CURRENT REGULAT0RY ASPECT FOR PHYTOPHARMACEUTICALS

IN INDIA

A.B.RAMTEKE (Consultant)

Clinical Development Service Agency

470, Udyog Vihar, Phase III, Gurgaon

Regulatory Authorities

Ministry of Chem & Fertilizers

Ministry of Health Ministry of Health

State Licensing Authority

(NPPA) National

Pharmaceutical Pricing Authority

Pricing Regulations

Health Secretary

(DGHS) Dir. General of Health Services

(CDSCO) Central Drugs Standard

Control Org.

(DCGI) Drugs Controller General (India)

Manufacturing , Sales & Inspections

Genetic Engineering Approval Committee

DBT

Review Committee of

Gene Manipulation

Dept. of AYUSH / ISM&H

Ministry of Science & Technology

DCG (I)

CDSCO

(Head Quarter) ZONAL OFFICES

SUB ZONAL

OFFICES PORT OFFICE

CENTRAL

DRUG TESTING

LABORATORIES

INDIAN

PHARMACOPOEIA

COMMISSION

•North Zone,

Ghaziabad

•East Zone,

Kolkata

•West Zone,

Mumbai

•South Zone,

Chennai

•Hyderabad

•Ahmadabad

•.Bangalore

•Delhi

•Mumbai

•Chennai

•Kolkata

•Hyderabad

•Ahmadabad

•CDL Kolkata

•CIPL Ghaziabad

•CDTL Mumbai

•CDTL Chennai

•RDTL Guwahati

•RDTL Chandigarh

•Ghaziabad

•New Delhi

•New Drugs

•Biologics, CT

•Imports, Export

• Medical Devices

• Diagnostics

• Cosmetics

• Policy making.

•Coordination's

•with States

•GMP Audits

•GMP Audits

•Coordination's

•with States

•Export

•Import

•Testing of drug

•Samples

•Validation of

•Test protocol

Existing Structure & Composition of CDSCO

Drug Definition (Drugs & Cosmetics Act, 1940)

• Section 3(a) [“Ayurvedic, Siddha or Unani drug” includes all medicines intended for internal or external use for or in the diagnosis, treatment, mitigation or prevention of disease or disorder in human beings or animals, and manufactured exclusively in accordance with the formulae described in, the authoritative books of Ayurvedic, Siddha and Unani (Tibb) systems of medicine, specified in the First Schedule;]

Authoritative text recognized by Drugs and Cosmetics Act in India

• The traditional experience has been documented and government of India in its wisdom has given regulatory status to these preparations as Ayurvedic drugs and there are more than 57 books recognized by Government of India and is laid down under The First Schedule of Drug and Cosmetic Act 1940

• The First Schedule has been inserted in regulatory book more than 50years back and has been amended time to time,

• The latest inclusion in 2010 was ayurvedic pharmacopoeia of India and its parts.

Indian Pharmacopoeia (IP)

• Indian Pharmacopoeia Commission is an autonomous body under Ministry of Health and Family Welfare, Government of India, which publishes Indian Pharmacopoeia,

• IP is the legally recognized book for standards of medicines in India,

• It specifies the standards in terms of identity, purity and strength of medicines,

• Therefore, Indian Pharmacopoeia (IP) laid down monograph for herbs and herbal products to maintain their quality.

Quality Standards of Indian Medicinal Plants

• Standards set as per WHO guidelines

• Use conventional and modern scientific approach

• Developed at 4 national laboratories

• 4 Volumes on Indian Medicinal Plants:

(Next Slide)

MEDICINAL PLANTS MONOGRAPHS ON DISEASES OF PUBLIC HEALTH IMPORTANCE • ANCIENT KNOWLEDGE

• ALLOPATHY SYSTEM OF MEDICINE

• SCIENTIFIC STUDIES

• INTEGRATION OF LEADS

SOME THRUST AREAS

» FILARIASIS

» MALARIA

» KALA-AZAR

» LIVER DISORDERS

» DIABETES MELLITUS

» ANTIINFLAMMATION

» IMMUNOMODULATORS

• (Courtesy ICMR)

