Recent developments of marketing authorization of botanical drugs in the USA - Charles Wu, Ph.D.
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Recent developments of marketing
authorization of botanical drugs in the USA
Charles Wu, Ph.D.
Botanical Review Team
Office of Pharmaceutical Quality, CDER, FDA
EMA Seminar
September 14, 2017
Disclaim
• This presentation reflects the views of the
author and should not be construed to
represent FDA’s views or policies.
2
Botanicals as
FDA Regulated Products
Foods - Health claims
Dietary Supplements - structure/function
claims
Drugs – Disease claims (Treatment,
diagnosis and prevention)
Monograph products
New Prescription Drugs
3
Definition of Botanical Drugs
Any product that contains 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,
powder, tablet, capsule, topical or injectable.
Excluded from botanicals:
• fermentation products,
• highly purified or chemically modified botanical substances,
• genetically modified plants, allergenic extracts and vaccines which contain
botanical ingredients.
4
Botanical drug vs. non-botanical drug
BotanicalDefinition of Botanical Drugs
Non-botanical
Naturally derived Chemically Synthesized
Complex heterogeneous Single molecule
mixture
Variation in raw materials Stable raw material
Unknown active component Known identity
Variable strength or potency quantifiable strength or potency
Unclear mechanism Known mechanism
5
General Regulatory
Approach to Botanical Drug Applications
• Incentives to encourage early phase trials of botanicals
– CMC Considerations
• Further purification not required
– Extend the control to botanical raw materials
• Identification of active constituents not essential
– Pharmacology/Toxicology
• Prior human use may substitute for animal toxicology studies
for initial trials
• Considerations of late phase clinical trials
– Same level of clinical efficacy/safety requirements as non-botanical drugs for
NDA-Adequate and well-controlled trials are required by law for new drugs
6
What Does BRT Do?
• Review of Botanical Drug Products- MAPP 5210.9 Rev 1
• BRT is a designated member of the OPQ review team
– Reviews INDs, pre-INDs, NDAs, citizen petitions (CPs), homeopathic
products and pharmacy compounding consults (503A & 503B)
• Performs Pharmacognosy Review
– Including an analysis of previous human experience and of the
phytochemical ingredient profile for all original IND and NDA
submissions
7
Pharmacognosy
Review of Botanical Drugs
• Medicinal plant biology
– Identification, potential misuse, and other Good Agricultural and Collection Practice (GACP) related raw
material control issues.
• Pharmacology of botanical drugs
– Old theories and new testing
• Potential risk/benefit based review approach during the 30-day IND safety in consideration of both
the botanicals and the diseases
• Prior human experiences
– Mostly in complementary and alternative medicine (CAM), systems such as Traditional
Chinese Medicine
• To support the IND safety in lieu of new animal toxicology studies
• More
– Ensuring quality and therapeutic consistency for late phase development (e.g., phase 3 trials
and NDA), including whether there is a need for bioassay(s)
8
Botanical Applications in CDER, FDA
(through 2016)
• More than 600 pre-INDs/INDs
– Approximately 1/3 are commercial, 2/3 are research
– 2/3 are single herb, 1/3 are multiple herbs
– Majority are in phase 2, and a dozen of them are in Phase 3
• Two NDAs submitted and approved
9Botanical IND Applications
by Year (2002-2016)
10Botanical INDs
by Therapeutic Areas
11Geographic Origin
of Botanical Raw Materials
12The First Botanical
NDA Approved under the Guidance
• Brand/Generic name: Veregen (sinecatechins)
• Botanical raw material: Green tea, the dried leaves
of Camellia sinensis from China
• Drug substance: Partially purified green tea extract,
mainly catechins (~90% by weight) made in Japan
• Formulation: 15% Ointment
• Indication: Genital/perianal warts
• Sponsor: MediGene, Inc., Germany
• Approval Date: October 31, 2006 13Efficacy of Veregen
(response rates)
Clinical response from Approval package: Veregen NDA #021902-FDA
14BRT Publication
Nature
Biotechnology
October 2008
26:1077
15The Second Botanical NDA
Approved under the Guidance
• Brand/Generic name: Fulyzaq/Crofelemer
• Botanical raw material/drug substance: crude plant latex of
Croton lechleri (“Dragon’s Blood”), oligomeric
proanthocynidin
• Formulation: 125 mg oral tablet
• Indication: HIV related diarrhea
• Sponsor: Salix Pharmaceuticals
• Approval Date: December 31, 2012
16Efficacy of Crofelemer
• Clinical response (intent-to-treat population), from NDA Medical Review (available in Drugs@FDA)
• Clinical response was defined as ≤ 2 watery stools per week during at least 2 of the 4 weeks of the placebo-controlled treatment
phase.
