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Botanical Drug Development

by | Jun 6, 2019 | Botanicals

Introduction

 

The use of plants as to treat various human maladies has been known since ancient times.  Many of today’s drug products contain plant-derived ingredients.

 

Botanical products may be classified as foods, dietary supplements, drugs, medical devices, or cosmetics, depending on their intended use. A product’s intended use is established byits advertising, labeling, and circumstances surrounding its distribution. For example, a botanical may be regulated as a Food if it is used for food and consumed primarily for its taste, aroma, or nutritive value. It may be a Dietary supplement if it is labeled as a dietary supplement and otherwisemeets the definition of a dietary supplement as defined in the Dietary Supplement Health and Education Act (DSHEA) of 1994.  It may be a Drug if it is intended for use in the diagnosis, cure, mitigation, or treatment of disease in humans.

 

Botanical drug products often have unique features such as being comprised of complex mixtures, lack of a distinct active constituent(s), and substantial prior human use.

 

Fermentation products, products derived from animals or minerals, highly purified substances, and materials derived from botanicals that are genetically modified with the intention of producing a single molecular entity are not considered botanical drug products.

 

In order to market a botanical drug product within the U.S., a company must follow the appropriate regulatory procedures. A botanical drug product may be marketed in the United States under either an over-the-counter (OTC) drug monograph, a dietary supplement or an approved new drug application (NDA).

 

Over-the-Counter (OTC) Botanicals

 

The OTC drug review process is a three-phase public rulemaking process resulting in the establishment of standards (monographs or non-monographs) for an OTC therapeutic drug category. The monographs represent regulatory standards for the marketing of non-prescription drug products not covered by NDAs. These standards provide the marketing conditions for some OTC drug products including the active ingredients, labeling, and other general requirements. For a botanical drug substance to be included in an OTC monograph, there must be published data establishing a general recognition of its safety and effectiveness, including the results of adequate and well-controlled clinical studies. A manufacturer would also need to submit a petition in accordance with 21 CFR 10.30 and 330.10(a)(12), or a Time and Extent Application in accordance with 21 CFR 330.14 to amend the monograph to include a botanical drug substance. Several botanical drug substances (e.g. psyllium and senna) are included in the OTC drug review and witch hazel is currently marketed under a monograph.

 

Botanicals as Dietary Supplements

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There are numerous botanical preparations that are marketed in the U.S. as dietary supplements.  A dietary supplement is a product taken by mouth that contains a dietary ingredient intended to supplement the diet. The dietary ingredients in these products may include: vitamins, minerals, herbs or other botanicals, amino acids, and substances such as enzymes, organ tissues, and metabolites.  Dietary supplements can also be extracts or concentrates, and may be found in many forms such as tablets, capsules, softgels, gelcaps, liquids or powders. Dietary supplements can also take other forms, such as a bar. If they do, information on their label must not represent the product as a conventional food or a sole item of a meal or diet.

 

Whatever their form may be, the Dietary Supplement Health and Education Act (DSHEA) of 1994, places dietary supplements in a special category under the general umbrella of foods, not drugs and requires that every supplement be labeled a dietary supplement. Dietary supplements are labeled to describe how a nutrient or dietary ingredient affects the structure or function in humans or to describe the documented mechanism by which a nutrient or dietary ingredient acts to maintain the structure or function.  The labeling on a dietary supplement cannot make a disease claim to diagnose, cure, mitigate, treat or prevent disease.

 

If a lawfully marketed botanical dietary supplement is studied for its effects on diseases in a proposed investigation (i.e., to cure, treat, mitigate, prevent, or diagnose disease including its associated symptoms), then it is an investigational new drug and will be subject to IND requirements.  This applies to studies in INDs sponsored for both commercial and academic research purposes.

 

NDA Route for Botanicals

 

Under current regulations, if there is no marketing history in the U.S. or a foreign country for a botanical drug product, and if available evidence of safety and effectiveness does not warrant inclusion of the product in an OTC drug monograph, or if the proposed indication would not be appropriate for nonprescription use, the manufacturer must submit an NDA to obtain FDA approval to market the product for the proposed use.

 

An NDA for a botanical drug could seek approval for either prescription or OTC use, depending on the indication and characteristics of the product and whether it is safe for use outside of the supervision of a practitioner licensed by law to administer it.