Role of AYUSH* in India

• Ø Medical Education management through Central Council of

Indian Medicines

• Ø Promote the cultivation of herbs

• Ø Promote the research work on Indian system of medicines

• Ø To lay down standards to maintain the quality of drugs

• Ø Develop regulation to promote the traditional system of medicines

• Ø To provide financial subsidy to Small Scale Industries to promote the manufacture of traditional drugs,

• Ø Regulate Clinical trials of these drugs to prove the safety and efficacy

• Ø Amend the regulation for the betterment of the system in the interest of general public,

* Department of Ayurveda, Yoga, Unani, Sidha and Homeopathy (AYUSH)

Approved Botanicals as Drugs (PhytoPharmaceuticals) by DCGI

• Ø Guglip extract and tablets I.P. – standardized Guggulu extract (Cammiphora mukul) – for cholesterol reduction, Ø Gingko biloba tablets (Gingko biloba leaf extract)- for treating short term loss of memory,

• Ø Gingseng tablet (Standardized Gingseng extract along with vitamins and minerals)- for immunity and energy

• Ø Silymarin syrup and capsules –for treating liver disorders,

• Ø Ginger capsules-standardized Ginger – for treating chemotherapy induced nausea.

Drug Definition (Drugs & Cosmetics Act, 1940)

Section 3(b) “drug” includes— • (i) all medicines for internal or external use of human beings or animals and all

substances intended to be used for or in the diagnosis, treatment, mitigation or prevention of any disease or disorder in human beings or animals, including preparations applied on human body for the purpose of repelling insects like mosquitoes;

• (ii) such substances (other than food) intended to affect the structure or any function of human body or intended to be used for the destruction of (vermin) or insects which cause disease in human beings or animals, as may be specified from time to time by the Central Government by notification in the Official Gazette;]

• 2[(iii) all substances intended for use as components of a drug including empty gelatin capsules; and

• (iv) such devices intended for internal or external use in the diagnosis, treatment, mitigation or prevention of disease or disorder in human beings or animals, as may be specified from time to time by the Central Government by notification in the Official Gazette, after consultation with the Board ;]

Drugs & Cosmetics Act • The Act Contains Part –I - five Chapters which includes 38

different Sections.

• Part II of the Act is –Drugs and Cosmetics Rules 1945,

• The D&C Rules contains 19 parts (Part XIX).

• Part X-A is for ‘ IMPORT OR MANUFACTURE OF NEW DRUG FOR CLINICAL TRIALS OR MARKETING.

• There are currently 171 Rules, followed by Schedule A to Y

• Schedule Y is for” Requirements & Guidelines for permission to import and /or manufacture of New Drugs for sale or to undertake Clinical Trials”.

What Is Schedule Y • It is “Schedule under Part X-A of Drugs & Cosmetics

Rule 1945 describe the information/data required for approval in Clinical Trial and/or to import or manufacture of new drug for marketing in India.

• It is outlined extensive study criteria in line with the globally accepted formats such as ICH and US FDA guidelines

• Refer to rules 122A, 122B, 122D, 122DA, 122DAA , 122 DAB, 122 DD and 122E.

Important Appendices of Schedule Y

Appendix I

Data to be submitted to

- Conduct clinical trial

- Import and

- Manufacture of New Drugs for marketing in the

country

Appendix I – A

Data required for grant of permission

- To import and / or

- Manufacture new drugs already approved in the

country (Subsequent Applicants)

16

Appendix II

- Structure

- Contents &

- Format for clinical study reports

Appendix III - Animal toxicology

- Systemic toxicity studies

- Male fertility study

- Female reproduction & Dev toxicity study

- Local toxicity

- Allergenicity, hypersensitivity

- Genotoxicity

- Carcinogenicity

17

Appendix IV

- Animal pharmacology

Appendix V

- Informed consent

Appendix VI

- Fixed dose combination

Appendix VII

- Undertaking by the investigator

Appendix VIII

- Ethics committee

Appendix IX

- Stability testing of new drugs

18

Appendix X

- Contents of the proposed protocol for conducting

clinical trials

Appendix XI

- Data elements for reporting serious adverse

events occurring in a clinical trial.

