Regulatory Approval

A robust, transparent, simple and well-established regulatory system is important to ensure safety, efficacy and quality of medicinal products as well as to support, facilitate, guide and encourage entrepreneurs, researchers and innovators in the field of pharmaceutical research.

In India,clinical trials are governed by the Government of India and various other institutes within the Government. To ensure safe and ethical conduct of clinical trials, one must comply with the Rules, Regulations and guidelines prescribed by the Government of India. These are:

Drugs and Cosmetics Act,1940 and Rules, 1945

They are enforced at the central and state level, to regulate clinical trials and ensure the efficacy and safety of all drugs, imported or manufactured, and marketed in India.  The Drugs Controller General (India) (i.e. DCGI), heads the Central Drugs Standard Control Organisation (CDSCO) and is responsible for enforcing these rules and acts.They ensure that the data produced is authentic, reliable and reproducible and provide the basis (if applicable) for permission to be granted to market the drug.

New Drugs and Clinical Trial Rules, 2019

They have been published vide Government of India Gazette notification 227E on 19^th March 2019. The rules describe the requirements and guidelines for permission to import or manufacture new drug for sale or to undertake a clinical trial/Bioavailability/Bioequivalence studies. Part XA and Schedule Y of the Drugs and Cosmetics Act and Rules are no longer applicable. However, New Drugs for veterinary use will continue to be regulated as per Part XA.

The New Drugs and Clinical Trial Rules, 2019 are divided into 12 chapters, eight schedules andinclude many tables. The chapters include:-

1. Chapter I (Rules 1 and 2, page 147 onwards): prescribes applicability and definitions
2. Chapter II (Rules 3,4 and 5, page 150):mentions the authorities and officers
3. Chapter III (Rules 6 to 14 – page 150 onwards): rules pertaining to ethics committees for clinical trial, bioavailability (BA) and bioequivalence (BE) studies.
4. Chapter IV (Rules 15 to 18 – page 153 onwards): rules pertaining to ethics committees for biomedical and health research. Chapter IV will come into force 180 days after the publication of the New Drugs and Clinical Trial Rules, 2019
5. Chapter V

• Part A (Rules 19 to 30 – page 155 onwards): rules pertaining to clinical trials.
• Part B (Rules 31 to 38 – page 159 onwards): rules pertaining to BA and BE studies.

6. Chapter VI (Rules 39 to 42 – page 161 onwards): rules pertaining to compensation and medical management in case of injury or death in a clinical trial, BA or BE study of a new drug or investigational new drug.
7. Chapter VII (Rules 44 to 51 – page 164 onwards): rules pertaining to BA and BE Study Centre.
8. Chapter VIII (Rules 52 to 66– page 166 onwards): rules for Manufacture of new drugs or investigational new drugs for a clinical trial, BA or BE study or for examination, test and analysis.
9. Chapter IX (Rules 67 to 73– page 170 onwards): rules for Import of new drugs or investigational new drugs for clinical trial or BA or BE study or for examination, test and analysis.
10. Chapter X (Rules 74 to 85 – page 172 onwards): rules for import or manufacture of new drug for sale or for distribution.
11. Chapter XI (Rules 86 to 96 – page 177 onwards): rules for import or manufacture of unapproved new drug for treatment of patients in government hospital and government medical institution.
12. Chapter XII (Rule 97 – page 180): Amendment of Drugs and Cosmetic Rules, 1945. The following rule has been inserted: Rule 122DAA: Part XA and Schedule Y shall not be applicable with respect to new drugs and investigational new drugs for human use from the date the New Drugs and Clinical Trials Rules, 2019, come into force.

