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PhytopharmaceuticalsA New Drug Class Regulated in India

Dr. Neeraj Tandon

Scientist-G and Head

Medicinal Plants Division

Indian Council of Medical Research

(Ministry of Health & Family Welfare, Govt. of India)

Ansari Nagar, New Delhi 110029

16th May , 2017

Global Scenario of Botanical Medicines

• Globally, herbal medicine has been considered an important alternative tomodern Allopathic medicine.

• Although the herbal medicines are very popular in the society, only fewmedicinal herbs have been scientifically evaluated for their potential in medicaltreatment.

• In most countries, the herbal drugs are poorly regulated and are often neitherregistered nor controlled by the health authorities.

• The safety of herbal medicines remains a major concern. In the United States,the FDA has estimated that over 50,000 adverse events are caused by botanicaland other dietary supplements.

• In addition, for most herbal drugs, the efficacy is not proved and the quality isnot assured.

• To address these issues, US-FDA has created a separate guidance document forbotanical products for NDAs and IND submissions - 2004 (first revision Aug 2015)

• Similarly, in India, CDSCO (DCGI) has created a separate guidelines for botanicalproducts called ‘phytopharmaceutical guidelines’– 2013 (first revision – Nov2015)

• Herbal medicine products include herbs, herbal materials,herbal preparations, and finished herbal products containingparts of plants, other plant materials, or combinations thereofas active ingredients.

• Herbs include crude plant material, eg. leaves, flowers fruit,seed and stems.

• Herbal materials include, in addition to herbs, fresh juices,gums, fixed oils, essential oils, resins and dry powders ofherbs.

• Herbal preparations are the basis for finished herbal productsand may include comminuted or powdered herbal materials,or extracts, tinctures, and fatty oils of herbal materials.

• Finished products consist of herbal preparations made fromone or more herbs.

Herbal medicines

• Regulatory scenario regarding herbal preparationsvaries from country to country

• Globally, several diverse regulatory approaches arein vogue

Regulatory scenario

GLOBAL REGULATIONS

USA

• US FDA has issued way back in 2000 adocument “Guidance to industry forBotanical Drugs”.

• As per this, detailed guidelines have beenprovided for chemistry, manufacture, quality,safety and efficacy of botanical origin leadsfor approval as drug.

• Such approvals are given by the same FDAwhich regulates synthetic drugs.

China

• In China, the state FDA regulates both synthetic drugs as well as TCM.

• Just like Indian drug regulations, TCM regulations are part of the sameregulatory system.

• Also Chinese regulations recognize and give weightages to history of useand efficacy for formulations listed in traditional Chinese compendiums.

• However, Chinese regulations have specific regulations that permitespecially processed/fractionated/potentiated Chinese herbalextracts/leads after review of scientific data for issue of what is called“Modern TCM Drugs”.

• For Modern TCM Drugs, it is even understood that the IPR protection isavailable incase inventive steps exist for the lead which is not specificallyindicated in the traditional Chinese compendiums.

• Artemisinin to treat Malaria, is a classic case of such a drug developmentin China which has even secured the Nobel Prize to the inventor fromChina.

South Africa

• It is learnt that South Africa government is consideringto bring in regulations onlines similar to the Indian“Phytopharmaceuticals as drugs” after the approval ofa South Africa botanical lead by US FDA as a drug.

• It may be recognized that South Africa has a richtraditional knowledge most of which is oral andtraditional with much less level of documentation asseen in Ayurveda, Siddha etc. in India.

• Despite this, South Africa is working to bring inregulations as part of the main drug regulations topromote traditional knowledge based herbal drugs.

United Kingdom

• In the UK, as part of the main pharmaceuticalregulations a separate chapter is included for herbalmedicines.

• Herbal medicines are also regulated under “productsunder general sale licenses.

• There is no separate dedicated rules yet notified forbotanical drugs where, well characterized botanicalextracts form the lead.

• However, applicants are permitted to apply for suchleads under the same drug regulations that apply tosynthetic drugs – this creates lot of problems whichshould be one reason for lack of botanical drugsapproved in the UK.

Europe

• In Europe, except in Germany where “FITOtherapy regulations permit botanicals asdrugs”, the situation is very similar to the UK.

