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How can herbal products be launched in India? What is the regulatory
requirement to sell an Ayurvedic product in India?
This is the uniqueness of the Indian Regulatory system. If a formula
contains only “Ayurvedic” ingredients (herbs and minerals listed
in the official books of Ayurved) then one has to make an application
to the State FDA with the references of the respective ancient text
eg. Bhavyaprakash Nigantu and the medical label claim. As long as
the claim is justified as per the ancient texts, the FDA allows
it. This way Ayurvedic marketers can make health claims on the basis
of history of use and ancient evidence of the generic preparation
or the ingredients thereof with no modern day evidence of their
own brand. Conclusion: It is easier to make label claims for Ayurvedic
Products in India than in most countries. As of mid 2006, there
was a move by some of the state authorities to make clinical data
a licensing requirement for Ayurvedic products also. It is not clear
however. The Indian herbal products including Ayurvedic, Unani,
Siddha and Homeopathic are regulated under the Drugs & Cosmetics
Act and licensing of such products remains a state subject. The
Drugs Controller’s office at New Delhi has little to do with it.
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How can non-Ayurvedic products be sold in the Indian market?
Can I make health claims for non-Indian origin botanicals?
If the ingredients used in the finished product are not Indian in
origin then the marketer cannot make health claims without substantiating
them. As of mid 2006, the laws pertaining to the licensing of non-Indian
nutraceuticals are not clear. New legislation is being debated in
the Indian Parliament, which will clarify these issues.
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Who is Vedic Lifesciences and what are their products?
Vedic Lifesciences is a Contract Research Organization for Natural
products (Nutraceuticals, Functional Foods, Natural Cosmetics and
Phytomedicines). Vedic Lifesciences does not make or sell any ingredients
or finished products but we can recommend suppliers of the same.
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Is the work done by Vedic Lifesciences recognized by the regulatory
agencies?
Competent authorities worldwide have different guidelines. Vedic
Lifesciences has studied the requirements of various markets and
carry out research as per these guidelines. There is no accreditation
program for a CRO by these agencies (Indian or international). The
work that Vedic does may meet requirements such as International
Conference on Harmonization’s Good Clinical Practices (ICH-GCP),
Good Laboratory Practices (GLP), Organization for Economic Cooperation
and Development (OECD), etc. as per mutual agreement with client
in the contract. If research is carried out as per the guidelines
then no matter where in the world it is done, it must be accepted
by any Agency including US FDA.
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What is the quality of the work done by Vedic Lifesciences?
Will it be acceptable in USA, Europe?
Research in healthcare products (pharmaceuticals and nutraceuticals)
is guided by guidelines and good research practices which are now
harmonized across the regulated world. If the research is done in
India but as per the international guidelines, then it must be accepted
by any Agency and any peer reviewed journal. Work done by Vedic
Lifesciences and its network of labs has been published in peer
reviewed international journals. As of mid 2006, Vedic Lifesciences
was putting together data on herbal products, which will be submitted
to European and American FDAs towards an Investigational New Drug
(IND) application for herbal medicine.
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Can herbal products be approved as pharmaceuticals? Are the
regulations very difficult? When does a supplement become a “medicine”
or a drug?
Yes, herbal products can be approved as medicine. No, the regulations
cannot be tougher than those for single molecules without any history
of use! If botanical or Nutraceutical products can meet the data
requirements for approval as pharmaceuticals then they can be prescribed
by doctors just as other conventional medicine. Moreover, Regulatory
agencies worldwide recognize certain the peculiarities of herbal
agents and have thus relaxed the submission requirements for data
pertaining to safety, chemistry, pharmacokinetics, clinical efficacy
and even the sequence of drug development. Regulations for Herbal
Medicinal Product (terminology in EU) or Botanical Drug Product
(terminology in USA) being more lenient than those for New Chemical
Entities, the herbal medicines route for a New Drug Application
is much faster and cheaper. It is not clear if the Indian regulator
allows a lighter data package for herbal drug approvals. However,
Ayurvedic products in India already enjoy the status of “medicine”,
are promoted like pharmaceuticals by medical representatives and
are prescribed by the hundreds of thousands of registered practitioners
in the country.
