Location via proxy:   [ UP ]  
[Report a bug]   [Manage cookies]                
Scribd Logo
Upload

Welcome to Scribd!

  • 183 views

    01 PQRI Lee Botanicals 20151

    Uploaded by

    刘朝阳
    This document summarizes a presentation given by Dr. Sau Lee on botanical drug development and quality standards. It discusses the challenges in developing botanical drugs due to their complex and variable nature. It provides an overview of the FDA's approach, including guidance documents and the role of the Botanical Review Team. It also reviews lessons learned from the approval of the first two botanical new drug applications, including the need for raw material control, clinical data from multiple batches, and other evidence to ensure consistent quality and therapeutic effects.

    Copyright:

    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd

    01 PQRI Lee Botanicals 20151

    Uploaded by

    刘朝阳
    183 views23 pages
    This document summarizes a presentation given by Dr. Sau Lee on botanical drug development and quality standards. It discusses the challenges in developing botanical drugs due to their complex and variable nature. It provides an overview of the FDA's approach, including guidance documents and the role of the Botanical Review Team. It also reviews lessons learned from the approval of the first two botanical new drug applications, including the need for raw material control, clinical data from multiple batches, and other evidence to ensure consistent quality and therapeutic effects.

    Original Description:

    Botanicals

    Copyright

    © © All Rights Reserved

    Available Formats

    PDF, TXT or read online from Scribd

    Did you find this document useful?

    Is this content inappropriate?

    This document summarizes a presentation given by Dr. Sau Lee on botanical drug development and quality standards. It discusses the challenges in developing botanical drugs due to their complex and variable nature. It provides an overview of the FDA's approach, including guidance documents and the role of the Botanical Review Team. It also reviews lessons learned from the approval of the first two botanical new drug applications, including the need for raw material control, clinical data from multiple batches, and other evidence to ensure consistent quality and therapeutic effects.

    Copyright:

    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd
    Download as pdf or txt
    183 views23 pages

    01 PQRI Lee Botanicals 20151

    Uploaded by

    刘朝阳
    This document summarizes a presentation given by Dr. Sau Lee on botanical drug development and quality standards. It discusses the challenges in developing botanical drugs due to their complex and variable nature. It provides an overview of the FDA's approach, including guidance documents and the role of the Botanical Review Team. It also reviews lessons learned from the approval of the first two botanical new drug applications, including the need for raw material control, clinical data from multiple batches, and other evidence to ensure consistent quality and therapeutic effects.

    Copyright:

    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd
    Download as pdf or txt
    of 23
    At a glance
    Powered by AI
    Some key takeaways are that botanical drugs are complex mixtures containing multiple chemical components and natural variations. FDA considers the entire botanical mixture as the active ingredient. Two botanical drugs have been approved by FDA so far.

    Some challenges in developing botanical drugs include that the active components are generally not well characterized, there are natural variations in chemical composition between batches, and a conventional approach for quality control may not be sufficient.

    FDA approved Fulyzaq as a botanical drug by implementing raw material controls, using a bioassay based on its mechanism of action, generating dose-response clinical data from multiple batches, and establishing clinical specifications based on multiple batches in pivotal trials.

    Botanical Drug Development

    and Quality Standards


    Sau (Larry) Lee, Ph.D.
    Acting Associate Director for Science
    Botanical Review Team Leader
    Office of Pharmaceutical Quality, CDER, FDA
    FDA/PQRI Conference on Advancing Product Quality
    October 6, 2015

    Disclaimer
    Opinions expressed in this presentation are those of the
    presenter and do not necessarily reflect the views or
    policies of the FDA.

    Outline
    What are botanical drugs?
    Scientific challenges in botanical drug development and
    evaluation
    FDA approach for evaluating botanical drug applications

    What are the botanical drugs?


    The term botanical means products
    that include plant materials, algae,
    macroscopic fungi, or combinations
    thereof.
    It excludes highly purified drug
    substances, products containing
    animals or animal parts and or
    minerals, materials derived from
    genetically modified botanical species,
    and fermentation products

    Botanical drugs may be available in


    various forms, including solutions,
    powders, tablets, capsules, topicals,
    or injectables.
    Two FDA-approved botanical NDAs:
    Veregen and Fulyzaq

    Botanical Drug Characteristics


    Botanical drugs are heterogeneous mixtures that contain:
    Multiple chemical components
    Potentially more than one chemical component that contributes
    meaningfully to the mixtures physiological or pharmacological
    action
    Latex from Croton Lechleri

    Chemical components in a botanical mixture and their


    biological activities are generally not well characterized.
    5

    Unique Characteristics of
    Botanical Drugs
    Botanical drugs exhibit batch-to-batch variations in
    properties (e.g., chemical composition).
    Natural variability at the plant and raw material levels
    Greater than the variability typically observed in non-botanical
    drugs (e.g., chemically synthesized and purified drug molecules)

