria treatment • Nobel Prize to Professor Youyou Tu in 2015

• Artemisia herb is still in use

• Dried-leaf Artemisia annua: A practical malaria therapeutic for developing countries?

Weathers PJ et al. World J Pharmacol. 2014; 3(4):39-55.

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Consideration of Botanical Drugs (2): Artemisia or its combinations to treat malaria?

Tanzania, a Wa-arusha man harvests Artemisia, a Chinese herb used for treating malaria for ages

James Duke, Fulton, MD Retired USDA Botanist and Herbalist

Cragg G, Ferreira J. et. al, C&EN, 83(18); p4 May 2, 2005

Dried-leaf Artemisia annua: A practical

malaria therapeutic for developing countries? Weathers PJ et al. World J Pharmacol. 2014 ;3(4):39-55.

http://www7.nationalgeographic.com/ngm/0707/feature1/gallery1.html http://ngm.nationalgeographic.com/2007/07/malaria/stanmeyer-photography

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Acknowledgement

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➢ Lily Flower (4 petals & 4 sepals) @ FDA WO Campus

Morning Glory @ Haidian, Beijing

Dr. Jiaqin Yao, Senior Pharmacologist of DDDP, for sharing his review summaries. Comments and Questions: Jinhui Dou Jinhui.Dou@fda.hhs.gov