• However, since the TMP directive has elapsedit is understood that medicine control agencyof Europe has begun exercise for regulations,for botanical drugs.

• In fact, this has caused a kind of trade barrierpreventing India Ayurvedic products to beapproved in EU nations.

In Indian regulations, the major class of Ayurveda, Siddha, or Unani (ASU) drugsincluded are

a. Classical ASU drugs as mentioned in the authoritative books of ASU systemdrugs, which are manufactured and named in accordance with the formulationsdescribed in the authoritative texts.

For this category, issue of license to manufacture is based on citation inauthoritative books and published literature, unless the drug is meant for a newindication when proof of effectiveness is required.

a. Patent or proprietary medicine makes use of ingredients referred in theformulations of authoritative texts but with intellactual intervention, innovation,or invention to manufacture requires proof of effectiveness, based on the pilotstudy as per relevant protocol for ASU drugs.

In 2010, Ministry of Ayurveda, Unani, Siddha, and Homeopathy (AYUSH)introduced Rule 158 (B) which made the requirement of proof of effectivenessfor licensing of a patent or proprietary ASU medicine. This was followed by therelease of GCP guidelines for voluntary use by the researchers interested intaking up clinical trials using ASU medicine.

Indian Scenerio

• The government of India has published a draft amendment to Drugs andCosmetics Act, and Rules (D & C Act and Rules) on 24th October 2013.

• This creates regulatory provisions of defining phytopharmaceuticals(botanical-base drugs) and a schedule providing requirements ofscientific data on quality, safety and efficacy to evaluate and marketingauthorization for a plant-based lead as drug on similar lines to synthetic,chemical moieties.

• In India, it is known that though the new draft regulation was notpresent, Guggulu tablets (for treatment of hypercholesterolemia),Gingko-biloba tablets (to treat liver disorders) have been approved andmarked as drugs by the Central Drugs Standards Control Organization(Drug Controller General of India)

• However, it is known that approval of Guggulu tablets took a more thana decade to get this approval as a drug.

• It had required efforts to convince the authorities that severalrequirements applicable to a synthetic chemicals were not possible for abotanical based product.

In India, ASU drugs have been under the purview of Ministry ofAyush.

In contrast, 2015 regulatory requirements forphytopharmaceuticals are under the purview of the CentralDrugs Standards Control Organization (CDSCO).

The gazette notification defines regulatory provisions forphytopharmaceuticals and regulatory submission requirementsfor scientific data on quality, safety and efficacy to evaluate andpermit marketing for an herbal drug on similar lines to synthetic,chemical moieties.

Indian Scenerio

•In Schedule Y, the newly added Appendix IB describes data

to submitted along with the application to conduct clinical

trial or import or manufacture of a phytopharmaceutical

drug in the country.

•The regulatory requirements for NDA for the

phytopharmaceutical drug include standard requirements

for a new drug-safety and pharmacological information,

human studies, and confirmatory clinical trials.

Appendix IB

Phytopharmaceutical drug is defined as purified and standardized

fraction with defined minimum four bioactive or phytochemical

compounds (qualitatively and quantitatively assessed) of an extract of a

medicinal plant or its part, for internal or external use of human beings

or animals for diagnosis, treatment, mitigation, or prevention of any

disease or disorder but does not include administration by parenteral

route.

The new regulation for phytopharmaceutical is in line with regulations in

USA, China, and other countries involving scientific evaluation and data

generation. It does not simply depend on traditional knowledge alone.

Phytopharmaceutical can be from a botanical (medicinal plant) from any

part of the globe.

Phytopharmaceutical drug

Why Phytopharmaceutical

• This regulation is expected to develop new drugs from botanicals in a scientific way and would help in the acceptance of the use of herbal products by modern medical profession.

• Phytopharmaceutical’s proposal would promote innovations and development of new drugs from botanicals in a scientific way, and would give boost to research in drug development for innovators, industry, and national laboratories and pharmaceutical research labs in India.

Scope and Potential

Complementary/Adjuvant use

Mainstay Therapy

Safer alternatives to Synthetic drugs

S. No.

Attributes Products licensed as Ayurvedicmedicines made using botanicals as actives

Products licensed as new drugs (Phyto-pharmaceuticals)

1. Manufacturinglicense/Marketing authorization

As Proprietary Ayurvedic medicine issued by licensing authority of the state in which the manufacture is undertaken.

