1. Drug Development and Regulatory Aspects in ASU Systems: Scope and Challenges
N.SRIKANTH
Deputy Director General
CENTRAL COUNCIL FOR RESEARCH IN AYURVEDIC SCIENCES
Ministry of AYUSH
Government of India

2. Start of process Natural products Botanical Animal Mineral
origins from India have initiated the scientific quest of Drugs since antiquity.

3. Start of process Some of the Ayurvedic plants
Interesting leads for drug discovery
Structural modifications of active principles leading to a cascade of new “chemical” drugs
In global use and pharmacology research

4. Start of process Ayurvedic Plant Impact Aloe vera
Cosmetic-pharmacology/Burns
Atropa belladonna
Acetylcholine pharmacology
Azadirachta indica
Antifungal
Cassia angustifolia
Laxative/ Indigestion
Curcuma longa
Anti-inflammatory/ Anti- diabetic
Cancer preventive
Commiphora wightii
Anti- arthritic/ Obesity, Lipid disorders
Glycyrrhiza glabra
Peptic ulcer
Psoralea coryllifolia
Leucoderma /Psoriasis
Rauwolfia serpentina
Anti-hypertensive / tranquillizer
Strychnos nux-vomica
Digestive/Nervine tonic
Tinospora cordifolia
Immune stimulant/ Hepatoprotective
Anticancer
Withania somnifera
Sedative/ Phytoestrogen
Zingiber officinale
Indigestion/ Nausea
Arthritis

5. Ayurvedic Plant isolates
Start of process
Ayurvedic Plant isolates
Impact
Holarrhena alkaloids
Amoebiasis
Mucuna pruriens
Parkinson’s disease
Pipeirdines
Bioavailability enhancers
Baccosides
Mental retention
Picrosides
For hepatic protection
Phyllanthins
Antivirals
Curcumines
Inflammation
Patwardhan B, Ethno pharmacology and drug discovery, J .Ethnophrama (Perspective paper), 2005

6. Start of process Some other therapeutic leads Gingerol Gugullosterones
Eugenol
Anethol
Apocynin
Genestein
Glycrrhizin
Polysaccaharides from TC
Biflavanoids from Semecarpus
Gallates
Bacosides
Boswellic acid
Catechins
Patwardhan B, Ethno pharmacology and drug discovery, J .Ethnophrama (Perspective paper), 2005

7. R&D from India as Value Addition to Drug Development
Plant
Scientists
Activity
Reported in
Impact
Phyllanthus niruri
Blumberg & Thyagarajan
Anti HBV
Lancet
Has become most common ingredient in hepatoprotectives
Withania somnifera
SK Bhattacharya
Adaptogen
Phyto
therapy Res.
International recognition as antistress agent
Boswellia serrata
SS Handa
Anti inflammatory
Phytomedicine & J .Ethnopharm
Sole International herb in its category
Commiphora mukul
Nitya Anand
Hypolipidemic
IJMR
Has become product of International interest

8. Resurgence
A resurgence of interest in Ayurveda and other AYUSH systems has resulted from the preference of health seekers towards
holistic approach
products of natural origin
About 80 % of population in India utilize AYUSH and LHTs to help meet their primary health requirements

9. Health Seeking attitude Role of AYUSH/TM
The most prevalent users of Traditional Medicine are individuals who have
Refractory conditions
Non–life-threatening conditions that may be chronic viz. neurological disorders, arthritis etc.
The second largest group of users are those struggling with
Chronic, potentially life-threatening diseases, such as Cancer and HIV/AIDS etc.

10. Health Seeking attitude Role of AYUSH/TM
Both groups turn to TM/AYUSH systems for a variety of reasons, such as
Management as main treatment option
to improve immune functioning
to improve overall functioning
to improve quality of life
to cope with side effects from conventional therapies, and
to relieve symptoms related to their illness

11. Mainstreaming and Integration
Growing recognition of AYUSH/ TM in India and across the globe and emerging market potential (trillion USD) have driven for
mainstreaming of their core potential
physical and functional integration of medical systems
fulfillment of the limitations and unmet needs

12. Need for Evidence Quality, Safety, Efficacy and Rational Use
At this juncture owing to vibrant changes towards these systems the
quality
safety
efficacy
rational use
of AYUSH/TM therapies have become important concerns both for policymakers and consumers as well.