13. Chapter XIII (Rules 98 to 107 – page 180 onwards): Miscellaneous

The eight schedules include:-

1. First Schedule (page 181 onwards): General principles and practices for clinical trial.
2. Second Schedule (page 185 onwards):Requirements and guidelines for permission to import or manufacture of new drugs for sale or to undertake clinical trial.
3. Third Schedule (page 209 onwards): Conduct of clinical trial, informed consent and responsibilities of the sponsor, investigator and ethics committee. It also provides prescribed formats for the following:

• Ethics Committee approval letter,
• Clinical trial protocol,
• Informed consent,
• Undertaking by the investigator,
• Data elements for reporting Serious Adverse Events (SAEs) occurring in a clinical trial or BA or BE study
• Clinical trial report
• Investigator’s Brochure

4. Fourth Schedule (page 223 onwards): Requirements and guidelines for conduct of BA and BE study of new drugs or investigational new drugs.
5. Fifth Schedule (page 228 onwards): Post Market Assessment.
6. Sixth Schedule (page 230 onwards): Fee payable for license, permission and registration certificate.
7. Seventh Schedule (page 234 onwards): Formulae to determine the quantum of compensation in the cases of clinical trial related injury or death.
8. Eighth Schedule (page 236): Application forms.

National Ethical Guidelines for Biomedical and Health Research Involving Human Participants (2017) – ICMR

These guidelines have been drafted and published by Indian Council of Medical Research (ICMR) and the clinical trial regulations mandate that these guidelines should be followed.

Good Clinical Practice (GCP) guidelines 2001 These guidelines have been published by the CDSCO, Directorate General of Health Service (DGHS), Ministry of Health, Government of India.

ICH GCP Guidelines E6(R2)

These guidelines have been published by the International Council for Harmonization, for multi country or Global Clinical Trials, where India is one of the participating countries.

In addition to complying with the above-mentioned documents, one may also need to refer to additional guidelines depending on the investigational product. For example:

New Drugs and Investigational New Drugs	New Drugs and Clinical Trial Rules, 2019
Medical Devices	Medical Devices Rules, 2017
Stem Cell Research	National Guidelines for Stem Cell Research, 2017
AYUSH	Good Clinical Practice guidelines for Clinical Trials in Ayurveda, Siddha and Unani Medicine (GCP-ASU), 2013

Clinical Trials of New Drugs or Investigational New Drugs that require approval from the Central Licensing Authority (CLA) i.e. CDSCO:

Such clinical trials are carried out by an individual Investigator or institution or organisation (Pharmaceutical Industry)with a drug / new drug developed in India or outside, which is proposed to be marketed in India. Such trials can only be conducted after obtaining a valid permission/approval from the CLA i.e. DCGI, CDSCO, New Delhi.

Application for permission to conduct a clinical trial of a new drug or investigational new drug, in India is to be submitted via Form CT-04. The Second Schedule of the New Drugs and Clinical Trial Rules, 2019 specify the documents, information and requisite fee receipt to be submitted with Form CT-04 (page 238). This document in accordance with Table 1 of the Second Schedule (page 202) of the New Drugs and Clinical Trial Rules, 2019 provides the format in which the required data needs to be submitted.

If all conditions are satisfactorily met, the permission to conduct the clinical trial will be granted in Form CT-06. The proposed timelines for applications submitted in Form CT-04, is 90 working days from submission of the application.

For drugs that are discovered in India, or research and development of the drug are being conducted in India, and if it is to be manufactured and marketed in India, then, applications for permission to conduct a clinical trial with these drugs, will be processed within a period of 30 working days, from the date of receipt of application.If no communication is received by the applicant within 30 working days of CDSCO’s receipt of application, permission to conduct the clinical trial will be deemed to have been granted. Applicants who have taken a deemed approval under the above-mentioned clause:

1. Shall be authorised to initiate the clinical trial in accordance to the New Drugs and Clinical Trial Rules, 2019.
2. Before initiating the trial, shall inform CDSCO in Form CT-4A.
3. Form CT-4A will become a part of the official record and be termed ‘Automatic Approval of the CLA’.

Note: An automatic approval is only valid for new drugs or investigational new drugs that are discovered in India, or research and development of the drug are being conducted in India,and if it is to be manufactured and marketed in India.

