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

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

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

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

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

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

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

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

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.

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

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

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.

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

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

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

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

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.

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

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

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.

Challenges: ASU-GCP

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 -2001 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 -2010 5 Good Clinical Practices(GCP) Guidelines for ASU Medicines Department of AYUSH M/o Health &F.W Govt. India -2013

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

Research Guidelines in Vogue

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

Regulations ASU Drug Trials/Product approvals Rule158(B) (Amendment) of Drugs and Cosmetic Act- 1940 vide Gazette Number 441 in August 2010

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

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)

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

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.

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

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.

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

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.

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

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.

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

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.

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

(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.

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

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, 2010. Cytochrome P450 inhibitory potential of Triphala-A Rasayana from Ayurveda. Journal of Ethnopharmacology 133, 120-125. (Elsevier). Subrata Pandit, Pulok K. Mukharjee, Sivasankaran Ponnusankar, Murugan Venkatesh, N. Srikanth, 2010. Metabolism medicated interaction of x-asarone and Acorus calamus with CYP3A4 and CYP2D6. 10. 1016/j.fitote.2010.11.009. (Elsevier)

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.

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.

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

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

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.

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