    Many botanical drug candidates have previous human-use


    experience.
    Dietary supplements in the U.S.
    Herbal medicines (e.g., Europe)
    Traditional medicines (e.g., China)

    Challenges
    Botanical drugs are complex
    Multiple chemical components
    Not well-defined active component(s)
    Natural variations

    CDER generally considers the entire mixture as the active


    ingredient (API) for botanical drugs
    Regulations on fixed combination drugs do not apply to the botanical
    mixture derived from a single botanical raw material

    Botanical products intended to be marketed as drugs in the United


    States are expected to meet the same standards as non-botanical
    drugs for quality, safety, and efficacy.
    A conventional CMC approach for small-molecule drugs (mainly based on
    chemical testing) is generally insufficient for quality control of botanical
    products.
    Information on prior human use may provide some indication of the
    safety profile of botanical products.
    Level of clinical efficacy and safety requirements is the same for
    botanical and non-botanical drugs.
    7

    FDA approach to
    evaluation of botanical drugs
    Encourage research and development of botanicals as new
    drugs
    CDER Botanical Review Team
    2004 FDA Guidance for Industry: Botanical Drug Products
    2015 FDA Draft Guidance for Industry: Botanical Drug
    Development

    CDER Botanical Review Team


    Established in 2003
    Previously under the Office of New Drugs
    Transferred to the Office of Pharmaceutical Quality in 2013

    Provides scientific expertise on botanical issues to the


    review staff
    Ensures consistent interpretation and implementation of
    the Botanical Guidance and related policies
    Consolidates experiences in regulatory review of botanical
    applications and compiles information on the status of
    botanical drug submissions for agency management

    Pharmacognosy Review by
    CDER Botanical Review Team
    Medicinal plant biology
    Identification, potential misuses of related species

    Prior human experiences


    Mostly in traditional medicine/complementary and alternative
    medicine (CAM) systems, such as traditional Chinese medicines
    Evidence of prior and current uses
    Extensive review of past experiences and current uses
    Documentation of marketing history (volume of sales, adverse events, etc.)
    All types of old data be considered and reviewed to determine relevance

    Pharmacology of botanical drugs


    Old theories and practices and new testing

    Product quality
    Ensuring quality and therapeutic consistency based on integrated
    totality-of-evidence approach

    10

    BRT Current Members


    Sau (Larry) Lee, Ph.D. ,
    Associate Dir. & Team Leader
    Sau.Lee@fda.hhs.gov
    Jinhui Dou, Ph.D.,
    Pharmacologist &
    Pharmacognosist
    jinhui.dou@fda.hhs.gov
    Cassie Taylor, Ph.D.,
    Chemist
    Cassandra.Taylor@fda.hhs.gov
    Charles Wu, Ph.D.,
    Senior Pharmacologist
    charles.wu@fda.hhs.gov
    11

    2004 FDA Botanical Guidance:


    Key Principles
    Information on prior human use may substitute for animal
    toxicology studies
    Non-clinical evaluation may be reduced or delayed for certain
    botanical products entering phase 1 and 2 trials

    Flexible CMC approach is emphasized


    Identification of active components in a botanical mixture may not
    be necessary
    But relevant chemical marker(s) needed for quality control

    Further purification generally not needed


    But additional control of botanical raw material needed

    The level of overall clinical efficacy/safety requirements is


    the same for botanical and non-botanical drugs for NDA
    approval
    The risk/benefit analysis approach will be the same
    12

    Botanical Applications in CDER


    Up to 2014
    More than 600 pre-INDs/INDs
    Approx. 1/3 commercial, 2/3 research
    2/3 single botanical raw material, 1/3 multiple botanical raw
    materials
    Majority in phase 2, and a handful of them in phase 3
    Two NDAs approved

    13

    Botanical Applications in CDER


    IND
    Review Distribution
    Anesthesia, Analgesia, and Addiction

    1%
    4%
    1%

    Anti-infective

    10%

    7%

    Anesthesia
    Analgesia
    Addiction

    Antiviral
    3%

    Bone, Reproductive, and Urologic


    5%
    1%

    Cardio-Renal
    Dermatological Dental

    4%

    Gastroenterology
    Hematology

    Dermatological Dental

    Oncology

    9%
    34%

    Metabolism and Endocrinology


    Neurology
    Nonprescription Clinical
    Oncology

    7%

    Psychiatry
    Pulmonary Allergy

    3%
    1%

    7%

    1%

    Transplant and Ophthalmology


    Urologic Reproductive

    14

    2015 FDA Draft Botanical Guidance


    Revises the final FDA Botanical Guidance issued in 2004
    The recommendations for early-phase trials remains the same