 

An NDA must contain substantial evidence of effectiveness derived from adequate and well-controlled clinical studies, evidence of safety, and adequate chemistry, manufacturing, and controls (CMC) information. The format of an NDA submission and the requirements for its various sections are set forth in 21 CFR 314 and discussed in several CDER guidance documents.

 

If there is insufficient information to support an NDA for a botanical drug, the sponsor may need to first develop the product further under an investigational new drug (IND). In general, an IND is required under section 505(i) of the Act and 21 CFR 312 when a botanical product is studied in the U.S. for a drug use, even if such study is intended solely for research purposes. Under 21 CFR 312.22, an IND must contain sufficient information to demonstrate that the drug product is safe for testing in humans and that the clinical protocol is properly designed for its intended objectives.

 

Because botanical drug products have certain unique characteristics, CMC documentation that should be provided for botanical drugs will often be different from that for synthetic or highly purified drugs, whose an active constituent(s) can be more readily chemically identified and quantified.

 

To support initial clinical trials, the nonclinical pharmacology and toxicology information that must be provided under 21 CFR 312.22(b) for legally available botanical products with no known safety issues may be reduced compared to that expected for synthetic or highly purified new drugs that are not legally marketed and for which there is no prior human experience.

 

Botanical drug products that are derived from a single part of a plant, or from a single species of alga or macroscopic fungus are not considered to be fixed-combination drugs within the meaning of 21 CFR 300.50 and 330.10(a)(4)(iv). Consequently, they do not have to meet the requirements for combination drugs, principally, the need to demonstrate that each component or active constituent makes a contribution to the claimed effects. Botanical drugs composed of multiple and easily separable parts of a single species of plant (e.g., flowers and bark of a woody plant), or of parts from different species of plants algae, or macroscopic fungi, currently are subject to the combination drug requirements. However, FDA is considering revising its regulations to allow for the exemption of such botanical drugs from application of the combination drug requirements under certain circumstances.

 

FDA Botanical Review Process

 

The FDA Center for Drug Evaluation and Research (CDER) established the Botanical Review Team in 2003, published a Guidance for Industry: Botanical Drug Products in 2004, and recently revised and published in 2016 the Guidance for Industry: Botanical Drug Development. The guidance provides additional recommendations on quality, nonclinical, clinical, and other unique aspects associated botanical drug development. In this guidance, FDA described a “totality-of-evidence” approach that overcomes the limited ability to characterize the entire botanical mixture or its active components by available analytical techniques. In addition to conventional CMC data, this totality of the evidence approach considers other information including raw material control, clinically relevant bioassay(s), and other data generated based on a multiple-batch and multiple-dose clinical trial of the botanical product. The available evidence is used to ensure that the quality consistency of the botanical product is sufficient to ensure therapeutic consistency. The degree of reliance on these other data for ensuring consistency of quality depends on the extent that the botanical mixture can be characterized and quantified.

 

Since the publication of the botanical Guidance in 2004, over 400 botanical product INDs have been submitted to the Office of New Drug (OND) at CDER for clinical investigation as treatments for various diseases, such as cancer, infectious diseases, and arthritis, just to name a few.

 

Approved Botanical Drugs

 

Three recent NDAs that have been approved for marketing botanical products as prescription drugs in the US.

 

Veregen (sinecatechins), a topical ointment for the treatment of genital and perianal warts. Veregen is derived from green tea leaves. It was developed by Germany’s MediGene.

 

Fulyzaq (crofelemer) is an oral drug for the treatment of HIV/AIDS related diarrhea. Fulyzaq is made from the red sap of the Croton lechleri plant, a South American tree referred to as the dragon’s blood tree because of its red latex.

 

Epidiolex (cannabidiol) [CBD] is an oral solution for the treatment of seizures associated with two rare and severe forms of epilepsy. This is the first FDA-approved drug that contains a purified drug substance derived from marijuana. CBD does not cause intoxication or euphoria (the “high”) that comes from tetrahydrocannabinol (THC). Epidiolex’s effectiveness was studied in three randomized, double-blind, placebo-controlled clinical trials involving 516 patients with either Lennox-Gastaut syndrome or Dravet syndrome. Epidiolex, taken along with other medications, was shown to be effective in reducing the frequency of seizures when compared with placebo.  GW Pharmaceuticals, it manufacturer, is already investigating other CBD-derived drugs to treat different forms of epilepsy, as well as forms of brain cancer and schizophrenia.

