Get a sharper focus

Most of the research and development cash spent on nutraceutical product development is driven by marketing goals and the need to comply with regulations about truth in marketing communications, although investing in safety and efficacy data is also on the rise.

Short-term animal studies are also seen as a low-cost means of product differentiation. However, the nutraceuticals industry pays the least attention to the earliest component of any product development programme - quality standardisation - which means that subsequent clinical research is highly dependent on supplier specifications and test reports.

Studies to find the mechanism-of-action of the dietary ingredient or the finished supplement are fast gaining in popularity. Recent times have also seen bioavailability of herbals being questioned and much effort spent on developing a more bioavailable version of an existing ingredient that was claimed to be poorly available from an oral dose. Enormous possibilities exist in formulating elegant, convenient and stable dosage forms for dietary supplements, yet there seems to be little awareness of the potential value to be created by research into novel delivery systems.

The Vedic nutraceutical development plan is based on an assumption of a polyherbal product comprising two to eight commonly used plant extracts in a solid oral dosage form.

We strongly recommend using Asia as an outsourcing destination for nutraceutical research, given the budgetary challenges that most companies face. Also, the labs, hospitals and contract research organisations in that part of the world are now of internationally acceptable quality for human and animal research.

India in particular is becoming a favoured destination for conducting clinical trials, the main reason being the ample patient pool available, expertise available in the form of GCP (good clinical practice) trained and aware investigators, English-speaking staff, adherence to timelines and low costs.

The guiding principle in Vedic's strategy is that most of the herbal ingredients will have a long history of usage in the country of origin and have no safety concerns at the recommended dosage for the indication. This means that early studies in man can be undertaken without extensive toxicology and in parallel with sub-chronic studies.

We strongly recommend that a chemistry manufacturing and controls dossier is in place before embarking on a final human study so that there is no doubt about the integrity and stability of the investigational product entering such an expensive study.

After having established a proof of concept in humans, one can plan the mechanism-of-action studies using in vitro and other models if available.

According to pharmaceutical convention, drug developers typically take up clinical development of a molecule only after most non-clinical evaluations. In contrast, the the proponents of reverse pharmacology propose that all non-clinical development be done only after initial clinical trials are successful.

However, reverse pharmacologists do not take into account the variability that may be introduced into the data when a substandard product undergoes large-scale human trials. Our approach strikes a balance between the two.

Acute oral toxicity and genotoxicity studies

We recommend that, even if there is a substantial history of safe human usage, new dietary supplements undergo the basic acute oral toxicity and Ames test (biological assay to assess the mutagenic potential of chemical compounds) first before entering the clinic.

This basic safety evaluation assumes greater importance when any of the plants have been extracted or purified using methods or solvents not described in the traditional medicine and texts.

This early toxicology may be carried out in non-GLP (good laboratory practice) settings but according to the applicable guidelines.

Dose determination study

The primary objective of this study is to explore all the possible benefits of the supplement in a diverse consumer population and to identify the sub group that will benefit the most from the product.

Subject sub-grouping is possible on the basis of demographics, such as age, gender, physical constitution and habits, as well as on severity of condition and disease sub-type. Well-planned exploratory work lays a strong foundation for the proof-of-concept confirmatory trial.

According to conventional pharmacology, one must have adequate proof of concept and dosage data from in vivo animal studies before the first human study on a new product.

Chemistry, manufacturing and controls (CMC)

CMC involves quality standardisation of the nutraceuticals product. This is like a passport for the product. It identifies it. It is unchanging and allows the product to enter different phases of the subsequent safety and efficacy evaluation as well as allowing it to be manufactured at multiple locations during research and commercial launch. CMC for botanicals comprises agricultural records, phytochemistry, impurities, dosage form design and standards and stability.

Agricultural records

It is no longer sufficient just to identify the botanical source of ingredients. One must also maintain records of the geographical origin and agricultural practices such as place of collection or cultivation, time of harvest and method of drying.

Phytochemistry (active ingredient assays)

At Vedic we employ our proprietary Phytoray approach, which is an array of diverse test systems to phytochemically characterise a poly- or mono-herbal product, including non-chromatographic assays for groups of compounds such as alkaloids and glycosides. We also use HPTLC (high performance thin layer chromatography) fingerprinting and quantification of abundantly available but unique markers and HPTLC quantification of select markers that require higher sensitivity. This approach is unique in the industry and has yielded useful and practical methods for our clients.

Impurities analysis

Choice of tests to be run, the number of batches to be evaluated and the stages of manufacture to be included in the impurity testing programme are determined carefully. They are based on the nature of the product, expected impurities, if any, results of the reverse testing procedure (finished product first) and statistical sampling methods. Tests routinely done are heavy metal testing, pesticide analysis and microbial load. But tests for mycotoxins, aflatoxins and solvent residues may also be recommended.

The relevance of active ingredient and impurity analysis before the second human study (phase II b) and sub-acute toxicity studies cannot be overemphasised. For example, the 28-day study would be a waste if significant heavy metal contamination had already been detected at the impurity analysis stage.

Formulation development

There are unique challenges in nutraceutical formulation development, particularly large daily doses of herbals, taste-masking, the hygroscopic nature of some extracts and the higher potential for active-active and active-excipient interactions.

Stability

Packaging research and the pharmaceutical, chemical and microbial stability of finished product forms containing natural ingredients are less studied but require urgent industry attention.

Sub-Acute 28-day oral toxicity study

This is essential for confirming the safety of possible higher therapeutic doses in the second clinical trial. Identify organs of toxicity, if any. Moreover, ethics committees for human trials may suggest a 28-day study before they approve a longer treatment trial for an unproven nutraceutical.

Mechanism-of-action studies

It is debatable whether these studies should be carried out before or after the clinical trials. The knowledge of a confirmed or possible mechanism of action can indeed be a good tool to clinical trial design in selecting possible biomarkers for efficacy endpoints as well as for choice of the control group.

A hallmark of natural agents is their multiple mechanisms of therapeutic benefit. Hence, mechanism-of action-studies on multi-ingredient products are debatable unless one explores mechanisms of the key individual ingredients.

Proof-of-concept and bioavailability

The primary objective of this study is the establishment of clear benefit for the product as a nutritional supplement for the indicated condition and for the target population, as compared with a group receiving either no intervention or only standard medical care without supplementation. This is possible with a randomised controlled trial, which has been planned and executed under the best practices for biostatistics and clinical trial project management.

The end goal of this study is a publication and a clear demonstration of efficacy. Extensive safety evaluations are always a part of any phase II study and should be included in a nutraceutical study even if the plant ingredients have an extensive history of ethnic usage.

There is an opportunity to conduct a pilot assessment of bioavailability of the key phyto constituents of the dietary supplement in human subjects. Results from this study can greatly aid formulation chemists in correctly selecting possible biologically active markers rather than markers that may have been in vogue earlier but were found to be poorly available orally, let alone active.

Because of the absence of regulatory guidelines for 'grandfathered' nutraceuticals, flexibility in research project size and sequence is entirely in the hands of the sponsors and the marketing department. However, Vedic believes its approach can substantially reduce the risks of failure and associated costs in nutraceutical product development.

''Jayesh Chaudhary is the founder and chief executive of Vedic Lifesciences, which offers natural products contract discovery and development services to clients worldwide. Email: vedic@ayuherbal.comhttp://www.vediclifesciences.com​''