Seeds of Confusion: Understanding FDA

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Seeds of Confusion Understanding FDAs
Regulation of Botanical Drugs Versus Dietary
Supplements

• Ivan Wasserman
• Partner
• Manatt, Phelps Phillips, LLP

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Botanicals

• The term botanicals includes plant materials,
  algae, macroscopic fungi, and their combinations.
• It does not include
• Materials derived from genetically modified
  botanical species (i.e., cloning)
• Fermentation products or
• Highly purified or chemically modified substances
  derived from botanical sources.

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Botanical Products

• Botanical products may be
• Foods (including dietary supplements)
• Drugs (including biological drugs)
• Medical devices or
• Cosmetics

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Botanical Product
Applied to body for cleansing, beautifying, or
altering appearance
Consumed for its taste, aroma, or nutritive value
What is the intended use?
Cosmetic
Food
To affect structure or function of body
To prevent disease
To diagnose, cure, mitigate, or treat disease
Authorized health claim?
Meets dietary supplement definition in 21 U.S.C.
321 (ff)?
Conventional Food or Dietary Supplement
No
Drug
No
Yes
Yes
Structure/function claims comply with all
requirements of 21 U.S.C. 343(r)(6)?
Is the proposed indication appropriate for
nonprescription use?
Yes
No
No
Has it been marketed for a specific OTC
indication for a material time and to a material
extent?
No
Yes
Dietary Supplement
Is there sufficient evidence of safety and
effectiveness and adequate CMC information to
support an NDA?
Yes
Does available evidence of safety and
effectiveness warrant inclusion in an OTC
monograph?
No
Yes
No
Is marketing exclusivity desired?
No
Yes
Go to Attachment B
OTC monograph
Yes
NDA application
IND
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Dietary Supplements

• Dietary supplements are products intended to
  supplement the diet that bear or contain one or
  more of the following dietary ingredients
• A vitamin
• A mineral
• An herb or other botanical
• An amino acid
• A dietary substance for use by man to supplement
  the diet by increasing the total dietary intake
  or
• A concentrate, metabolite, constituent, extract,
  or a combination of any ingredient mentioned
  above.

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Dietary Supplements

• Must be intended for ingestion
• Cannot be represented for use as a conventional
  food or as a sole item of a meal or the diet
• Has not been approved as a new drug, certified as
  an antibiotic, or licensed as a biologic
• Has not been authorized for investigation as a
  new drug.

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Dietary Supplement Claims

• Dietary supplements may bear the following
  claims
• Benefit related to a classical nutrient
  deficiency disease
• How the product is intended to affect the
  structure or function of the human body
• The documented mechanism by which the product
  acts to maintain such structure or function or
• Describes general well-being from consumption of
  the product.

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Claims Disease vs. Structure/Function

• Dietary supplements may not claim to diagnose,
  mitigate, treat, cure, or prevent a specific
  disease or class of diseases.

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Definition of Disease

• Section 101.93(g) defines disease as
• ...damage to an organ, part, structure, or
  system of the body such that it does not function
  properly (e.g., cardiovascular disease), or a
  state of health leading to such dysfunctioning
  (e.g., hypertension) except that diseases
  resulting from essential nutrient deficiencies
  (e.g., scurvy, pellagra) are not included in this
  definition.

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What is a Disease Claim?

• A claim to diagnose, mitigate, treat, cure or
  prevent disease
• Has an effect on a specific disease or class of
  disease
• Has an effect on the characteristic signs or
  symptoms of a specific disease or class of
  diseases, using scientific or lay terminology.

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What is a Disease Claim?

• Has an effect on abnormal condition associated
  with a natural state or process, if the abnormal
  condition is uncommon or can cause significant or
  permanent harm.

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What is a Disease Claim?

• Factors that can contribute to the decision that
  a disease claim is being made
• Name of the product (CancerCure)
• Use of pictures or symbols (Rx or EKG)
• Belongs to a class of products that is intended
  to diagnose, mitigate, treat, cure or prevent a
  disease (antibiotic, analgesic)
• Is a substitute for a product that is a therapy
  for a disease (Herbal Viagra).