Appendix XII

- Compensation in case of injury or death during

Clinical trial. (Rule 122 DAB) (GSR No. 53-E , 30th Jan 2013)

19

Application Form 44

Form 44

(See Rules 122A, 122B, 122D and 122DA)

Application for grant of permission to import or manufacture a New Drug or to undertake clinical trial.

I/We ______ of ______ hereby apply for grant of permission for import and / or clinical trial or for approval to manufacture of a new drug or fixed dose combination or subsequent permission of already approved new drug.

Contd:

Application Form 44 (contd.) With Information / Data Required

1. Particulars of New Drug:

• Name of the drug:

• Dosage form:

• Composition of the formulation:

• Test specifications:

– Active ingredients:

– Inactive ingredients:

• Pharmacological classification of the drug:

• Indications for which proposed to be used:

• Manufacturer of the raw material:

• Patent status:

Application Form 44 (contd.)

1. As Per Appendix 1

• Chemical and pharmaceutical information

• Animal pharmacology

• Animal toxicology

• Human / clinical pharmacology

• Exploratory clinical trials

• Confirmatory clinical trials

• Bioavailability / Bioequivalence, dissolution and stability data

Application Form 44 (cont.)

• Regulatory status in other countries

• Marketing information:

– Proposed product monograph

– Drafts of labels and cartons

• Application for test license: (next page)

Test License To Import New Drug For Testing / Clinical trial Purpose

• Application:

–Form 12 application

–Material justification plan

–Treasury Challan of Rs 100 for first drug, followed by Rs 50 for additional drug

– License will be in Form 11

New Drug Approval Committee (NDAC)

• Since April 2011, Twelve New Drug Approval Committees (NDACs) were constituted to advise DCG(I) in matters related to review and regulatory approval of clinical trials and new drugs {except INDs} of 12 different therapeutic categories.

• Details of the NDACs along with the names of the committee members are posted at CDSCO web-site www.cdsco.nic.in

cdsa

“ New Drug Advisory Committee” (NDAC) to advise DCG(I) in matter related to review & regulatory approvals of clinical trials and new drug (except IND) of following categories :

1. Antibacterial, Antiparasitic & Antiviral,

2. Analgesics, Anesthetics and Rheumatology,

3. Cardiovascular and Renal,

4. Dermatology and Allergy,

5. Gastroenterology & Hepatology,

6. Metabolism & Endocrinology,

7. Neurology & Psychiatry,

8. Oncology & Hematology,

9. Ophthalmology,

10. Pulmonary,

11. Reproductive & Urology,

12. Vaccines.

( Details regarding names & addresses of subject Experts may be seen at www. cdsco.nic.in

New Drug Advisory Committee (NDAC)

GAZETTE NOTIFICATION (GSR 702 E)

• GSR 702 ( E) dated 24th October 2013 defines –

“ Phytopharmaceutical drug” includes processed or unprocessed standard material derived from plants or parts thereof or combination of parts of plants, extracts or fractions thereof in a dosage form for internal or external use of human being or animals and intended to be used for diagnosis, treatment, mitigation or prevention of any disease or disorder in human beings or animals, but does not include administration by parenteral route”.

GSR 702 ( E) dated 24th October 2013 (Contd)

“ APPENDIX I-B” –Data to be submitted along with Application to conduct Clinical Trial or Import or Manufacture of a Phytopharmaceutical drug in the country.