This approval is going to encourage other companies to investigate [other cannabis] compounds for different diseases from pain to Alzheimer’s to multiple sclerosis to Tourettes’; basically, a whole spectrum of diseases.

 

These three NDA approvals show that new therapies derived from complex botanical mixtures can be developed to meet modern FDA standards of quality, safety, and efficacy as new drugs.

 

The biggest market for botanicals is China, where they already are accepted. GlaxoSmithKline is working with botanicals on products for immune disorders, while Sanofi wants to develop alternative medications for diabetes and cancer for sale there.

 

Development of a Botanical Drug

 

Clinical data collected from non-U.S. phase 1 and phase 2 studies may be used to support a phase 3 study in a new IND.  The botanical product (drug substance and formulation/dosage form) used in the proposed Phase 3 study should be the same as the product in Phase 1 and Phase 2 clinical studies and also in the preclinical studies.  If different formulations were used, the bioequivalence of all tested products will need to be determined.

 

To facilitate the clinical development of botanical drugs, CDER focuses discussions in the Guidance on INDs first, especially the initial phases of clinical development.  For NDA approval, the standards for the safety and efficacy of a botanical drug are the same as those for a conventional chemical drug with the same indication. However, the quality standards for a botanical drug may be different from that for a purified chemical drug.  The Guidance contains recommendations for establishing appropriate quality standards for botanical drugs.

 

CDER recognizes that prior human experiences with the botanical products may be documented in many different forms and sources, some of which may not meet the quality standards of modern scientific testing.  Sponsors are encouraged to provide as much data as available.  The quality of the submitted data will have to be assessed case-by-case.  CDER maintains the same standards for safety and efficacy for marketing approval whether it is a botanical-sourced product or a purified chemical. The Botanical Guidance simply recommends the use of different types of data for preliminary safety consideration (e.g., large quantities of mostly anecdotal human data in place of well-controlled animal studies) of human trials in an IND.

 

Multiple formulations may be included in one IND as long as they are being studied in a single clinical trial.  It is important to provide in the IND application the rationale for using multiple formulations and the criteria used to assign patients to different treatment regimens.  The final determination regarding formulation variations of this type is made by the review division.

The CDER review division will evaluate the known risk and the potential benefit of an investigational new drug in the proposed study.  When the potential benefit of an investigational drug outweighs its risk in the studied patient population, an IND is often allowed.  For example, a relatively higher level of toxicity of an investigational drug used in a study of terminally-ill cancer patients may be acceptable.

 

Guidance for Botanical Drug Development

 

The Botanical Guidance applies to all dosage forms of botanical products. As with conventional chemical drugs, the type of quality testing for botanical products varies from dosage form to dosage form. For example, injectable products are required to be sterile and pyrogen-free whereas oral tablets may not. In addition, the human experience of an orally administered dietary supplement may not be applicable to an identical botanical product with the same ingredient(s) when given by a non-oral route of administration.

 

Prior Human Experience

 

Under 21 CFR 312.23(a)(9), a sponsor must submit information about prior human experience with the investigational drug, if available. Many botanical drugs have been previously marketed or tested in clinical studies, including clinical studies reported in literature. Where clinical studies have been conducted, the study reports should be submitted in the IND with a critical review of the data quality and the data’s relevance to the proposed use. The botanical drug’s marketing history also should be described. In particular, it should include documentation of the annual sales volume, an estimate of the size of the exposure population, and rates of adverse effects, as well as provide references to compendia and publications (e.g., books of medical practice in Ayurveda, traditional Chinese medicine, Unani, Siddha, and other herbal medicine and pharmacognosy textbooks).

 

For botanical drugs only available in foreign markets, the information’s reliability and relevance to the proposed clinical study should be justified. A sponsor planning to support its IND with a well-designed and well-conducted foreign clinical study or studies not conducted under an IND should refer to 21 CFR 312.120 and related FDA guidance documents.

 

In addition to a thorough review of the past human experience with the botanical drug and the drug’s botanical raw material(s), the sponsor should also present information to bridge the past experience with the current proposed investigation.

 

This information may include a:

  • Description of the amount of raw material or traditional preparation that is equivalent to the dose proposed in the IND study,
  • Comparison of the identity of the investigational botanical drug with traditional

preparations described in the literature, and/or

  • Comparison of the clinical settings in which the drugs have been used with the setting(s) in which they are proposed to be used.