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Can herbal products be approved as OTC drugs?
Yes, single or polyherbal agents can be approved as OTC drugs also.
There are guidelines available on US FDA and EMEA websites. Indian
Ayurvedic products are already sold as “Ayurvedic Medicine” over-the-counter
or promoted by medical representatives.
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What are the main requirements that Agencies have for evaluating
any botanical / supplement / nutraceutical / functional or fortified
food?
No matter which country, which regulatory authority, what product
form, the criteria for allowing the import or marketing of a oral
or topical agent for health or nutrition remain similar. As label
claim or regulatory status of the product approaches that of a pharmaceutical
these data requirements get more detailed. But according to us,
authorities are broadly concerned about the three key aspects of
all products for human use: Quality, Safety and Efficacy.
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What is Quality of a Human Use product?
The dictionary meaning of Quality is “meeting a standard”. Quality
of a Human use product, be it supplement on pharmaceutical, usually
implies meeting the standards of physical, chemical and microbial
“limits”. Since efficacy and safety of human use products may vary
between brand to brand, limits of “purity” and “impurities” must
be defined. Who sets these limits? Most pharmaceutical products
have to comply to limits set by either the pharmacopoeia or other
competent authorities. Drug companies have their own high standards
for Chemistry, Manufacturing & Controls (CMC), however such rigorous
standards of quality are not applied to all nutritional supplements
and fortified foods. Fixation of limits for physical attributes,
chemical actives, chemical, microbial & radiation impurities and
stability or shelf life is the first step towards building a dependable
human use product. Since most supplements are delivered as pharmaceutical
dosage forms such as tablets and capsules, they need to comply to
the limits of these dosage forms such as hardness, disintegration,
etc. Only when all manufacturing batches of the nutraceutical can
comply to these limits can the product be called a “standard” product.
This CMC data of the product thus becomes the passport or fingerprint
for the botanical product. Without such a passport it is meaningless
to conduct further work on Safety and Efficacy testing of herbal
supplements.
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What constitutes as adequate evidence of Safety of a Human Use
product?
It is a misconception that a Nutraceutical or Functional Food or
ingredient thereof does not need to go through safety testing. “Its
only a food!”, will justify some puzzled brand-owners or suppliers.
Food and supplements are consumed for a longer period, in larger
quantities and by a larger population than drugs. Hence there is
a greater need to screen such novel agents for a longer term in
animals and humans if they are not completely natural or don’t have
a sufficient history of use. Extent of exposure in the population
without any reported side effects can be a critical factor when
FDA decides on the extent of toxicity studies that need to be conducted
for approval of such substances. Most developed nations have a dilemma
where they must encourage reasonably priced supplements to take
care of their ageing population at lower medical costs but at the
same time protect their citizens from potentially unsafe products.
In conclusion, Nutraceuticals may require upto 90 days of animal
toxicology in one rodent species and basic Mutagenicity to be considered
safe for human use. Topical use products also need to go through
topical safety testing. Safety of herbal supplements in humans can
be conveniently studied in a Phase II trial thereby largely doing
away with expensive Phase I studies in healthy volunteers. Regulations
for phytomedicine may differ from country to country.
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What kind of Clinical Trials are considered Proof of Concept
or adequate evidence of Efficacy?
For a clinical trial to be considered conclusive, more than 1000
patients may be required depending on nature of claim being made.