13. Rational -ASU-GCP Guidelines
This necessitated Health authorities the promotion of evidence based use
substantiated by research studies
espousal of suitable guidelines & ethics

14. Currant Scenario Emphasis on adequate application of Core Concepts
The clinical trials designed to examine the
safety
efficacy
of AYUSH-TM therapies/approaches, the fundamental aspects of holistic systems need appropriate and adequate positioning

15. Understanding the Differences
While designing the research trials it is pivotal to comprehend differences in designing of the trials between
AYUSH
Modern Medicine

16. Understanding the Differences
Differences are mainly due to the
basic approach to health and disease perceptions
epistemological
AYUSH is holistic in approach in
diagnosis
prognosis
management

17. AYUSH/TM Vs Conventional
This holistic approach is its ‘strength’ as well as ‘Challenge ’
Holistic’ approach of AYUSH is indeed good in clinical practice
For ‘research’, however, this approach poses considerable difficulties to devise parameters and design suitable models for clinical studies/trials.

18. Challenges: ASU-GCP Diverse concepts Complex approaches
Clinical Trial Design
Diagnosis & Therapy
Clinical Efficacy
Outcome measures
Drug interaction
Harmonization

19. Challenges: ASU-GCP
Complexity of too many “variables” of in terms of ‘objective’ parameters as in case of ‘Prakriti’(psycho-somatic constitution of individual) in clinical trials.
Clinical investigations in Ayurveda are made difficult by factors such as use of complex, individualized treatments

20. Challenges: ASU-GCP
Their problems include difficulties in accruing, randomizing, and retaining patients and in identifying appropriate placebo interventions.
Strong commitment is required from the research community to create evidence and provide information to the public and health professionals.

21. Challenges: ASU-GCP

22. Research Guidelines in Vogue
SNo
Details
Authority
1 .
Good Clinical Practices(GCP) Guidelines
Central Drugs Standard Control Organization. Directorate general of health Services, Drug Controller General of India (DCGI), M/o Health &F.W Govt. India
2 .
Ethical Guidelines for Biomedical Research in Human Participants
Indian Council of Medical
Research)M/o Health &F.W Govt. India (last amendment in 2006)
3 .
Guidelines for Pre -Clinical Animal Studies
CPCSEA-Committee for the purpose of control and supervision of Experiments on Animals M/o Environment and Forests, Govt. of India (last amendment in 2010) 4.
Guidance on Clinical Trial Inspection
Central Drugs Standard Control Organization, Directorate general of health Services, Drug Controller General of India (DCGI), M/o Health &F.W Govt. India 5
Good Clinical Practices(GCP) Guidelines for ASU Medicines
Department of AYUSH M/o Health &F.W Govt. India

23. Research Guidelines in Vogue
M/o Health & F.W.
Govt. of India
20013
Indian council of medical research
2006
M/o Health & F.W.
Govt. of India
2001
M/o Environment and Forests, Govt. of India
2010

24. Research Guidelines in Vogue

25. Ethics- Law & Guidelines
Category
Requirements
Guidelines +
ASU
Herbal……?

26. Regulations ASU Drug Trials/Product approvals
Rule158(B)
(Amendment) of Drugs and Cosmetic Act vide Gazette Number 441 in August 2010

27. Regulatory requirements for Ayurveda Siddha and Unani
Product approvals
(experimental and clinical studies)

28. Regulatory Requirements
The regulatory requirements for product approvals /licensing (experimental and clinical studies) of ASU Drugs are based on Category of Pharmaceutical product
Classical Formulation/it’s variants-3 categories -D&C Act Section 3(a)
Patent or Proprietary Medicine-4 categories D&C Act Section 3(h)(ii)