Since 2017, applications to conduct clinical trials in India are to be submitted online via the SUGAM portal (hosted and developed by CDSCO). This portal provides comprehensive step –by-step instructions on how to fill the form online and the information that is required.

The Submission Dossier must include the information mentioned in Second Schedule (page 185 onwards) of the New Drugs and Clinical Trial Rules, 2019 and the following documents:

• Investigator’s Brochure (IB) (in accordance to Table 7 of the Third Schedule (page 220) of the New Drugs and Clinical Trial Rules, 2019)
• Proposed Study Protocol (in accordance to Table 2 of Third Schedule (page 213) of the New Drugs and Clinical Trial Rules, 2019)
• Sample Case Record Form (CRF)
• The Informed Consent Documents (ICDs) (that satisfy the requirements in Table 3 of Third Schedule (page 215) of the New Drugs and Clinical Trial Rules, 2019 and National EthicalGuidelines for Biomedical and Health Research Involving Human Participants, 2017)
• Investigator’s Undertaking (Table 4 of the Third Schedule (page 217) of the New Drugs and Clinical Trial Rules, 2019)
• Ethics Committee clearance or approval – if available (Table 1 of Third Schedule (page 212) of the New Drugs and Clinical Trial Rules, 2019).

Applications to conduct a clinical trial for Investigational New Drug (IND) are reviewed by the IND Committee, under the Chairmanship of Director General, ICMR, New Delhi.The Ethics Committees considering applications to conduct clinical trials,have to be constituted and registered (with CDSCO) as per Rules7 and 8 of the New Drugs and Clinical Trial Rules, 2019. The validity of permission to initiate a clinical trial granted via Form CT-06 or CT 4A, is valid for a period of two years (from the date of its issue), unless extended by the CLA.

The process after an application to conduct a clinical trial is submitted to the CDSCO headquarter, is:

Flow diagram for approval of clinical trial applications

Flow diagram: Evaluation for grant of import or manufacture permission

The expert Committees that are involved in the evaluation of clinical trial protocols include various Subject Expert Committees (SECs) and the Investigational New Drugs (IND) Committee under DG, ICMR for evaluation of clinical trial protocol of IND. The Technical Advisory Committee reviews the recommendations proposed by these committees, under the guidance of Directorate General of Health Services (only in cases of appeals). The Apex Committee under the Chairmanship of Secretary, Health and Family Welfare is responsible for the overall monitoring of clinical trials in the country

There are provisions in the New Drugs and Clinical Trial Rules, 2019 for a pre and post submission meeting with CDSCO. The details of this are in Rules 98 and 99, of Chapter XIII of the New Drugs and Clinical Trial Rules, 2019 (page 180).

The rules and regulations governing the conduct of clinical trials in India may change from time-to-time, as new information is made available. This page on CDSCO’s website lists all gazettes and notifications that are released and may impact a study or trial. It is recommended that researchers check the CDSCO site periodically (including the FAQ section) to ensure that their trial application and conduct is in line with the current regulatory requirements as mandated by CDSCO.

The Handbook for Applicants and Reviewers of Clinical Trials of New Drugs in India (2017) elaborates on the requirements, types of review and focus of review (by CDSCO and the SEC) for a clinical trial application. It is advisable to refer to this document before submitting an application.

Clinical Trials that do not require an approval from the CLA:

Clinical Trials of drugs already approved for a certain claim and initiated by any investigator, academic or research institution for:

• a new indication or,
• new route of administration or,
• new dose or new dosage form,

where, the results of such a trial are intended to be used only for academic or research purposes and not for seeking approval of the regulatory authority of any country for marketing or commercial purpose are referred to as Academic Trials. Such trials do not require permission from DCGI.