• p-values and CIs were calculated based on the methods of Posch and Bauer (2005).
• If less than 5 days of data were available in a week, the subject was classified as a non-responder for that week.
• Subjects who discontinued prematurely during the 4-week period were classified as non-responders.
• Subjects who used an ADM or opiate pain medication for > 3 days during the efficacy assessment period were also
non responders.
17BRT Publication
Science
January 2015
347:316-18
1819
Quality Control of
Botanical Drugs Remains Challenging
• Botanical products contain a complex mixture of
components
• Active components may not be fully identified
• Considerable variations in chemical composition and
bio-pharmacological activity
• Conventional CMC approaches used for QC of small-
molecules alone sometimes are not sufficient
20New Botanical Guidance
(Published on Dec. 2016)
• Revises the final FDA Botanical Guidance issued in
2004
– The current thinking for early phase trials
remains the same
• Provides additional specific recommendations to
better address late-phase development and NDA
submission for botanical drugs
• Recommends a totality-of-evidence approach to
ensure the consistency of quality and thus
therapeutic effects of botanical drug products for
approval and marketing
21Therapeutic Consistency for Botanicals
An Integrated Assessment
22What is New in the Revised Guidance?
To better address late-phase development and NDA submissions
for botanical drugs, the following considerations should be taken:
• Botanical Raw Material control (BRM)
– Ensure authenticity and quality control of BRM following GACP, with a
Certificate of Analysis
• Quality control by CMC
– Need for a comprehensive systematic approach to monitor the
chemical profiles of botanical materials, intermediates, substances,
and products.
23What is New in the Revised Guidance?
Biological Assays:
• A biological assay is an important method for measuring a
botanical drug’s potency and activity to ensure quality and
therapeutic consistency
• The biological assay should be as closely related to the drug’s
presumed mechanism of action as possible
• Other less relevant assays may also be considered and
evaluated in individual cases
24What is New in the Revised Guidance?
Clinical data:
• Dose-response data
– If the clinical effects are not sensitive to dose (but are still superior to the
placebo control group), it can reasonably be assumed that the variations
within the established specifications probably will not affect the therapeutic
consistency of drug products.
• Multiple batch clinical data
– Clinical studies in which subjects are randomized to receive different drug
product batches can be used to assess treatment-by-batch interactions. Lack of
significant interaction could provide confidence that therapeutic effects will be
independent of drug batches within the established specification.
25Totality-of Evidence Approach
for Botanical Drug Development
In summary, to ensure the batch-to-batch therapeutic
consistency of a botanical drug, the following holistic
approaches need to be taken:
• Well-controlled raw materials
• Robust manufacturing process and quality controls including
comprehensive fingerprints
• Clinically relevant bioassay
• Multiple-dose & -batch clinical data
26Botanical Review Team (BRT)
Botanical Review Team Website:
https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/uc
m090946.htm
Botanical Guidance:
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/UCM458484.pdf
For more information, Please contact to: CDER-OPQ-Inquiries@fda.hhs.gov
The BRT members:
Charles Wu, PhD Team Lead (Acting)
Cassandra Taylor, PhD
Jing Li, PhD
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