Dear Nguyen

This is a very large question and it have to be divided into several section:

First question is of course the intended indication and use of the substance/product, then;

1. A very thorough review of all available data for the particular active ingredient/s with emphasis on the safety (toxicology), both in-vitro and in-vivo.

2. There has to be sufficient animal data to support the use in-vivo.

3. Studies on the pharmacokinetics and metabolism have to be in place.

4. Dose-finding supportive data have to be in place.

5. Any studies performed in humans have to be performed in accordance with the WHO guidelines for clinical studies in humans.

Generally, for pharmaceuticals, the process of obtaining sufficient data for a particular substance (chemical oo plant-derived) is within the time-frame of 8 – 10 years. However if the plant/substance has a very long tradition as a herbal remedy – data from this use should and could be used as guidance.

This is a very short answer to a complex question.

Dear Nguyen,

Since you already have the preclinical to clinical ideas of drug development, another aspect worthy to mention is satisfying the regulatory requirement of drug licensing authorities. This includes a number of tests designed to determine the major toxicities of the herbal medicine or compound prior to administering on human, to ascertain to effect of the body organs and other parts of the body.

However,these tests can be made using in vitro methods (e.g. with isolated cells), many tests can only be made by using experimental animals, since it is only in an intact organism that the complex interplay of metabolism and drug exposure on toxicity can be examined.

Furthermore, NPR reported scientists are developing palm-sized mock human organs, designed to test drugs and help understand the basic function of healthy or diseased organs. Researchers are hopeful this technology may speed up drug development and make it less expensive.[Richard Harris (2 January 2015). "Researchers Create Artificial Organs On Microchips". NPR.]

Thank you for your informative comment, Dr Nnamdi.

I wonder if there is any formal strategy (e.g. a flowchart) for herbal medicine research, from pre-clinical to clinical study.

I found this one: 

Guidelines on clinical study of traditional medicines in WHO African Region. Brazaville, WHO Regional Office for Africa, 2004 (document reference

AFR/TRM/04.4), WHO (document reference AFR/TRM/04.4).

That really depends very much if the herbal medicine is a single plant preparation, or a herbal mixture, or if you are looking at testing a lead compound. However, in general, if you want to get any preparation approved as drug you will have to follow basically the same process you would follow for the development of a regular allopathic drug, always depending on the requirements of the local regulatory authority. 

Thank you Dr Rainer for your informative comment.

Later on reading some references, especially "guidelines on clinical study of traditional medicines in WHO African region", I concur that the general procedure is essentially the same.

Dear Nguyen

This is a very large question and it have to be divided into several section:

First question is of course the intended indication and use of the substance/product, then;

1. A very thorough review of all available data for the particular active ingredient/s with emphasis on the safety (toxicology), both in-vitro and in-vivo.

2. There has to be sufficient animal data to support the use in-vivo.

3. Studies on the pharmacokinetics and metabolism have to be in place.

4. Dose-finding supportive data have to be in place.

5. Any studies performed in humans have to be performed in accordance with the WHO guidelines for clinical studies in humans.

Generally, for pharmaceuticals, the process of obtaining sufficient data for a particular substance (chemical oo plant-derived) is within the time-frame of 8 – 10 years. However if the plant/substance has a very long tradition as a herbal remedy – data from this use should and could be used as guidance.

This is a very short answer to a complex question.

The herbal drug from which the medicine is to be prepared has to be established safe for human consumption by doing a literature research first.The medicinal properties/active principles should be gathered and then tested by animal models.this will give a data for making dosage forms from the said drug.these dosage forms should be then tried out on humans. 

Your study in this regard should be comprehensive, as there are many established experience based practices of Herbal medicine like Ayurveda, Siddha, Tibetan Medicine, Unani medicine and may more, where the dosage according to forms and diseases are already described and are in practices. In such sciences Reverse Pharmacology studies are best for re-validation. 

In cases of herbs which are new in therapeutics, Pharmacognosy, Quality, Safety, Efficacy, Dosage forms are to be studied before clinical trials.

Dear scientists, thank you very much for your kind responses.

 You may please consult the following documents for having a general idea

1. General guidelines for methodology of research in Traditional Medicine -published by WHO

2.Good Clinical practice guidelines for Ayurveda ,siddha and unani medicine  published by Ministry of AYUSH,Govt.india

How ever  the requirements   are  generally based on  type of intervention proposed for validation clinically  such as  1. validation of  a formulation as such mentioned in a codified /documented literature for its clinical use/indications/dose  etc. or 2.  Clinical study of  new leads/  development of NCE from plants.

The  evidence  or compliance for  quality and safety are paramount in all the cases .