Clinical Trials involving Medical Devices:

As per the National Ethical Guidelines, a medical device is a medical tool which does not achieve its primary intended action in or on the human body by pharmacological, immunological, or metabolic means but which may be assisted in its intended function by such means. It may be an instrument,apparatus, appliance, implant, material or other article, whether used alone or in combination, including a software or an accessory, intended by its manufacturer to be used specially for human beings or animals for one or more of the specific purposes of:

1. Detection, diagnosis, prevention, monitoring;
2. Treatment or alleviation of any physiological condition or state of health, or illness;
3. Replacement or modification or support of the anatomy or congenital deformity;
4. Supporting or sustaining life;
5. Disinfection of medical devices; or
6. Control of conception.

The Central Licensing Authority in India (i.e. CDSCO) introduced the Medical Devices Rules, 2017, which came into effect on the 1^st January 2018. These rules are applicable for:

1. Substances used for in vitro diagnosis and surgical dressings, surgical bandages, surgical staples, surgical sutures, ligatures, blood and blood component collection bag with or without anticoagulant covered under sub-clause (i);
2. Substances including mechanical contraceptives (condoms, intrauterine devices, tubal rings), disinfectants and insecticides notified under sub-clause (ii);
3. Devices notified from time to time under sub-clause (iv), of clause (b) of section 3 of the Drugs and Cosmetics Act, 1940 (23 of 1940);

The Medical Devices Rules, 2017 are divided into 12 chapters, seven schedules and many tables.

Medical devices (other than in vitro diagnostic medical devices) are classified in the following manner, according to the risks involved:

Class	Level of Risk	Examples
A	Low	Thermometers / bandages / tongue depressors
B	Low-moderate	Hypodermic needles / suction equipment
C	Moderate-high	Lung ventilator / bone fixation plate
D	High	Heart valves / implantable defibrillator

Regulation / Governance

Central Licensing Authority	State Licensing Authority
The CLA, i.e. CDSCO is responsible for enforcing the Medical Devices Rules, 2017 for: i. Import of all classes of medical devices. ii. Manufacture of classes C and D iii. Clinical investigation and approval of investigational medical devices iv. Clinical performance evaluation and approval of new in vitro diagnostic medical devices v. Coordination with State Licensing Authorities.	The State Drugs Controller is the State Licensing Authority responsible for enforcing the Medical Devices Rules, 2017 for: i. Manufacture for sale or distribution of Class A or B medical devices ii. Sale, stock or exhibit or offer for sale or distribution of medical devices of all classes.

Clinical Investigation of Medical Devices:

Application to conduct a clinical investigation for investigation medical device is to be made to the CLA (CDSCO) via Form MD-22, by a sponsor, along with the information specified in the Seventh Schedule (page 202). The CLA grants the permission to conduct a clinical investigation for an investigational medical device via Form MD-23 (Rule 52 of the Medical Devices Rules, 2017).

For Clinical investigation of an investigational medical device one must:

1. Obtain an approval from the CLA.
2. Obtain an approval from a registered ethics committee.
3. Register the trial with the Clinical Trials Registry of India (CTRI), prospectively.
4. Comply with The Medical Devices Rules, 2017 published by the CDSCO, Good Clinical Practice Guidelines, published by the CDSCO, ethical principles described in the National Ethical Guidelines for Biomedical and Health Research Involving Human Participants, 2017 published by the ICMR.
5. The enrolment of participants in the clinical investigation must begin within a year of obtaining an approval from the CLA. Prior permission must be obtained from the CLA, if the applicant is not able to initiate enrolment within the prescribed timeframe.

Clinical Performance Evaluation of New In Vitro Diagnostic Medical Devices:

Application to conduct a clinical performance evaluation of new in vitro diagnostic medical device is to be made to the CLA via Form MD-24, by the sponsor, along with the applicable fee (specified in the Second Schedule) and information (specified in sub-rule 2 of Rule 59, page 159). If all requirements are satisfactorily met, the CLA grants permission to conduct clinical performance evaluation of new in vitro diagnostic medical device via Form MD-25.

The approval process for applications received online via the SUGAM portal with respect to medical devices can be accessed here. The Online System for Medical Devices launched by CDSCO allows an applicant to submit and track the status of applications pertaining to medical devices.

