Botanical drugs – what is the best way forward for regulatory and market approval?

In the US, botanical dietary supplements can be sold without US Food and Drug Administration (FDA) approval,¹ prompting many vendors to promote the use of botanical products as dietary supplements,² rather than pursue a path of regulatory approval. However, as with drugs, dietary supplements require evidence that they are safe and that claims on product labels are truthful and not misleading.¹

For use as prescription drugs, a botanical product must be approved by the FDA: to date, only two have gained this approval. Veregen®, a treatment for genital and perianal warts that is derived from green tea (Camellia sinensis Kuntze),^2,3 was the first ever botanical drug to be approved by the FDA. The second was crofelemer, Mytesi™, an indicator drug for HIV-associated diarrhoea extracted from the blood-red latex of the South American croton tree.² It was first approved as Fulyzaq™ in December 2012 and in October 2016, Napo Pharmaceuticals launched the new brand, Mytesi.³

Is two too few?

It begs the question of why only two botanical drug products have obtained FDA approval and fulfilled the Botanical Guidance definition of a botanical product.³

A botanical product intended for diagnosing, curing, mitigating, preventing or treating disease would meet the definition of a drug under section 201(g)(1)(B) of the US Federal Food, Drug and Cosmetic Act (FD&C Act)⁴ and would therefore be subject to regulation as a drug. The FDA’s role in the regulation of botanical drug products includes an assessment of their safety and efficiency⁵ but insufficient evidence for efficacy is one of the most common reasons why new drug candidates fail to reach this step.² The prerequisite to present statistically significant evidence for having efficacies of clinical relevance is crucial because FDA requires “adequate and well-controlled” multicentre clinical studies on any new drug candidate to document and support its safety and efficacy, and imposes the maximum level of scrutiny prior to approval.² It is crucial for these efficacy studies to have a well-defined target population (according to FDA protocol eligibility criteria), proper experimental controls (such as placebo or active treatment), appropriate outcome measures (agreed upon by the FDA), independent monitoring and accurate analysis.²

In addition, the nature of botanical products adds another layer of complexity in terms of obtaining FDA approval. The FDA has acknowledged that the interpretation of regulations, including definitions of ‘identity’, ‘active ingredient’ and ‘purity’, needs to be “extended from a narrow, chemical mindset to accommodate the complex nature of botanical drug substance”,⁵ yet the heterogenous nature of botanical drugs can make it difficult to ascertain whether just one or all the constituents are active.⁶ Thus, it is critical to ensure the consistency of therapeutic effect across batches (see box).^4,6

Five patent issues that European biosimilar developers should consider before entering the US market

Quality control of the botanical drug substances was one of the critical factors that led to barricades during the development of Veregen and Mytesi.⁶ In fact, the FDA did not initially recommend approval of Mytesi (crofelemer) due to insufficient information to assure the identity, strength, purity and quality of the drug product.⁴

Since only two botanical drug products have been approved by the FDA to date, the FDA botanical drug development pathway is considered a relatively new route to market and still in its infancy.⁶ There is a lack of research into effective development strategies and risk mitigation techniques for firms wishing to develop botanical drug products and the limited available guidance is another likely reason why so few have achieved FDA approval.⁷

Lastly, another reason for the lack of botanical drug products reaching FDA approval status is that the process is capital intensive and loss of some or all project funding during the development of botanical drugs will bring the project to a complete standstill.^7,2 Funding cuts are caused by several different factors, including the state of the economy as a whole, investor pessimism, a lack of patents and/or poor project planning.²

Approach taken by regulators in the UK

The Medicines and Healthcare products Regulatory Agency regulates herbal medicines in the UK.

Herbal medicines placed on the market since April 2011 must have either a traditional herbal registration (THR) or a Marketing Authorisation (MA).⁸ The correct pathway depends on whether the herbal medicine is intended for use with minor health conditions, in which case the THR scheme is the appropriate route, or for major health conditions, which will require a full MA application.⁹

Traditional Herbal Registration

The Traditional Herbal Medicines Directive (Directive 2004/24/EC) is implemented in the UK by the Medicines (Traditional Herbal Medicinal Products for Human Use) Regulations 2005 and came into force on 30 April 2011.¹⁰

Directive 2004/24/EC introduced a registration scheme for traditional herbal medicines and requires herbal remedies sold over the counter in the UK to be registered.¹¹ In order to market such a product, companies must apply for a THR but it should be noted that this is only granted to eligible products; ie, those used for minor health conditions (such as a cold) and without the supervision of a medical practitioner¹⁰ (whether for diagnostic purposes or for prescription or monitoring of treatment).^10,12 The THR scheme is also limited to products used for oral or external use and/or inhalation.¹⁰ To achieve THR registration, companies must demonstrate that their herbal medicinal product has been traditionally used to treat the stated condition for a minimum of 30 years (at least 15 years of which must have been in the EU).¹⁰

Evidence of safety, adherence to appropriate manufacturing standards and provision of appropriate product information to users is also required to gain registration under the scheme.¹¹ The THR scheme does not require any evidence that the herbal medicine actually works nor does it offer any guarantee regarding its effectiveness but the prolonged-use requirement does lend credence to efficacy.¹¹

The THR pathway was created with the purpose of establishing a simplified registration procedure for all traditional herbal medicines that do not fulfil the requirements for the MA (strict) pathway under Directive 2001/83/EC.¹³ Currently, over 350 herbal remedies have been granted a THR licence.¹⁴

Marketing authorisation

In the UK, medicinal products placed on the market are required to have marketing authorisations in accordance with The Human Medicines Regulations 2012 (S.I. 2012/1916).