As a new drug whose import of marketing is authorized by DCGI (CDSCO)

2. Number of herbs/botanicals

Can be single or combination of more that one with each ingredient being listed in the authoritative texts of First Schedule or their processed materials including extracts as permitted under Chapter IV-A of DCAR

Recommended a phytopharmaceutical from a single botanical to begin with. Combining more than one is not barred but would need a lot more scientific data on the rationale, interactions and other aspects which are much more difficult to generate.

3. Source of the Botanical

Has to be mentioned in one of the authoritative texts of ayurveda as per first schedule of DCAR

Can be any botanical form any part of Globe.

4. Combination with mineral/metel

Permitted as per DCAR Not permitted as the definition of phytopharmaceutical has no provision

5. Extracts of botanicals

Extracts of herb as per Chapter IV-A applicable to ayurveda

Purified/fractionated extracts that meet the definition of phyto-pharmaceutical and needs to be supported by scientific data.

• For phytopharmaceutical drug, there is a lot of stress on:

• Available information on the plant, formulation and route ofadministration, dosage, therapeutic class for which it is indicatedand the claims to be made for the phytopharmaceutical

• Supportive information from published literature on safety andefficacy and human or clinical pharmacology information.

• Data generated on:

– Identification, authentication and source of the plant used forextraction and fraction

– Process for extraction and subsequent fraction and purification

– Formulation details of phytopharmaceutical drug

– Manufacturing process of formulaiton

– Stability data

Part I (Already known information)1. Data to be submitted by the applicant

1.1 A brief description or summary of the phytopharmaceutical drug

1.2 Published literature on plant or phytopharmaceutical drug

1.3 Information on any contraindications, side effects

1.4 Published scientific reports on safety and pharmacological studies of phytopharmaceutical

drug

1.5 Present usage of the phytopharmaceutical drug

2. Human or clinical pharmacology information

2.1 Published scientific reports on pharmacological studies including human studies or clinical

studies or epidemiological studies

2.2 Pharmacodynamic information

2.3 Monographs, if any, published on the plant or product or extract or phytopharmaceutical

IND Filing of Phytopharmaceutical DrugsData to be submitted along with application to DCGI

Part II (data generated by applicant)

Data generated by applicant

3. Identification, authentication and source of plant used for extraction and fractionation

3.1 Taxonomical identity

3.2 Morphological and anatomical description, confirmation of identity and authenticity. (Furnish

certificate of confirmation of botanical identity by a qualified taxonomist)

3.3 Natural habitat and geographical distribution of the plant

3.4 Season or time of collection.

3.5 Source of the plant including its geographical location and season or time of collection.

3.6 A statement indicating whether the species is any of the following, namely endangered or

entitled to special protection under the Biological Diversity Act, 2002 or any known genotypic,

chemotypic and ecotypic variability of species.

3.7. A list of grower or supplier (including names and addresses) and information on the harvest

location; growth conditions; stage of plant growth at harvest; harvesting time; collection,

washing, drying and storage conditions; handling, garbling and transportation; grinding,

pulverizing of the plant material; and sieving for getting uniform particle size of powdered plant

material.


Part II

3.8. Quality specifications, namely foreign matter; total ash; acid insoluble ash; pesticide residue;

heavy metal contamination; microbial load; chromatographic finger print profile with

phytochemical reference marker; assay for bio-active or phytochemical compounds; and

chromatographic fingerprint of a sample as per test method given under quality control of the

phytopharmaceutical drug.

3.9 . An undertaking to supply specimen sample of plant duly labelled and photocopy of the

certificate of identity confirmation issued by a qualified taxonomist along with drawings or

photographs of the diagnostic morphological and histological features of the botanical raw

material used for the confirmation of authenticity.

4. Process for extraction and subsequent fractionation and purification

4.1. Quality specifications and test methods for starting material.


4.2. Steps involved in processing

(a) details of solvent used, extractive values, solvent residue tests or limits, physico-chemical

tests, microbial loads, heavy metal contaminants, chromatographic finger print profile with

phytochemical reference markers, assay for active constituents or characteristic markers, if

active constituents are not known;

(b) characterization of final purified fraction;

(c) data on bio-active constituent of final purified fraction;

(d) information on any excipients or diluents or stabilizer or preservative used, if any.