The more pronounced the expected benefit versus a control group,
the larger the sample size required. However, for a “proof of concept”,
a study in as much as 100 patients divided between the groups receiving
the test substance and a standard or placebo control is considered
an industry standard. Again this could vary depending on nature
of product and the research methodology. However, as a precursor
to such a proof of concept study, it is desirable to have a smaller
non-comparator pilot study using several doses of the test substance
to determine the dose-response relationship of the product under
investigation. Hence such a study would typically have 10 to 30
cases recruited in each dose group to be tested but no control would
be used. Typically 3 doses must be tried if there is no prior data
on the optimum adult dose of the nutraceutical. In some specific
cases it may be possible to combine a Phase II A dose determination
study with a Phase II B proof of concept study. Vedic Lifesciences
has devised several methodologies to reduce clinical development
costs without compromising on data quality of the price sensitive
nutraceutical industry. Cost and time to complete human proof of
concept studies can be further reduced if they are preceded with
well-conceived Bioefficacy studies invitro or invivo. Prior knowledge
of possible doses and mechanisms of action can greatly aid in minimizing
potential losses in clinical development phase and maximizing the
returns from every dollar spent.
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If I have to plan research on my herbal agent what is the correct
sequence to follow?
First Quality, then Safety and then Efficacy. Also refer to our
flowchart of suggested sequence.
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Are there any GMPs for Herbal Supplements or Nutraceuticals?
Indian companies must comply to Schedule T of the Drugs & Cosmetics
Act 1940 which relates to the Good Manufacturing Practices that
need to be followed for producers of Indian medicines like Ayurvedic,
Siddha, Unani and Homeopathy. It is not clear at the time of hosting
this page whether Dietary Supplements manufactured or imported into
the United States require to comply to GMPs and if yes then what
are these guidelines. Some US dietary supplement companies are following
Food GMPs whereas some are implementing Drug GMPs. However, it is
desirable for all Nutraceutical companies worldwide to have their
own internal standards and quality systems in tune with the higher
Drug GMPs because this will result in higher product quality and
possibly prepare them in advance for a more regulated environment
in times to come. Vedic Lifesciences can help companies in achieving
GMP compliance in a phased manner.
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We want to conduct a clinical trial for our herbal supplement,
but don’t know where to start. Please help. Is our product ready
for a clinical trial?
Now we have some questions! Is your formula already tested for its
quality and batch-to-batch uniformity? Will the physico-chemico-microbiological
and pharmaceutical attributes of your products remain stable and
within limits during the entire conduct of a clinical study which
can be sometimes be as much as 12 months? Do you accurately know
the dose at which it will elicit the maximum health benefit without
producing any side effects and without becoming too expensive? Do
you have some idea of its mode of action in humans or in animals?
Do you think that your present formulation is bioavailable at sufficient
levels? Out of the multitude of possible health benefits that herbals
can have, have you identified with a degree of confidence the most
important and marketable claim you want to make on the label? If
your answer to most of these questions is yes, then your product
is ready for a clinical trial.
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We buy only patented and clinically proven ingredients for our
range of supplements. Do we still need to prove our formula?
If your finished product (supplement of functional food or cosmetic)
contains only one active ingredient, then clinical trials may not
be necessary. However, as soon as you are combining two or more
ingredients in a hitherto untried proportion for human use, you
must test for the efficacy of this new combination even if the individual
actions of its components is known and proven.
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We have a marketed product already. Which Phase trial do I need
to conduct?
Normally marketed product undergo what is called as Phase IV study
or a Post Marketing Surveillance. However that term will apply more
appropriately to products where Phase I, II and III data is already
available. Hence if there is no prior trial done, a marketed product
will have to go through Phase II studies.
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How long does it take to do a human trial?
A Phase IIA study can take between 9-12 months and another similar
period to complete a Phase IIB study. In some cases the two can
be combined in consultation with our biostatistician. It takes us
about 2-3 months to write up a strong protocol after signing up,
followed by IRB approvals, trial supplies import, labeling and distribution
and site selection and initiation that can be normally achieved
in 2-3 months. The time to recruit the required number of subjects
will clearly depend on the sample size and the selection criteria
but can typically extend upto 3 months from date of site initiation.