Companies can therefore also legally sell herbal medicines in the UK by gaining a licence under an MA. The MA pathway is applicable for herbal medicines designed to treat more serious health conditions and require a medical prescription or the supervision of a medical practitioner.¹⁴ Interestingly, GW Pharmaceuticals was successful in gaining full regulatory authorisation in the UK for its prescription cannabis-based medicine, Sativex®, an oromucosal spray for the treatment of spasticity due to multiple sclerosis. This represented the world’s first prescription medicine derived from a cannabis plant to gain such approval.¹⁵

There are several different routes to marketing authorisation. Herbal medicines that contain a new active substance require a full application which must contain the results of pharmaceutical tests (physico-chemical, biological or microbiological), pre-clinical (toxicological and pharmacological) tests and clinical trials,¹⁶ and is therefore similar to the process in the US for botanical drugs, which usually involves Phase I, II and III clinical studies.

Regulatory pathways in the EU

The EU regulatory framework is, unsurprisingly, similar to that in the UK (as the UK framework derives from the EU Directives) and consists of the Traditional Use Scheme and full MA.

Traditional Use Scheme

Directive 2004/24/EC, which amended Directive 2001/83/EC (Chapter 2a) in 2004, introduced the provisions for a simplified registration of traditional herbal medicinal products (THMP) in the EU.¹⁷ This allowed the registration of medicinal products under a pathway called the Traditional Use Scheme (TUS) whereby, just like the THR scheme in the UK, if it can be shown that the product has been in medicinal use throughout a period of at least 30 years (with at least 15 years within the EU), then it can qualify as a THMP.¹⁸

The national competent authorities (NCA) of the EU Member State are responsible for the registration of THMPs.¹⁹

Market authorisation

The regulator of the EU Member State is responsible for the MAs of well-established use applications and stand-alone or mixed applications.²⁰ However, if the centralised authorisation procedure applies, then the European Medicines Agency (EMA) is responsible for evaluating applications and the European Commission grants the authorisation.²⁰ The EMA has scientific guidelines (on quality, non-clinical, clinical and safety) in relation to herbal medicinal products, which should assist companies when preparing MA applications.²¹

It should be noted that, irrespective of the regulatory pathway, the quality requirements are the same for herbal medicinal products and should comply with the relevant European Pharmacopoeia monographs and/or the pharmacopoeia of a Member State.²⁰

Good manufacturing practice (GMP)

Commission Directive (EU) 2017/1572 (which supplemented Directive 2001/83/EC) lays out the principles and guidelines of GMP in the EU. For herbal medicinal products (and any other medicinal product), GMP describes the minimum standard that a medicines manufacturer must fulfil in their production processes.²⁰ NCAs are responsible for inspecting manufacturing sites situated in their own territories.²⁰ While there are differences between the EU and US GMPs, both share many fundamental principles such as mandating batch release procedures and QC testing prior to release for distribution.²²

Navigating botanical medicine’s regulatory maze

In conclusion, the regulatory journey for botanical drugs is complex. While traditional herbal therapies hold promise, securing regulatory approval remains elusive. With only two botanical drug products approved for marketing as prescription drugs in the US, the scarcity raises questions about efficacy, safety and the formidable barriers in the regulatory process. The intricate nature of botanical products further compounds the challenge, demanding a paradigm shift in regulatory interpretation and QC standards.

In the UK, the dichotomy between traditional herbal registration and MA delineates the regulatory framework for herbal medicines, catering to both minor and major health conditions. Meanwhile, the EU mirrors this framework, offering a traditional use scheme alongside the rigorous process of MA.

Amid these regulatory mazes, adherence to GMP emerges as a beacon of standardisation, ensuring quality and safety across manufacturing processes. However, the journey towards regulatory approval remains arduous, fraught with financial constraints, regulatory ambiguities and scientific complexities.

As the botanical drug development pathway evolves, stakeholders must navigate these turbulent waters with caution, leveraging insights from regulatory experiences and fostering collaborative efforts to pave a smoother path forward. Only through concerted action can the full potential of botanical medicines be realised, offering new avenues of treatment and wellness to global healthcare landscapes.

References

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4. Botanical Drug Development Guidance for Industry [Internet]. 2016. Available from: https://www.fda.gov/media/93113/download
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