4.3. Details of packaging of the purified and characterized final product, storage conditions and

labeling.

5. Formulation of phytopharmaceutical drug applied for

5.1. Details of the composition, proportion of the final purified fraction with defined markers of

phytopharmaceutical drug per unit dose, name and proportions of all excipients, stabilisers

and any other agent used and packaging materials.

5.2. Test for identification for the phytopharmaceutical drug.

5.3. Quality specifications for active and inactive phytopharmaceutical chromatographic finger

print profile with phytochemical reference marker and assay of active constituent or

characteristic chemical marker.


6. Manufacturing process of formulation

6.1. The outline of the method of manufacture of the dosage form, along with environmental controls,in-process quality control tests and limits for acceptance.

6.2. Details of all packaging materials used, packing steps and description of the final packs.

6.3. Finished product’s quality specifications, including tests specific for the dosage form, quality andchromatographic finger print profile with phytochemical reference marker and assay for activeconstituent or characteristic marker, if active constituents are not known.

7. Stability data

7.1. Stability data of the phytopharmaceutical drug described at 4 above, stored at room temperature at 40 ± 2 °C and humidity at 75% RH ± 5% RH for 0, 1, 2, 3 and 6 months.

7.2 Stability data of the phytopharmaceutical drug in dosage form or formulation stored at roomtemperature at 40 ± 2 ° C and humidity at 75% RH ± 5% RH for 0, 1, 2, 3 and 6 months, in the packintended for marketing.

8. Safety and pharmacological information

8.1. Data on safety and pharmacological studies to be provided.

8.2. Animal toxicity and safety data:

(a) 28 to 90 days repeat dose oral toxicity on two species of animals;

(b) In-vitro genotoxicity data (Ame’s test and Chromosomal aberration test as per Schedule Y);

(c) dermal toxicity tests for topical use products;

(d) teratogenicity study (only if phytopharmaceutical drug is intended for use during pregnancy).

9. Human studies

9.1. Clinical trials for phytopharmaceutical drugs to be conducted as per applicable rules and guidelines

for new drugs.

9.2. For all phytopharmaceutical drugs, data from phase I (to determine maximum tolerated dose and

associated toxicities) and the protocols shall be submitted prior to performing the studies.

9.3. Data of results of dose finding studies performed and the protocols shall be submitted prior to

performing the studies: Provided that in the case of phytopharmaceutical drug already marketed for

more than five years or where there is adequate published evidence regarding the safety of the

phytopharmaceutical drug, the studies may be abbreviated, modified or relaxed.

10. Confirmatory clinical trials

10.1. Submit protocols for approval for any specific or special safety and efficacy study proposed specific

to the phytopharmaceutical drug.

10.2. Submit proposed protocol for approval for human clinical studies appropriate to generate or

validate safety and efficacy data for the phytopharmaceutical dosage form or product as per

applicable rules and guidelines.

10.3. Submit information on how the quality of the formulation would be maintained during the above

studies.



11. Regulatory status

11.1. Status of the phytopharmaceutical drug marketed in any country under any category like functional

food or dietary supplement or as traditional medicine or as an approved drug.

12. Marketing information

12.1. Details of package insert or patient information sheet of the phytopharmaceutical drug to be

marketed.

12.2. Draft of the text for label and carton.

13. Post marketing surveillance (PMS)

13.1. The applicant shall furnish periodic safety update reports every six months for the first two years

after approval the drug is granted.

13.2. For subsequent two years the periodic safety update reports need to be submitted annually.

14. Any other relevant information

Any other relevant information which the applicant considers that it will help in scientific evaluation of

the application.”.

A. New class of drugs would encourage introduction of extensiveevaluation through biomedical sciences, help in the acceptance andexpand use of herbal products by modern medical profession.

B. Across the world, there is a rising interest and demand for plants as apossible source of therapeutics for unmet medical needs, and thisstep would bring this aspiration one step closer to reality.

C. Number of national laboratories in India, scientists groups, andindustrial research and developments (R & Ds) who have beenworking on botanical leads can look forward to take this route forgetting marketing permissions.

D. New entrants/investors will get encouraged to invest in this route fordrug development.

Possible Advantages in this area

Possible difficulties in this area• Of the 282 pre-INDs and INDs submitted, only 36% were multiple-plant

combinations, reflecting the difficulties in working with more complexpreparations.