Add to that 2-3 months of therapy period, it takes a minimum of
8 months to get the last patient out of the study. This is followed
by data analysis and reporting. Hence the final report can take
about 12 months after the study is finalized with us and work begun.
This is our typical duration but we have done smaller studies in
shorter time.
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What is the cost of a Phase II clinical trial?
Cost of a Phase II human study for an oral or topical use product
cannot be generalized but our cost is generally divided into 4 components:
The Fixed Costs are protocol, ICD and CRF designing, printing, IEC/IRB
submissions, investigator meetings, trial supplies importation and
labeling, insurance, statistical analysis and reporting. The Variable
Fee covers trial supply management, site selection, initiation,
monitoring and data management. The Institutional fees include IEC
approvals, investigator’s grants, subject compensation and travel
allowances. Finally, one of the major costs can be Laboratory Costs
which include biochemical, radiological and other path investigations
for screening subjects and for safety and efficacy measurements.
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Are clinical trials possible on personal care products?
Clinical trials are essentially testing of human use products for
their efficacy in humans. Quality, Safety and Efficacy still remain
the three requirements for personal care products also. Endpoints
for personal care studies can sometimes be different from nutraceuticals
or pharmaceuticals and the studies may be done on healthy volunteers
using novel instrumentation.
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Do we need to necessarily do animal research before clinical
testing on humans?
Clinical trials are not cheap in terms of time and money and cannot
be repeated on the same product too often. Vedic Lifesciences would
like to maximize the outcomes from each human study. Though animal
studies are not mandatory prerequisite to human studies on Nutraceuticals
and Supplements, the former can throw a lot of light on the pharmacology
of the product and help in designing the human studies better.
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Will the clinical trial data on an Indian population accepted
in my country?
Yes. Agreed that there may be some genetic, dietetic and other differences
between the Asian race and major markets for Nutraceuticals. However,
other than some metabolic diseases, clinical data from any population
would be treated as a valid proof of concept for further product
development or marketing or publication in peer-reviewed journals.
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What are the quality standards for Clinical Trials?
The standards for conduct and reporting of human clinical trials
are laid down in Good Clinical Practices (GCP). All human trials
done by Vedic Lifesciences are as per these best practices specified
by the International Conference on Harmonization (ICH) and the India
Regulatory Agency. We have been audited by international audit firms
for GCP.
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Why is India a favorite destination for Clinical Trials worldwide?
India is often being considered as possible destination for Drug
Trials because of various factors such as large patient population,
databank of healthy volunteers, trained English-speaking medical
personnel, state of the art lab support and well equipped trial
centers and hospitals. Our strength in informatics and data management
also helps us deliver quality results at lower costs. Trials are
conducted as per GCP guidelines and most labs have GLP and ISO certifications
in place. Mumbai is well connected by air and surface to the rest
of the country and by air to all major international airports. Central
lab facilities are at par with international standards. Ethics committees
follow GCP and trying to cut down approval times. Health regulators
presently don't have a stand on herbal supplements clinical trials
but they are approving drug trials on a fast track basis if submissions
are complete.
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Are the Preclinical studies conducted in India upto International
standards? Will they be accepted in N. America, Europe and Japan?
The systems for non-clinical efficacy, safety and quality testing
are laid down in Good Laboratory Practices. Our toxicology partner
labs in India are GLP compliant and audited by international auditing
agencies. A majority of our Quality and Bioefficacy non-clinical
testing partner labs though not GLP certified, conduct their work
as per GLPs and are closely monitored by Vedic Lifesciences trained
monitors and QA managers.
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I am a consumer / startup enterprise interested in some general
information on Dietary Supplements. Where can I find it?
The NIH Office of Dietary Supplements has covered a variety of preliminary
information that can answer some frequently asked questions:
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