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Structure Function Claim vs. Disease Claim?

• Examples Structure Function
• supports weight loss
• supports cartilage and joint function
• improves absentmindedness
• Examples Disease
• treats obesity
• reduces joint pain
• cures Alzheimer's

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New Dietary Ingredients

• A new dietary ingredient is one that was not
  sold in the U.S. in a dietary supplement before
  October 15, 1994.

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New Dietary Ingredient Notification

• 75 days prior to marketing an NDI, you must
  submit information to FDA showing the basis on
  which you have concluded that a dietary
  supplement containing such dietary ingredient is
  reasonably expected to be safe.
• Not needed if present in the food supply as an
  article used for food in a form in which the food
  has not been chemically altered.

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NDI Notifications

• The FDA sends an acknowledgement of receipt after
  submission of the NDI notification
• FDA will not disclose the existence of, or the
  information contained in, the new dietary
  ingredient notification for 90 days after the
  filing date of the notification
• After the 90th day, all information in the
  notification will be placed on public display
  (except for trade secret or confidential
  commercial information)
• Failure of the agency to respond to a
  notification does not constitute a finding that
  the new dietary ingredient is safe or is not
  adulterated.

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Botanical Drug Products

• A botanical drug product may be marketed under
• (1) an OTC drug monograph or
• (2) a New Drug Application (NDA) or an
  Abbreviated New Drug Application (ANDA).

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Marketing Botanical Drugs Under an OTC Drug
Monograph

• For a botanical drug to be included in an OTC
  drug monograph, there must be data establishing
  general recognition of safety and effectiveness,
  usually including results of adequate and
  well-controlled clinical trials.
• Cascara, psyllium, and senna are botanical drugs
  currently included in an OTC drug monograph.

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Marketing Botanical Drugs Under an OTC Drug
Monograph

• A request to amend an OTC drug monograph can be
  submitted by a citizen petition.

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Time and Extent Application (TEA)

• 21 C.F.R. 330.14
• No fee, no time frame, and no patent exclusivity
• Can be used to amend the OTC drug monograph
• U.S. marketing experience after OTC drug review
  began.
• OTC drugs with marketing experience outside of
  the U.S.
• Meets material extent and material time
  requirements of 201(p).

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Time and Extent Application (TEA)

• Can be used for
• Active ingredient or botanical substance
• Dosage form
• Dosage strength
• Route of administration.
• Marketed for 5 continuous years in the same
  country and in sufficient quantity.

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Time and Extent Application (TEA)

• Step 1 Submission of TEA and publication of
  Federal Register notice of eligibility
• Step 2 FDA reviews safety and efficacy data to
  determine GRASE

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Marketing Botanical Drugs under a New Drug
Application (NDA)

• A botanical drug product that is not generally
  recognized as safe and effective for its
  therapeutic claims is considered a new drug.
• Any person wishing to market a botanical drug as
  a new drug must obtain FDA approval of an NDA or
  ANDA of that product.

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Applicability of Combination Drug Regulations

• Botanical drug products that are derived from a
  single plant or from a single species of alga or
  macroscopic fungus are not considered to be
  fixed-combination drugs within the meaning of 21
  C.F.R. 300.50 and 330.10(a)(4)(iv).
• These single plant drug products do not need to
  demonstrate that each component or active
  ingredient makes a contribution to the claimed
  effects.
• They also do not need to meet other requirements
  for combination drugs.

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Applicability of Combination Drug Regulations

• Botanical drugs that are derived from multiple
  parts of a single species of plant, alga, or
  macroscopic fungus (of from different species),
  are subject to the combination drug requirements.

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Investigational New Drug Application
Requirements for Botanical Drugs

• An Investigational New Drug Application (IND)
  is required when a botanical drug is studied in
  the U.S. for drug use, even if such study is
  intended solely for research purposes.
• Note if the intent is to study the effect of a
  product on the structure or function of the body,
  no IND is needed.

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IND Requirements

• The amount of information that needs to be
  submitted in an IND depends on the novelty of the
  drug, the extent to which it has been studied
  previously, the drug products known or suspected
  risks, and the developmental phase of the drug.