    Provides additional specific recommendations to better


    address late-phase development and NDA submission for
    botanical drugs
    Veregen approved in 2006
    Fulyzaq approved in 2012

    Recommends an integrated (the so-called totality of


    evidence) approach to ensure the consistency of quality and
    thus therapeutic effects of botanical drug products for
    approval and marketing

    15

    Integrated Approach to
    Quality Control of Botanical Drugs
    To ensure that marketed product batches deliver a therapeutic effect
    consistent with that observed for product batches tested in clinical
    studies (i.e., therapeutic consistency)
    Fit-for-Purpose
    Clinical Design
    Multiple
    batches
    Dose response

    Raw Material
    Control
    Cultivar control
    Good Agricultural
    / Collection
    practices (GACP)

    Bioassay

    Analytical Testing
    Chromatography
    Spectroscopy

    Manufacturing
    Process Control

    16

    Case Study: Fulyzaq


    The 2nd botanical NDA (approved on December 31, 2012)
    Delayed-release oral tablet containing 125 mg crofelemer
    Crofelemer, a botanical drug substance derived from the crude
    plant latex of Croton lechleri (Dragons Blood)

    1st FDA approved drug for symptomatic relief of noninfectious


    diarrhea in patients with HIV/AIDS on antiretroviral therapy
    17

    Crofelemer Structure
    An oligomeric proanthocyanidin mixture primarily composed of (+)catechin, (-)-epicatechin, (+)-gallocatechin, and (-)-epigallocatechin
    monomer units linked in random sequence
    Latex from Croton Lechleri

    Multiple analytical methods collectively provide extensive information


    on the structural signatures of crofelemer (e.g., the composition of
    proanthocyanidin oligomers)
    These analytical methods were ultimately considered insufficient to
    support the characterization of quality control of this complex mixture
    18

    Additional Data to Support


    Therapeutic Consistency of Fulyzaq
    Botanical raw material control
    Implementation of Good Agricultural and Collection Practices
    (GACP)
    Restriction of harvesting botanical raw material to specific ecogeographic regions (EGRs)
    Reduces the variability at the plant and raw material levels

    Bioassay
    Based on well-known mechanism of action (i.e., crofelemer targets
    and controls dual intestinal chloride channels: cAMP-stimulated
    cystic fibrosis transmembrane conductance regulator Cl- channel
    and the calcium-activated Cl- channel)
    Potentially provides more flexibility for the manufacturer to make
    postapproval changes (e.g., expansion of EGRs to increase and
    diversify the botanical raw material supply)
    19

    Additional Data to Support


    Therapeutic Consistency of Fulyzaq
    Dose-response clinical data generated based on multiple
    batches
    The drugs effects were not sensitive to the tested doses in a range
    of 125 500 mg bid
    The estimated drug concentrations in the GI tract after oral dosing
    of 125 mg bid are several-fold higher than the concentrations used
    to saturate the targeted chloride ion channels
    Multiple batch data did not reveal noticeable clinical differences
    among drug product batches manufactured from different drug
    substance batches
    Natural variations observed in crofelemer were unlikely to have
    significant impact on the efficacy of Fulyzaq

    20

    Lesson Learned from


    Botanical NDAs
    Approval of botanical NDAs is possible
    Practical approach for quality control of botanical
    products can be developed
    Raw material controls required
    Clinical relevant specifications for drug substance/product can
    be established if multiple batches are used in the pivotal clinical
    trials
    Other data, e.g., from bioassay and/or multiple-batch, dose
    response clinical trials, may be needed, in conjunction with
    conventional CMC data, to help ensure therapeutic consistency

    Clinical trials of botanical drugs are no more difficult


    than non-botanical drugs
    21

    Lesson Learned from


    Botanical NDAs

    Science 2015 Jan 16;347(6219 Suppl.):S32-4


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

    http://www.sciencemag.org/site/products/collectio
    nbooks/TCM_Jan_16_2015_high%20res.pdf

    22

    Challenges of Developing Products


    from Multiple Botanical Raw Materials
    A botanical mixture from one plant species is not
    considered as a fixed combination drug
    The mixture as a whole is considered as the active ingredient

    Number of INDs for botanical products derived from


    multiple botanical raw materials is increasing
    FDA currently considers botanical products derived from
    multiple botanical raw materials as fixed-combination drugs
    However, FDA recognizes that demonstrating each botanical raw
    materials contribution to the efficacy of a product with multiple
    botanical raw materials may not always be feasible

    FDA is looking into the requirements for fixed-combination


    drugs to accommodate the practical issues of botanical
    products
    23

    You might also like