• Of the 282, 113 (40%) were submitted by commercial sponsors; the remaining169 (60%) were proposed by academic investigators, mostly to conduct small-scale proof-of-concept studies and without intention to commercialize theproducts.

• Despite the increasing IND activity, progress in developing new drugs frombotanicals has been slow, with only two botanical NDA submissions andapprovals to date.

• Possible reasons for the disappointing pace of development include the“difficulties in characterizing ill-defined mixtures to provide assurance ofquality ” before entering large phase 3 studies, and the “ problematictranslation of unreliable experiences in traditional alternative medicine intotestable hypotheses” that can be applied in modern clinical research

Botanical Drugs In India

• Gugglip tablets – is perhaps the first drug cleared inIndia-Guggul (Commiphora mukul) based-Ethyl acetateextract-standardized to guggulsterones E & Z, 25 mg/tab,official in IP, for hypercholesteremia, reduction in Lipidprofile.

• Ginseng Extract capsules – Standardized togingkobilobides – for treatment of temporary loss ofmemory

• Sylimarin Extract Capsules – to treat liver disorders.

• Ginger capsules – Standardized to 6-gingerols, fortreatment of chemotherapy induced nausea (nevermarketed)

Drugs Approved by US FDA

• In 2004, FDA US created a pathway for drug makers to getapproval of drugs derived from plants.

• In has received about 500 applications, it approved onlytwo prescription botanical drugs until today.

• First-2006, when the FDA OK’d Veregen (sinecatechins),an ointment for genital warts that is derived from greentea leaves. It was developed by Germany’s M/SMedigene.

• Second-2012, Fulyzaq (crofelemer) is made from the redsap of the Croton lechleri plant, a South American treereferred to as the dragon’s blood tree because of its redlatex. A drug marketed by M/S Salix Pharmaceuticals forthe treatment of diarrhea in HIV/AIDS patients who areon anti-retroviral therapy.

• Dr. Tu Youyou won the Nobel Prize in medicine

for her artemisinin isolated from Artemisia

annua for malaria.

• With the new phytopharmaceutical

regulation, the Indian scientists would

develop noble inventions to discover

phytopharmaceutical drugs for unmet medical

needs.

Summary

• Introduction of Phytopharmaceuticals as a new class of drugis an important, timely and progressive step

• It would inculcate higher level of scientific inputs in herbbased products.

• PPh may be specially suitable for mutitarget based diseaseslike metabolic syndrome

• PPh may help as a booster dose for the Herb based drugbusiness.

CSIR-IIIM

Confidential

Food Safety and Standards Authority of India (FSSAI)Guidelines for food supplements and neutraceuticals

• Food or health supplements• Neutraceuticals• Foods for special dietery uses• Foods for special medical purpose• Functional foods

Food Safety and Standards Regulations 2015 for

Published in Gazette on 24th November 2016

Under this guidelines, following ingredients are allowed to be used in foods/ neutraceuticals:

• Plant extracts• Botanical ingredients• Vitamins, minerals, trace elements• Amino acids and other nutrients• Food additives• Probiotics• Prebiotics

CSIR-IIIM

Confidential

Schedule Content Numbers/ other information

I List of vitamins and minerals and their components 15 vitamins, 15 minerals(permissible overages provided)

II List of amino acids and other nutrients 11 essential amino acids, 14 non-essential amino acids, 4 nucleotides

III List of vitamins, minerals and trace elements allowed to be used in food

Vitamins and minerals

IV List of plants or botanical ingredients 400 botanical plants listed (along with their permitted range for usage)

V List of food additivesa. For health supplements, neutraceuticalsb. for special dietary usec. for special medical purposed. for special medical purpose for weight reductione. to be used as GMP levelf. To be used in formats such as tablets, capsules

INS no., name of additive and permitted level mentioned.

VI List of ingredients as neutraceuticals List of pure natural products, extracts (with marker content), and their purity criteria, permitted range(187 ingredients listed)

VII List of strains as probiotics (live microbes) 28 microorganisms listed

VIII List of prebiotic compounds 13 compounds listed

FSSAI Guideline: Schedules

CSIR-IIIM

Confidential

This list contains 400 medicinal plants

Plants listed in the Schedule IV shall be used after due processing on in their extracts in permissible usage range given the table.