PART-1:

1. Basic Information: Summary of the drug , including name, route of administration, dosage, therapeutic class.

- Relevant Published literature, Scientific reports including product as a traditional medicine. Information on contraindications, side effects and present usage of the product.

GSR 702 ( E) dated 24th October 2013 (Contd)

2. Human or Clinical Pharmacology information:-

- Published Scientific Reports in respect of pharmacological studies, human clinical trials relevant to the drug.

- Pharmacodynamic information (if available)

- Pharmacopeia Monographs, if any on product, extract or plant.

GSR 702 ( E) dated 24th October 2013

PART –II – Data generated by Applicant:

1. Pharmacognostic description: Morphological, Taxonomical identity , Natural habitat & geographical distribution of Plant (s), Season or time of collection, list of growers / suppliers etc.

• Quality Specifications: (a) Foreign matter, (b) moisture content; ( c) volatile matter, if any (d)total ash (e ) acid insoluble ash, (f) extractive value; (g) pesticide residue;(h) heavy metal contamination; (i) microbial load; (j) aflotoxins, if any (k) chromatographic finger print profile with phytochemical reference maker/(s); (l) assay for active constituent(s) or characteristic maker

if active constituents are not known.

2. Processing of Extract or Phytopharmaceutical:

• Quality Specifications & Test methods for starting material.

GSR 702 ( E) dated 24th October 2013 (Contd)

• Detail steps used in processing of phytopharma;

• Details of packaging, storage and labeling,

3. Formulation of Phytopharmaceuticals drug applied for:

• Details of composition, unit dose, name, all excipients,

Tests for identification and Quality specifications…..

4. Manufacturing process of Formulation:

• Outline method of manufacture, dosage form, in-process

quality control tests, packaging steps & final packs.

5. Stability Data:

6. Safety & Pharmacological Information:

GSR 702 ( E) dated 24th October 2013 (Contd)

7. Animal Toxicity and Safety Data:

• 28 to 90 days repeat dose oral toxicity in two species (rodent & non-rodent as per Schedule-Y)

• In-vitro Genotoxicity (Ame’s test –Schedule-Y),

• Dermal toxicity for topical use products,

• Teratogenicity study ( only for product intended for usage during pregnancy ),

8. Human Clinical Trials : Phase- I, Phase-II and Phase- III as per Schedule- Y.

GSR 702 ( E) dated 24th October 2013 (Contd)

9. Regulatory status : Status of product out-side India,

10.Marketing Information : Details of Package- Insert,

11.Post Marketing Surveillance (PMS): Furnish Periodic Safety Update Reports (PSUR) every six

months, for first two years after approval granted.

Comments / Suggestions on GSR 702 (E )

1. This is regulatory provisions of defining phytopharmaceuticals ( botanical-based drug) and will be regulated under Chapter IV of D & C Rules

2. A schedule providing requirements of scientific data on quality, safety and efficacy to evaluate and marketing authorization for plant based drug.

3. Ayurveda, Siddha, and Unani (ASU) drugs are currently regulated under Chapter IV-A of D & C Rules, hence the said GSR 702 (E) will not have any impact on ASU regulation.

4. Phytopharmaceuticals would need to be evaluated for safety (Toxicology) & Efficacy as per Schedule Y .

Comments / Suggestions on GSR 702 (E )

5. The word “ Unprocessed Standardized Material” should be deleted from definition.

6. Details of contaminants limits should be based on daily consumption instead of per dose content. (2008).

7. Safety study ( animal toxicity) may be exempted in case of extract from 100% water.

Challenges and future perspectives:

• Develop mechanisms to recognize and not block

the traditional use, at the same time assuring the

quality, safety and efficacy of medicinal plants.

• Build policies and regulations aligned with

traditional practices,

• Regulation of Phytopharmaceuticals as “new drugs”, ( under Rule 122 E)

• Need to engage in workshops and training courses

and Exchange of information,

Contact for Suggestions / Comments

E mail - ramteke.cdsa@thsti.res.in