1. Ivan Wasserman Partner Manatt, Phelps & Phillips, LLP
Seeds of Confusion: Understanding FDA’s Regulation of Botanical Drugs Versus Dietary Supplements
Ivan Wasserman
Partner
Manatt, Phelps & Phillips, LLP

2. 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.

3. Botanical Products Botanical products may be:
Foods (including dietary supplements);
Drugs (including biological drugs);
Medical devices; or
Cosmetics

4. Conventional Food or Dietary Supplement
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 prevent
disease
To affect structure or function of body
To diagnose, cure, mitigate, or treat disease
Authorized
health claim?
Conventional Food or Dietary Supplement
Meets dietary supplement definition in 21 U.S.C. 321 (ff)?
Yes No
Drug No
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
OTC monograph
Go to Attachment B
Yes
NDA application
IND

5. 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.

6. 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.

7. 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.

8. Claims: Disease vs. Structure/Function
Dietary supplements may not claim to diagnose, mitigate, treat, cure, or prevent a specific disease or class of diseases.

9. Definition of “Disease”
Section (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.

10. 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.

11. 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.

12. 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”).

13. 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”

14. 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.

15. 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.

16. 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.

17. 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”).

18. 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.

19. Marketing Botanical Drugs Under an OTC Drug Monograph
A request to amend an OTC drug monograph can be submitted by a citizen petition.

20. Time and Extent Application (“TEA”)
21 C.F.R. §
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).

21. 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.

22. 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

23. 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.

24. 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. § and (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.

25. 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.

26. 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.

27. 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 product’s known or suspected risks, and the developmental phase of the drug.

28. 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.

29. Description of Product and Documentation of Human Use
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.

30. 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.

31. 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.

32. 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 §
Additional details with respect to these requirements are found in 21 C.F.R. § (a)(7)(iv)(a)-(e).

33. 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.

34. 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.

35. 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.

36. 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.

37. 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:

38. 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.

39. Contact Information
Ivan Wasserman
Partner
Manatt, Phelps & Phillips, LLP
Washington, DC
(202)