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General Phase I and II IND Requirements for
Botanical Products Without Safety Concerns

• IND submissions for botanical products without
  safety concerns generally include
• Description of product and documentation of human
  use
• Chemistry, Manufacturing, and Controls
  information
• Pharmacology/Toxicology Information
• Bioavailability and
• Clinical considerations.

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Description of Product and Documentation of Human
Use

• Description of product
• Common or usual names of the plant, alga, or
  macroscopic fungus
• Synonyms (e.g., Latin, Greek, English, etc.)
• Name of variety, species, genus, and family
• Chemical class of active constituent.
• Documentation of Human Use
• History of use (historical sources)
• Current marketed use.

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Chemistry, Manufacturing, and Controls for
Botanical Drug Products

• CMC documentation requirements for botanical
  drug products are different from that of
  synthetic or highly purified drugs.
• It is not essential for a manufacturer to
  identify the active constituents of a botanical
  drug, if such identification is not feasible.
• The nonclinical pharmacology and toxicology
  information requirements for botanical drug
  products are far lower than those for synthetic
  or highly purified new drugs.
• In most cases, additional toxicology and CMC data
  will not be required for initial clinical trials.

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Chemistry, Manufacturing, and Controls

• The following information submission are
  recommended
• Botanical raw material standard of identity
• Botanical drug substance general methods of
  preparation
• Botanical drug product manufacturing standards
• Qualitative description of finished product
• The composition or quantitative description of
  the finished product.

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IND Requirements for CMCs

• With regard to environmental analyses, plants
  that are obtained from their native setting on
  either public or private land are considered to
  be taken from the wild, which is considered an
  extraordinary circumstance under 25.21.
• Additional details with respect to these
  requirements are found in 21 C.F.R.
  312.23(a)(7)(iv)(a)-(e).

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Pharmacology/Toxicology Information

• Information as to the safety and effectiveness of
  the following
• The final formulation of the intended commercial
  botanical drug product
• The individual botanical ingredients
• The known chemical constituents of the botanical
  ingredients
• General toxicity
• Target organs or systems of toxicity
• Relationship of dosage and duration to toxic
  responses
• Pharmacological activity.

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Pharmacology/Toxicology Information

• After the submission of initial clinical studies,
  further pharmacology and toxicology studies of a
  botanical drug generally would be needed before
  later phases of clinical development and before
  marketing approval.

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Bioavailability

• Botanical products often consist of more than one
  chemical constituent, and the active constituents
  are often unknown.
• Therefore, standard pharmacokinetic measurements
  are often difficult to obtain.
• When feasible, sponsors are encouraged to monitor
  blood levels of known active constituents,
  representative markers, or major chemical
  constituents in a botanical drug product.

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Clinical Considerations

• The initial clinical trial for a product marketed
  under DSHEA should be a well-controlled study
  demonstrating effectiveness.
• Sponsors are encouraged to initiate more
  definitive trials early in the development
  program to determine whether a botanical product
  has efficacy for one or more claimed indications.
• Safety data should be collected during trials.

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Botanical Drug IND Statistics 2006

• Active INDs 2006
• Commercial 5,445
• Non-commercial 8,672
• INDs Received 2006
• Commercial 713
• Non-commercial 1,150
• Source http//www.fda.gov/cder/rdmt/cyactind.htm

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Botanical Review Team

• The CDER Botanical Review Team (BRT) provides
  scientific expertise on botanical issues to the
  reviewing staff and ensures consistent
  interpretation of the Guidance for Industry
  Botanical Drug Products.
• The BRT participates in all phases of review,
  meetings and decision-making processes for all
  botanical pre-Investigational New Drug (IND)
  applications, INDs, and New Drug Applications
  (NDAs).
• Headed by Shaw T. Chen, M.D. Ph.D.,Associate
  Director for Special Product Review Botanical
  Drug Products.

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Contact Information

• Ivan Wasserman
• Partner
• Manatt, Phelps Phillips, LLP
• Washington, DC
• [phone]
• iwasserman_at_manatt.com