 

The Agency will determine the relevance of prior human experience with traditional preparations to the assessment of botanical drugs’ safety in clinical studies proposed under INDs on a case-by-case basis.

 

The requirements for the description of Botanical Raw Materials Used and Known Active Constituents or Chemical Constituents are detailed in 21 CFR 312.23(a)(3)(i)

 

The Sponsor is expected to provide the following general information for each of the botanical raw materials used as the source of the botanical drug substance in a botanical drug product:

  • Scientific name of the plant species according to international binomial nomenclature convention, including the genus name, the specific epithet, and the name of the botanist who initially described and nominated the species.
  • Synonyms, especially those used in recent publications of scientific studies related to the species.
  • Sub-specific rank (subspecies, variety, and form) and cultivars, if applicable.Family name.
  • Botanical parts used (e.g., aerial parts, roots, rhizomes, flowers, and/or leaves) as the botanical raw material(s).
  • Common or usual names of the plant, alga, or macroscopic fungus in English and other languages (e.g., Chinese or Spanish), especially the languages of the region in which the species and the raw materials have medicinal or other significance.
  • Active constituents identified as individual compounds or chemical classes, if known. If active constituents are not known, chemical constituents that have been identified (e.g., those can be used as a characteristic profile for identification and quality control purposes).

 

Botanical Raw Materials (21 CFR 312.23(a)(7)(i))

 

A botanical drug substance can be derived from one or more botanical raw materials of the same or different plant species. The following recommendations apply to each individual botanical raw material used.

 

For raw material control, trained personnel should identify the plant species, plant parts, alga, or macroscopic fungus used via methods including organoleptic, macroscopic, and microscopic examination. This identification should be done against a voucher specimen (i.e., reference specimen). A genetic taxonomic method (e.g., DNA barcoding described in the United States Pharmacopeia (USP) General Chapter <563>: Identification of Articles of Botanical Origin) may be developed at this stage. If more than one variety of a given species is used, each variety should be specified. The botanical raw material supplier and drug substance manufacturer for each batch should retain and store under appropriate conditions a sample of the plant, plant parts, or other botanical materials. These samples can be used to further verify identity, if needed.

 

The sponsor should provide the following information:

  • Identification of the plant species, plant parts, alga, or macroscopic fungus used.
  • A certificate of authenticity.
  • Whether the plant species is:

− Determined to be endangered or threatened under the Endangered Species Act or theConvention on International Trade in Endangered Species of Wild Fauna and Flora,

−Entitledto protection under some other federal law or international treaty to which theUnited States is a party, and/or

−In acritical habitat that has been determined to be endangered or threatened.

  • The following items for each grower and/or supplier, if available:

−Name and address,

−Description and characterization of the plant species, as well asvarietiesand cultivars(if applicable),and botanical identification (macroscopic and microscopic),

−Harvest location(e.g., by global positioning system(GPS)coordinates), growth conditions, stage of plant growth at harvest,and harvest time/season, and

−Post-harvest processing(e.g., washing, drying, and grinding procedures);controlof foreign matter (i.e., inorganic and organic contaminants such as soil, insects,and algae/fungi);preservation procedures;handling, transportation, and storageconditions;tests for elemental impurities;microbial limits; tests for residualpesticides,including parent pesticides and their major toxic metabolites;and tests foradventitioustoxins(e.g., aflatoxins), foreign materials,and adulterant.

 

Botanical Drug Substance (21 CFR 312.23(a)(7)(iv)(a))

 

The sponsor should provide the following information for the botanical drug substance, regardless of whether it is prepared from one or more botanical raw materials:

