Seeds of Confusion: Understanding FDA’s Regulation of Botanical Drugs Versus Dietary Supplements

Seeds of Confusion: Understanding FDA’s Regulation of Botanical Drugs Versus Dietary Supplements

Ivan WassermanPartner

Manatt, Phelps & Phillips, LLP

Ivan WassermanPartner

Manatt, Phelps & Phillips, LLP

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BotanicalsBotanicals

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; orHighly purified or chemically modified substances derived from botanical sources.

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; orHighly purified or chemically modified substances derived from botanical sources.

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Botanical ProductsBotanical Products

Botanical products may be:Foods (including dietary supplements);Drugs (including biological drugs);Medical devices; orCosmetics

Botanical products may be:Foods (including dietary supplements);Drugs (including biological drugs);Medical devices; orCosmetics

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Botanical Product

What is the intended use?

Applied to body for cleansing, beautifying, or

altering appearanceCosmetic

Consumed for its taste, aroma, or nutritive

valueFood

To diagnose, cure, mitigate, or treat disease

To affect structure or function of body

To preventdisease

Drug Meets dietary supplement definition in 21 U.S.C. 321 (ff)?

Authorizedhealth claim?

Conventional Food or Dietary

Supplement

Structure/function claims comply with all requirements of

21 U.S.C. 343(r)(6)?

Dietary Supplement

Is the proposed indication appropriate

for nonprescription use?

NoYes No Yes

Has it been marketed for a specific OTC indication for

a material time and to a material extent?

Does available evidence of safety and effectiveness

warrant inclusion in an OTC monograph?

Yes

Yes

No

Is there sufficient evidence of safety and effectiveness and

adequate CMC information to support an NDA?

No

No

Is marketing exclusivity desired?

Yes

Yes NDA application

Yes

IND

No

Go to Attachment B

Yes

No

OTC monograph

No

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Dietary SupplementsDietary 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; orA concentrate, metabolite, constituent, extract, or a combination of any ingredient mentioned above.

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; orA concentrate, metabolite, constituent, extract, or a combination of any ingredient mentioned above.

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Dietary SupplementsDietary 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.

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 ClaimsDietary 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; orDescribes general well-being from consumption of the product.

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; orDescribes general well-being from consumption of the product.

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Claims: Disease vs. Structure/Function Claims: Disease vs. Structure/Function

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

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”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.

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?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.

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?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.

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?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”).

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? 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”

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 IngredientsNew Dietary Ingredients

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

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 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.

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 NotificationsNDI 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.

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 ProductsBotanical 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”).

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 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.

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 Marketing Botanical Drugs Under an OTC Drug Monograph

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

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Time and Extent Application (“TEA”) Time and Extent Application (“TEA”)

21 C.F.R. § 330.14No 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 C.F.R. § 330.14No 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”) 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.

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”) 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

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”) 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.

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 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.

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 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.

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 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.

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 RequirementsIND 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.

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.

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General Phase I and II IND Requirements for Botanical Products Without Safety Concerns 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; andClinical considerations.

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; andClinical considerations.

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Description of Product and Documentation of Human Use 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.

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 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.

“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 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.

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 CMCsIND 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).

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 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.

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 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.

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 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.

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 ConsiderationsClinical 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.

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 Botanical Drug IND Statistics: 2006

Active INDs: 2006Commercial: 5,445Non-commercial: 8,672

INDs Received: 2006Commercial: 713Non-commercial: 1,150

Source: http://www.fda.gov/cder/rdmt/cyactind.htm

Active INDs: 2006Commercial: 5,445Non-commercial: 8,672

INDs Received: 2006Commercial: 713Non-commercial: 1,150

Source: http://www.fda.gov/cder/rdmt/cyactind.htm

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Botanical Review TeamBotanical 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.

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 InformationContact Information

Ivan WassermanPartnerManatt, Phelps & Phillips, LLPWashington, DC(202) 585-6529iwasserman@manatt.com

Ivan WassermanPartnerManatt, Phelps & Phillips, LLPWashington, DC(202) 585-6529iwasserman@manatt.com