Dear Nyugen,

If by evidence you mean the therapeutic effect of a herb/herbal formulation on a disease; then you can peruse the various literature and traditional medicine manuscripts. And if you mean the other preclinical/clinical studies which are prerequisite to a trial, then our friends above have very well elaborated that. Also, not all will be required for your herb. As mentioned before a literature review for the said herb or similar herbs, will help you in formulating a general plan.

Dear Dr. Nyugen Long,

Being a clinician, is your question reflective of your objective to explore the avenue of herbal medicine, which is immensely vibrant and rapidly growing, for improving a specific health condition? Do you have an herbal medicine (remedy) in consideration, for which you wish to assess (and ensure) safety and efficacy?  An herbal medicine can comprise raw or processed ingredients from one or several plants, with potential therapeutic or human health benefits. Information on the salutary benefits of an herbal medicine preparation could also been gathered based on history of prolonged use with perceived benefits (supplanted with cultural beliefs and multiple anecdotal observations).

Drug development, as you are well aware of, is a very long and laborious process. There are major steps that are imperative to be completed before the process of drug development. Prior to undertaking a clinical study, the following issues need to be considered and sorted out. You need an active (with therapeutic health/benefits) herbal medicine or extract, with a beneficial end-point (biologic activity) to evaluate. Your test material may be a purified extracts a powdered plant extract, partly purified active substances isolated and characterized from herbs, or a single chemical moiety.  

It is assumed that administration of your herbal preparation produces a measureable modification (modulation) in the base-line function of an experimental animal. This interventional measure translates to possible amelioration of a human disorder/chronic or degenerative health condition/disease. The end result might also be prophylactic. However, we are dealing with (herbal) medicines here.  You may need to have (broadly representative) an active compound in mind; this will facilitate the standardization of your preparation and ascertain the quality of the herbal medicine. Such a molecule may not necessarily be the active principle behind therapeutic activity.

Here is a useful link (WHO):

http://apps.who.int/medicinedocs/en/d/Jh2946e/2.3.html

Essential Medicines and Health Products Information Portal A World Health Organization resource 

Research Guidelines for Evaluating the Safety and Efficacy of Herbal Medicines

(1993; 94 pages)

The anticancer agent, taxol (Taxol), an alkaloid, was identified in Pacific yew, Taxus brevifolia Nutt., a small understory tree from the Pacific Northwest forests (USA). There was an issue of sourcing high enough concentrations of taxol from this tree as a the bark from a single tree only yielded quantities of taxol sufficient for about one dose of the drug. The isolation of 0.5 g of pure taxol from the bark of Taxus brevifolia took about two years. The common yew, Taxus baccata, widely grown as an ornamental tree contains an abundant taxol derivative, which can be transformed to taxol by chemical manipulation; Dr. Robert Bolton of Florida State University invented a process for such taxol production, which was licensed and developed to produce taxol.

A literature search for previous work done can be carried out.Studies can be done to confirm its action,carrying the work forward,its efficacy in certain disease.after literature search physico chemical analysis of the drug has to be done.To see a particular action animal model is to be selected and studies conducted.In vivo or in vitro studies can be done.

A complex question indeed. You may look at it this way: Two major requirements most be satisfied - 1. Ethical requirements and 2. Drug requirements. The earlier may be considered to have three components; institutional or governmental requirements, drug ethics or objective requirements and volunteer or subjective requirements. The second arm which is DRug Requirement basically constitutes data from pharmacodynamics, pharmacokinetics and toxicology. Such data may take as long as ten or more years to generate. It could be shortened by rich data gathered from years of ethnomedical practices. Now, the cumbersome of this issue will be apparent if my friend Dr Long will require any expanciation on any of the requirement. Thanks.

Before conducting any clinical trial we need three main findings-reports 1- Quality -Standard of the material or drug as such. Quality include many a parameters like Organoleptic tests, Physical and Chemical nature, Dosage form etc. 2- Safety and toxicity of drug conducted in Vitro or Vivo - animal or cell lines. 3- Efficacy-Pharmacological actions and in particular action for which drug is to be taken for clinical trials. In conducting Clinical trial many formalities are to be completed like designing protocol, permission from institutional ethical committee etc. In nut shell Q-Quality, S-Safety and E-Efficacy are major requirements for conducting clinical trials.  

Herbal medicines are usually associated with two issues that are considered in providing evidence in support for clinical investigation: 1. long history of prior use, 2. Many components contributing to claimed effect. Thus: i. instead of detailed statements regarding manufacturing/quality of a pure single active ingredient expected of conventional investigational drug you simply standardize the herbal medicine processing steps and assay its main or putative components chemically or by bio assay ii. provide pre-clinical data supporting its efficacy and safety (or conduct them if absent), iii) No need for phase 1 since medicine has prior use in humans already,, iv. get an idea of dose from herbal medicine use as starting point.