The Development of Plant-Based Medicines for Prescription

Despite the fact that herbal or plant-based medicines are widely used and trusted by the public and have been for many years, few have been approved by regulatory agencies in the Western world (e.g., the US Food and Drug Administration (FDA) and European Medicines Agency (EMA)) as prescription medicines. As many as 50% of cancer patients for example use alternative medicines, and social media are full of pleas from patients for greater access. In recent years, for example, cannabis-based products have achieved huge exposure in social and mainstream media, despite having been used for millennia. As long ago as 1992, the US Congress determined that patients might be ill-served by the lack of availability of botanical products as prescription medicines, and established the Office of Alternative Medicines at the National Institutes of Health. In the UK, there is a category of “Traditional Herbal Medicine” (THR), where a plant-based compound with many years of use can be recognized by the Medicines and Healthcare products Regulatory Agency (MHRA). However, this category of medicines is limited to minor health conditions, where medical supervision is not required, such as a common cold. If the THR is to be used for a major condition, then a full marketing authorization is required before marketing is permitted.

Why have so few botanical medicines been approved as prescription medicines?

In 2004, the FDA published draft guidelines regarding the development and approval of botanical medicines, so there exists a road map for manufacturers to follow. The FDA created a botanical review team, to work across divisions, who act as specialist advisers to the FDA on herbal medicines. These botanical drug guidelines have since been updated, and the FDA has published a series of Q&A resources to help explain them. Since these guidelines have been published, there have been more than 400 investigational new drug (IND) applications granted for botanical medicines, but only three have reached the new drug application (NDA) stage of development. These are firstly an ointment derived from Camellia sinensis (green tea), used for the treatment of genital warts (sinecatechins), an extract of the latex of the “Devil’s Blood” tree (crofelemer), used for the treatment of drug-induced diarrhea in HIV/AIDS, and cannabidiol, extracted from the cannabis plant, and used to treat three rare childhood-onset epilepsy syndromes.

Cannabidiol serves as the most recent of the aforementioned botanical medicines and presents as a good example of some of the issues behind the development of a plant-based medicine. This author was fortunate to be a leader of the development program and regulatory effort which led to the FDA’s approval of cannabidiol (Epidiolex^®). Social and mass media contain many examples of claims that cannabis is a helpful medicine for many conditions, including childhood-onset epilepsy and there is a long history of cannabis-based medicines being used in epilepsy. But equally, tetrahydrocannabinol (THC), one of the two major cannabinoids found in the plant, reliably provokes seizures in toxicology studies and probably in humans. This observation encapsulates one of the issues. There are parents of children with treatment-resistant epilepsies who insist that their child requires THC, and it seems highly likely that this is based on bona fide observations of their child, but this does not mean that THC is likely to be helpful for childhood-onset epilepsy generally. In fact, the existing safety data suggests the exact opposite.

For this reason, the FDA and MHRA both require a level of evidence for herbal medicines which is the same as the level of evidence required for wholly synthetic compounds. This includes an understanding of drug metabolism, of the potential for drug–drug interactions and knowledge of the medicine’s mechanism of action. This is a high hurdle for botanical medicines. But perhaps most challenging of all is the requirement to show that the material being used by patients is of constant composition, or that minor variations between one batch and another do not affect efficacy and safety.

Again, cannabidiol provides an example of these manufacturing issues. It is widely used as a herbal medicine for multiple indications. There have now been several publications where the composition of over-the-counter cannabidiol products has been shown to be unacceptably variable; the FDA themselves reported that few products contain what they claim to contain.

We have yet to resolve the paradox whereby patients insist that a particular herbal medicine works for them and therefore the government should pay for it, and the requirement that any prescription medicine has to meet well-established criteria for efficacy and safety across a population. How to resolve that paradox is a discussion for another day.

About the author

Dr Stephen Wright is an independent consultant in medicines development from Limber Scientific. He has played a key role in the successful development of several highly successful medicines, on both sides of the Atlantic and elsewhere. His expertise covers the regulatory strategy around CMC as well as preclinical and clinical development. He has particular experience with successful Schedule 1 substance development (cannabinoids and hallucinogens).