FSSAI Schedule IV: List of Plants

CSIR-IIIM

Confidential

FSSAI Schedule VI: List of Ingredients (extracts/ pure NPs)

This list contains 187 ingredients

Vol. 1 (Abe-Ale)2004

Vol. 2 (Ali-Ard)2004

Vol. 3 (Are-Azi)

2004

Vol. 4 (Ba-By)2004

Volume 5 (Ca-Ce)2007

Volume 6 (Ch-Ci)2008

Volume 7 ( Cl -Co)2008

Volume 9 (Da-Dy)2009

Volume 10 (Ec-Ex)2011

Volume 11 (Fa-Gy)2013

Volume 12 (Ha-Hy)2013

Volume 13 (Ib-Ky)2013

Volume 14 (La-Ly)2015

Volume 8 (Cr-Cy)2009

Volume 15 (Ma-Me)2016

Number of species 4342 Number of References 66364 Number of pages12570


Reviews on Indian Medicinal Plants (1–16)

Volume 17 (Mi-My)2017


Quality Standards of Indian Medicinal Plants (1–14)

Volume 1 (32 plants)

2003


2004


2005


2006


2008


2008

Total monographs - 484


2008


2010


2011


2012


2013


2014

Volume 13 (35 plants)2015

Volume 14 (35 plants)2016

Phytochemical Reference Standards of

Selected Indian Medicinal Plants

Vol. 1 (2010)

30 Monographs

Vol. 2 (2012)

30 Monographs

Vol. 3 (2014)

30 Monographs

Vol. 4 (2016)

30 Monographs

120 PRS

Perspectives of Indian Medicinal Plants in

the management of Liver Disorders

CONTENTS

• INTRODUCTION

• AN OVERVIEW OF BIOLOGY OF LIVER

• PERCEPTION OR LIVER DISORDERS

• MANAGEMENT OF LIVER DISORDERS

• MEDICINAL PLANTS AND FORMULATIONS USED IN LIVER DISORDERS

• MEDICINAL PLANTS USED IN LIVER DISORDERS AND INVESTIGATED WITH MODERN APPROACH

• METHODS AND PARAMETERS OF HEPATOPROTECTIVE EVALUATION OF MEDICINAL PLANTS

41

Perspectives of Indian Medicinal Plants in

the management of Lymphatic Filariasis

CONTENTS

INTRODUCTION TO DISEASE

PLANT DRUGS MENTIONED/ USED/CLAIMED ININDIAN SYSTEM OF MEDICINE FOR TREATMENTOF FILARIASIS

MEDICINAL PLANTS MENTIONED IN ÄYURVEDAFOR TREATMENT OF FILARIASIS ANDINVESTIGATED WITH MODERN APPROACH

MEDICINAL PLANTS USED IN INDIA ANDINVESTIGATED BUT NOT MENTIONED INÄYURVEDA FOR TREATMENT OF FILARIASIS

DETAILS OF DRUG FORMULATIONS MENTIONEDFOR TREATMENT OF ÇLÉPADA IN ÄYURVEDA

42

Perspectives of Indian Medicinal Plants in the management

of Diabetes Mellitus

CONTENTS

INTRODUCTION TO DISEASE

PLANT DRUGS MENTIONED/ USED/CLAIMED ININDIAN SYSTEM OF MEDICINE FOR TREATMENT OFFILARIASIS

MEDICINAL PLANTS MENTIONED IN ÄYURVEDAFOR TREATMENT OF FILARIASIS AND INVESTIGATEDWITH MODERN APPROACH

MEDICINAL PLANTS USED IN INDIA ANDINVESTIGATED BUT NOT MENTIONED IN ÄYURVEDAFOR TREATMENT OF FILARIASIS

DETAILS OF DRUG FORMULATIONS MENTIONEDFOR TREATMENT OF ÇLÉPADA IN ÄYURVEDA

Safety Reviews on Selected Indian Medicinal Plants

Thank you…..

Documents

Phytopharmaceuticals A New Drug Class Regulated in …bnpl.org.in/PDFfiles/drneerajtandon.pdf · drugs, which are manufactured and named in accordance with the formulations ... garbling