Botanical Drug Development – How Natural Health Products Can Become Drugs
known, and often the marker compound for the plant is not the only potentially active constituent, meaning that standardisation is much more difficult than with SCEs. Incoming raw materials for BDs must undergo 100% testing across several domains including the plant part, extraction methodology, identity, characterisation or standardisation, stability, purity and variability. It is critical that companies producing BDs have sufficient reliable sources of their raw ingredients. Some companies have gone so far as to purchase all the farms required for their source material to ensure supply and quality. The rest of the regulatory Chemistry, Manufacturing and Controls (CMC) requirements for BDs are similar to those for SCEs regarding process validation (i.e. installation, operational and performance qualification). Often, the NHPs from which the BDs are derived have been manufactured under other regulatory categories, and upgrades may be required to meet these CMC requirements.2
The other distinctive feature of these products is that human usage data exist before the product undergoes phase I testing. In some cases, human usage may have been thousands of years of traditional use, or the sales of millions of dosages under a different regulatory category, for example, as food or as a dietary supplement. These data do not substitute for adequate and well-controlled clinical trials, but it does provide a glimpse into the efficacy and safety profile of the product that cannot be obtained with SCEs. The first BD was approved by the FDA in 2006. The product was Veregen® – a green tea extract for the topical treatment of genital warts. This first approval has validated the theory that such botanical drugs are possible and that complex botanical preparations can be standardised to meet the FDA’s requirements.1
Clinical Development Process for Botanical Drugs
From the perspective of a clinical trial development plan, the pathway may not be as linear as traditional development plans because certain steps may be skipped or re-ordered by the FDA. Also, there are many companies simultaneously running clinical studies under multiple regulatory categories. In the US, a less purified version of the product may be sold and studied as a dietary supplement and later the BD IND application may be filed. The opposite is not true; if the BD IND application is filed first, the product cannot later be sold as a dietary supplement. If the NHP has an application in the dietary supplement marketplace, it may therefore be advantageous to run clinical studies in that regulatory category in order to obtain human dose justification and safety data that can be used to support the IND application. This type of human data does not exist in the usual SCE development route and, on occasion, the FDA has allowed companies to reduce certain pre-clinical requirements and to skip all or part of some phase I requirements. The other advantage to the parallel track approach (i.e. developing the product under both the dietary supplement and the BD category) is that sales of the dietary supplement version of the product can be used to support the BD clinical trials.
Most aspects of the BD clinical trial plan are identical to SCE studies, including the need for adequate and well-controlled studies, the following of International Conference on Harmonisation (ICH)/World Health Organization (WHO) Good Clinical Practice (GCP) standards, and the statistical requirements. End-point selection will be based
DRUG DEVELOPMENT
Figure 1: Natural Health Products as a Disruptive Technology
Old market’s supply curve
Old market’s demand curve
Traditional pharmaceuticals
New market’s supply curve
At this point, supplement quality/efficacy is sufficient for old market values
New market’s demand curve
Natural health products Time Source: Christensen CM, 2000.4
on the therapeutic area, but may also take into account prior human use data for the product. The other area in the design of clinical trials different from that of SCEs is the careful consideration of the way in which diet may interact with the investigational product. As NHPs usually have a history of traditional use as medicine or even food, they may be present in the background diet of certain cultures and in various geographic locations. This must be accounted for in the selection of the target population by choosing subjects who will not be exposed to the test ingredients through their diet and who will not be exposed to other non-pharmaceutical (i.e. dietary supplement) products that may contain the same ingredients. All subjects should be monitored for potential drug–drug and herb– drug interactions.
Who is Involved in Botanical Drugs Today? There are two groups of companies advancing the field of BD development. The first is the NHP (non-pharmaceutical) companies who have often developed the NHP under the dietary supplement or food category, and are investing in developing their product into a BD. These are generally smaller companies, usually Asian, European or Australia/New Zealand, and have invested in clinical trials for the food or dietary supplement version of their product. They have raised enough financing internally or externally to file the IND application and begin phase I and/or phase II studies, but cannot finish the job alone. The second group of companies advancing this field comprises the forward-thinking pharmaceutical companies who see the opportunity and consumer demand. These companies need new products, have the resources to finance the later-stage studies and have the marketing and distribution relationships as well as the sales forces necessary to commercialise these products. It is only when these two groups of companies work together in synergy that a BD product would have a chance of success.
The Opportunity
Opportunity knocks today. NHPs can be developed into BDs, the proof of concept of this model being Veregen. The development of NHPs into BDs will require co-operation between those companies developing these products, and those companies with the experience and resources to successfully navigate both the
35
Quality of care
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68