  • Qualitative description of the drug substance.It should includethe name, appearance,active constituents, physicochemical properties, biological activity, andany prior clinical use of each botanicalraw materialused to prepare the drug substance. If the active constituents, biological activity, and/orprior clinical useareunknown, the applicationshould clearlystatethis. Fora multi-plantdrugsubstance, the applicationshould state whether the drug substance is prepared by combining individually processed botanicaldrug substances or processing combined botanical raw materials. •Quantitative description of the drug substance. The strength of a botanical drug substance should generally be expressed as the absolute dry weight of a processed botanical substance. The batch size and yield of the process relative to the botanical raw material should be provided. When the active constituents or other chemical constituents are known and measurable, the amount in which they are present in the botanical drug substance should be declared. The composition of multi-plant drug substances, in terms of the relative ratio of the individually processed botanical drug substances or of the botanical raw materials before processing (as applicable), should be expressed.
  • Name and address of the drug substance manufacturer (i.e., processor).
  • Description of the manufacturing process. The description should include each process step (e.g., pulverization, decoction, expression, aqueous and/or ethanol extraction), the quantity of botanical raw material, solvents, temperature and time for extraction and/or drying, and in-process controls. The yield of the process, expressed as the amount of the original botanical raw material relative to the amount of the extract, should be indicated. If more than one botanical raw material is introduced to produce a multi-plant substance, the quantity of each raw material and the sequence of addition, mixing, grinding, and/or extraction should be provided. If a multi-plant substance is prepared by combining two or more individually processed botanical drug substances, a separate description of the process leading to each botanical drug substance should be provided.
  • Quality control tests performed on each batch of the drug substance, analytical procedures that were used, available test results, and proposed acceptance criteria. The quality control tests should include, but not be limited to, tests for the following attributes:

− Appearance.

− Strength by dry weight (equivalent to botanical raw material).

− Chemical identification for the active constituents, if known, or the chemical constituents.

 

In general, the sponsor should use the best available analytical technology to address the issue of analytical resolution. When the resolution is inadequate in one particular method, multiple methods should be used to provide complementary data for adequate chemical identification and quantification.

 

The characteristic profile of chemical constituents can be determined based on spectroscopic and/or chromatographic methods. Examples of spectroscopic methods include ultraviolet, infrared, Fourier transformed infrared, mass spectroscopy, and liquid chromatography–mass spectrometry (LC-MS). Examples of chromatographic methods include high performance liquid chromatography (HPLC), gas chromatography (GC), thin layer chromatography (TLC), and capillary zone electrophoresis.

 

− Quantification for the active constituents, if known, or the chemical constituents. If several botanical raw materials are combined to produce a multi-plant substance and a quantitative determination of each individual active or chemical constituent is infeasible, a joint determination can be made for several active or chemical constituents. When multiple active or chemical constituents are known, they should be chemically characterized and their relative amounts should be defined.

 

− Biological assay. If the active constituents are not known or quantifiable, a biological assay should be developed, prior to initiation of Phase 3 studies, to assess drug substance batch potency and activity relative to a reference standard.

 

– Mass balance. Methods should be developed to quantify other classes of compounds (e.g., lipids or proteins) that contribute to the mass balance of the botanical substance, prior to initiation of Phase 3 studies \

 

– Tests for residual pesticides as outlined in USP <561> and for any pesticides routinely used in the countries of origin of botanical raw materials.

 

– Tests for elemental impurities, residual solvents, and radioisotope contamination, if applicable.

– Tests for microbial limits.

– Tests for adventitious toxins, such as aflatoxins.

– Available stability data. The sponsor should develop stability-indicating analytical methods and conduct stability studies as the IND progresses.

 

Botanical Drug Product

 

The sponsor should provide the following information for a botanical drug product(21 CFR 312.23(a)(7)(iv)(b)):

  • Qualitative description of the drug product. It should include the dosage form, route of administration, names and functions of all ingredients (e.g., botanical drug substance, other drug substances, and excipients), and a statement declaring if the botanical drug substance is combined with other drug substances (e.g., a highly purified, biotechnology-derived, or other naturally derived drug substance).
  • Composition or quantitative description of the drug product expressed in terms of amount per dosage unit and amount per batch. The information should be provided in tabular form.

 

Summary

 

There are multiple regulatory pathways available for the commercialization of botanical drug products. It is the Sponsor’s responsibility to communicate with the appropriate government regulatory body to ensure that all requirements are met.  FDA treats botanical drug products as any other drug entity; safety, clinical and quality standards must be met for approval and commercial distribution.

 

References

 

US FDA Guidance: Botanical Drug Development, December 2016

United States Pharmacopeia 37 Section <561> Articles of Botanical Origin, Section <563> Identification of Articles of Botanical Origin, and Section <565> Botanical Extracts

Weishi Li, Botanical Drugs: A Future of Herbal Medicines, Journal of Contemporary Health Law & Policy, 2002, Volume 19, Issue 1, Article 6, pp 117-149

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