29. Classical ASU Medicines
Medicines manufactured exclusively in accordance with the formulae described in the authoritative books of ASU systems of medicine, as specified in the First Schedule of Drug and Cosmetics act1940
This Schedule I is a list of 57 books of Ayurveda, 30 books of Siddha and 14 books of Unani including Formularies and Pharmacopoeias of ASU systems

30. Patent & Proprietary ASU medicines
i) Formulations containing ingredients mentioned in the formulae described in authoritative text books (Does not include Injectables )
ii)Balya/Poshak/Muqawi/Unavuporutkal/positive health Promoter formulations having ingredients mentioned in books of First Schedule of the Drugs and Cosmetics Act and recommended for promotional and preventive health.
(iii)Saundarya Prasadak (Husane afza)/Azhagh-sadhan formulation having ingredients mentioned in Books of First Schedule of the Drugs and Cosmetics Act and recommended for oral, skin, hair and body care.
(iv)Aushadh Ghana (Medicinal plant extracts – dry/wet) extract obtained from plant mentioned in books of First Schedule of the Act including Aqueous or hydro-alcohol.

31. Regulatory requirements for Classical Ayurvedic, Siddha and Unani Drugs (Quality ,Pre- Clinical safety and Efficacy)

32. II.(A) For issue of license to the medicine with respect to Ayurvedic, Siddha and Unani, the conditions relating to safety study and the experience or evidence of effectiveness shall be such as specified in columns (5) and (6) of the Table given below:
S.No.
Category
Ingredient
Indication
Safety study
Experience/Evidence of Effectiveness
Published Literature
Proof of Effectiveness 1. 2. 3. 4. 5. 6. 7.
(A) Ayurveda, Siddha and Unani Drugs, given in 158-B as referred in 3(a).
As per text.
Not required
Required
Not required.
(B) Any change in dosage form of Ayurveda, Siddha and Unani Drugs as described in Section 3(a) of the Drugs and Cosmetics Act, 1940.
(C) Ayurveda, Siddha and Unani Drugs referred in 3(a) to be used for new indication.
As per text
New
If required
Required.

33. Regulatory requirements for Patent or Proprietary Ayurvedic, Siddha and Unani Drugs (Quality ,Pre- Clinical safety and Efficacy)

34. II. B. For issue of license with respect to Patent or Proprietary Medicine. The condition relating to Safety studies and experience or evidence of effectiveness shall be specified as follows:
S.No.
Category
Ingredient
Indication
Safety study
Experience/Evidence of Effectiveness
Published Literature
Proof of Effectiveness 1. 2. 3. 4. 5. 6. 7.
Patent or proprietary medicine
As per text
Textual rationale
Not required
Of Ingredients
Pilot study as per relevant protocol for Ayurveda, Siddha and Unani drugs.
Ayurveda, Siddha, Unani drug with any of the ingredients of Schedule E(1) of the Drugs and Cosmetics Act, 1940.
As per Text
Existing
Required
Required.

35. Regulatory requirements for Health promoters /Tonics Ayurvedic, Siddha and Unani Drugs (Quality ,Pre- Clinical safety and Efficacy)

36. Health promoters /Tonics
(III)For issue of license with respect to Balya and Poshak medicines the person who applied for license is required to submit the following:
The textual reference of ingredients used in the formulation as mentioned in the book of 1st schedule;
Conduct safety studies in case the product contains of any of the ingredients as specified in the Schedule E(1), as per the guidelines for evaluation of Ayurveda Siddha and Unani Drug formulations;
For textual indications the safety and effectiveness study is not required.

37. Regulatory requirements for Ayurvedic, Siddha and Unani Cosmetics (Quality ,Pre- Clinical safety and Efficacy)

38. Cosmetics
(IV) For issue of license with respect to Saundarya Prasadak (Husane afza/Azhagu Sodhan) the person who applied for license is required to:-
The textual reference of ingredients used in the formulation as mentioned in the book of 1st schedule;
Conduct safety studies, in case the formulation contains of any of the ingredients as specified in the Schedule E(1), as per the guidelines for evaluation of Ayurveda, Siddha and Unani formulation;
For textual indications the safety and effectiveness study is not required.