Clinical Trials with Stem Cells:

Stem cells and their derivatives fall under the definition of a ‘drug’ as per the Drugs and Cosmetic Act 1940 and are categorised into Investigational New Drug and Investigational New Entity, when used for clinical application. Thus, appropriate ethical principles and regulations must be followed, before initiating a clinical trial involving stem cells. The National Guidelines for Stem Cell Research, 2017 published by DBT and ICMR addresses issues related to stem cell research. The guidelines categorise stem cell research on the basis of ethical and/or safety concerns regarding the source of stem cells and levels of manipulation, which warrant additional review and monitoring as per existing regulations:

1. Permissible areas of research: In vitro studies using stem cells isolated from tissues can be done with a prior approval of the Institutional Committee for Stem Cell Research (IC-SCR) and the institutional ethics committee.
2. Restrictive areas of research: includes basic and translational research, requiring additional oversight or monitoring due to the contentious issues involved. For such trials, an approval from the CLA i.e. CDSCO is mandatory, other than an approval from the IC-SCR, National Apex Committee for Stem Cell Research and Therapy (NAC-SCRT), and the institutional ethics committee.
3. Prohibited areas of research: according to the current state of scientific knowledge and understanding, stem cell research in the following areas is prohibited in India:

• Research related to human germ line gene therapy and reproductive cloning.
• In vitro culture of intact human embryos, regardless of the method of their derivation, beyond 14 days of fertilization or formation of primitive streak,whichever is earlier
• Clinical trials involving xenogeneic cells
• Any clinical research on Xenogeneic-Human hybrids
• Use of genome modified human embryos, germ-line stem cells or gametes for developmental propagation
• Research involving implantation of human embryos (generated by any means)after in vitro manipulation, at any stage of development, into uterus in humans or primates
• Breeding of animals in which any type of human stem cells have been introduced at any stage of development, and are likely to contribute to chimeric gonadal cells.

Except haemopoietic stem cell transplantation for haematological disorders, any other use of stem cells are categorised as research, and conducted as a clinical trial. All trials must be conducted with clinical grade cells processed as per the applicable national Good Laboratory Practices, Good Manufacturing Practices, and follow Good Clinical Practice guidelines.

The current information on this page pertains to only clinical trials of certain investigational products. More information may be added in the next update of the toolkit.

For more information regarding various committees involved in the regulation and conduct of clinical trials of other investigational products, please refer to the Other Approvals section of the toolkit.

References and further reading:

• Drugs and Cosmetic Actand Rules, 1945, as amended up to the 31^st December 2016, Ministry of Health and Family Welfare, Government of India, available online (last accessed on 26.02.2019).
• New Drugs and Clinical Trial Rules, 2019, G.S.R. 227(E), Central Drugs Standard Control Organization, Ministry of Health and Family Welfare, available online (last accessed on 01.04.2019).
• Medical Devices Rules, 2017, G.S.R. 78(E), Central Drugs Standard Control Organization, Ministry of health and Family Welfare, available online (last accessed on 17.07.2019).
• Good Clinical Practices for Clinical Research in India, Central Drugs Standard Control Organization, Ministry of Health and Family Welfare, 2001, available online (last accessed on 26.02.2019).
• National Ethical Guidelines for Biomedical and Health Research involving Human Participants, Indian Council of Medical Research, 2017, available online (last accessed on 26.02.2019).
• ICH Harmonised Guideline, Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2), current step 4 version, dated 9^th November 2016, available online (last accessed on 26.02.2019).
• Gogtay, N.J., Renju, R. &Thatte, U.M., 2017, Regulatory requirements for clinical trials in India: What academicians need to know, Indian Journal of Anaesthesia, version 61, number 3, pages 192-99, available online (last accessed on 26.02.2019).
• Dan, S. et al, 2018, “New Drugs and Clinical Trials Rules – 2018” (GSR-104E) by CDSCO: It’s impact on BA/BE studies in India, Pharmaceutical Regulatory Affairs, volume 7, number 2, available online (last accessed on 26.02.2019).