39. Regulatory requirements for Ayurvedic, Siddha and Unani Plant Extracts (Quality ,Pre- Clinical safety and Efficacy)

40. (V) For issue of license with respect to medicine Aushadh Ghana [extract of medicinal plant (dry or wet).
S.No.
Category
Ingredient
Indication
Safety study
Experience/Evidence of Effectiveness
Published Literature
Proof of Effectiveness 1. 2. 3. 4. 5. 6. 7.
(A) Aqueous
As per text
Not required
Not required.
(A1) Aqueous
New indication
Required.
(B) Hydro-alcohol
If required
(B1) Hydro-alcohol
As specified
New indication**
Required
The standard protocol will also include concept of Anupan, Prakriti and Tridosha etc. published by Central Research Councils Ayurveda, Siddha, Unani and other Government/Research Bodies.
New indication means which is other than mentioned in Ist schedule books of Drugs and Cosmetics Act, 1940.

41. National Pharmaco-vigilance Programme for Ayurveda, Siddha and Unani (ASU) Drugs (for appropriate Regulatory interventions )

42. Drug Interactions& Safety studies of Ayurvedic drugs Evaluation of safety profile of herbs used in Ayurveda with CYP-450 enzymes inhibition method
Sl.
Plant &Markers 1
Piper longum
Piperine 2
Acorus calamus
A-asarone 3
Withania somnifera
Withanolide-A 4
Terminalia bellerica
Gallic acid 5
Terminalia chebula 6.
Bacopa monnieri
Bacoside A 7
Centella asiatica
Asiaticoside 8
Glycyrrhiza glabra
Glycyrrhizin 9
Emblica officinalis 10
Zingiber officinale
6-gingerol
CYP450-CO complex method-cDNA expressed recombinant human CYP 3A4 and CYP 2D6
Not shown potent inhibition of CYP isoforms compare to positive control ketoconazole and Qunidine.
Less likely to produce clinically significant drug interaction
Ponnusankar, Subrata Pandit, Ramesh Babu, Arun Bandyopadhyay, Pulok K. Mukharjee, Cytochrome P450 inhibitory potential of Triphala-A Rasayana from Ayurveda. Journal of Ethnopharmacology 133, (Elsevier).
Subrata Pandit, Pulok K. Mukharjee, Sivasankaran Ponnusankar, Murugan Venkatesh, N. Srikanth, Metabolism medicated interaction of x-asarone and Acorus calamus with CYP3A4 and CYP2D /j.fitote (Elsevier)

43. Drug Interactions& Safety studies of Ayurvedic drugs Evaluation of safety profile of herbs used in Ayurveda with CYP-450 enzymes inhibition method
Interaction of Piper longum with CYP isozymes was found to be highest among the selected plant and Zingiber officinale interaction was least.

44. Emphasis on ASU-GCP
The present research orients itself to drug constituents rather that at clinical protocols
This may enrich pharmacopeia not factual pharmaco-therapeutics with credible translational potential.

45. Emphasis on ASU-GCP
The demarcation of medical system would become a challenge in the perspective of medical ethics ……………….
while conducting RCTs & testing the safety & efficacy of AYUSH with conventional medicine
Safety and efficacy of add-on/ adjuvant therapies
……….wherein more than one medical systems are involved

46. Emphasis on ASU-GCP Holistic and individualistic Procedure based
Selection and assessment parameters  
Diet and lifestyle
Blinding
Difficulty in adopting gold standards
Use of crude ingredients and extracts
Limitations of Preclinical Safety/ toxicity/ efficacy

47. ASU-GCP Guidelines are Pivotal Clinical Research- Key to System development
Clinical research is the key to the development of the system.
Good clinical practices is an ethical and scientific quality standard for designing, conducting and recording trials and compliance with this standard provides assurance of protection of subjects
We may face certain difficulties in adopting GCP in the trials involving ASU principles but the solution exists for each problem.

49. Thank you