Data Requirements for Clinical Trial in India: New Drugs and Clinical Trial Rules 2019

Introduction

“Clinical Trial” in regard to a brand new drug or investigational new drug means, any systematic study of such new drug or investigational new drug in human subjects to come up with data for locating or verifying its,- (I) clinical or; (II) pharmacological, including pharmacodynamics, pharmacokinetics or; (III) adverse effects, with the target of determining the safety, efficacy or tolerance of such new drug or investigational new drug.

A new drug means (as per CDSCO):

• A drug, including active pharmaceutical ingredient or phytopharmaceutical drug, which has not been used in the country to any significant extent has not been approved as safe and efficacious by Central Licensing  Authority (CLA) i.e. DCG(I) with respect to its claims; or
• A drug approved by the CLA for certain claims and proposed to be marketed with modified or new claims including indication, route of administration, dosage and dosage form; or
• A fixed-dose combination of two or more drugs, approved by CLA separately for certain claims and proposed to be combined for the first time in a fixed ratio, or where the ratio of ingredients in an approved combination is proposed to be changed with certain claims including indication, route of administration, dosage and dosage form; or
• A modified or sustained-release form of a drug or novel drug delivery system of any drug approved by the Central Licensing Authority; or
• A vaccine, rDNA derived product, living modified organism, monoclonal antibody, stem cell-derived product, gene therapeutic product or xenografts, intended to be used as a drug;

PART A: Clinical Trial Study of New Drugs and Investigational New Drugs Clinical Trial

19. Clinical trial of new drug or investigational new drug

(1) No person or institution or organization shall conduct clinical trial of a new drug or investigational new drug

• Except in accordance with the permission granted by the Central Licensing Authority; and
• Without the protocol thereof having been approved by the Ethics Committee for clinical trial registered in accordance with the provisions of rule

(2) Every person associated with the conduct of clinical trial of a new drug or investigational new drug shall follow the general principles and practices as specified in the First Schedule.

(3) No person or institution or organization shall conduct clinical trial of a new drug or investigational new drug except in accordance with the procedure prescribed under the provisions of the Act and these rules.

20. Oversight of clinical trial site

The work of every clinical trial site shall be overseen by an Ethics Committee for clinical trial registered under rule 8, before initiation and throughout the duration of the conduct of such trial.

21. Application for permission to conduct clinical trial of a new drug or investigational new drug

(1) Any person or institution or organization which intends to conduct clinical trial of a new drug or an investigational new drug shall make an application to the Central Licensing Authority duly filled in Form CT-04.

(2) The application made under sub-rule (1) shall be accompanied with the information and documents as specified in the Second Schedule and fee as specified in the Sixth Schedule:

Provided that no fee shall be payable for conduct of a clinical trial by a person of an institution or organization funded or owned, wholly or partially by the Central Government or by a State Government.

22. Grant of permission to conduct clinical trial

(1) The Central Licensing Authority may, after scrutiny of the information and documents furnished with the application in Form CT-04 and such further inquiry, if any, as may be considered necessary,

• If satisfied, that the requirements of these rules have been complied with, grant the permission to conduct clinical trial for a new drug or investigational new drug in Form CT-06.
• In case, where the Central Licensing Authority considers that there are some deficiencies in the application and the same may be rectified, the said Authority shall inform the applicant about the deficiencies.
• If not satisfied that the requirements of these rules have been complied with, reject the application, for the reasons to be recorded in writing.

(2) The decision under sub-rule (1) shall be taken within ninety working days.

(3) The applicant, after being informed, as referred to in clause (ii) of sub-rule (1), by the Central Licensing Authority, may,

• Rectify the deficiencies within a period specified by the Central Licensing Authority;
• Where the applicant rectifies the deficiency, as referred in sub-rule  (1), and provides required information and documents, the Central Licensing Authority shall scrutinize the application again and if satisfied, grant permission to conduct clinical trial of the new drug or investigational new drug, or if not satisfied, reject the application within a period of ninety days reckoned from the day when the required information and documents were provided:  Provided that in case of rejection, the applicant may request the Central Licensing Authority, to reconsider the application within a period of sixty working days from the date of rejection of the application on payment of fee as specified in the Sixth Schedule and submission of required information and documents.

(4) An applicant who is aggrieved by the decision of the Central Licensing Authority under sub-rule

(1) or sub-rule (3), may file an appeal before the Central Government in the Ministry of Health and Family Welfare within forty-five days from the date of receipt of such decision and the that Government, may, after such inquiry, and after giving an opportunity of being heard to the appellant, dispose of the appeal within a period of sixty working days.

23. Permission to conduct clinical trial of a new drug or investigational new drug as part of discovery, research and manufacture in India

(1) Notwithstanding anything contained in these rules, where any person or institution or organization make an application under rule 21 to conduct clinical trial of a new drug or an investigational new drug which is complete as per these rules and fulfills the following conditions, namely:

• The drug is discovered in India; or
• Research and development of the drug are being done in India and also the drug is proposed to be manufactured and marketed in India, such application shall be disposed by way of grant of permission or rejection or processed by way of communication to rectify any deficiency of the application, as the case may be, as specified in rule 22, by the Central Licensing Authority within a period of thirty working days from the date of the receipt of the application by the said authority: Provided that, where no communication has been received from the Central Licensing Authority to the applicant within the said period, the permission to conduct clinical trial shall be deemed to have been granted by the Central Licensing Authority and such permission shall be deemed to be legally valid for all purposes and the applicant shall be authorized to initiate clinical trial in accordance with these rules.

(2) The applicant who has taken deemed approval under the proviso to sub-rule (1) shall before initiating the clinical trial, inform the Central Licensing Authority in Form CT-4A and the Central Licensing Authority shall on the basis of the said information, take on record the Form CT-4A which shall become part of the official record and shall be called automatic approval of the Central Licensing Authority.

24. Permission to conduct clinical trial of a new drug already approved outside India

Notwithstanding anything contained in these rules, where any person or institution or organization makes an application under rule 21 to conduct clinical trial of a new drug that is already approved and marketed in a country, as specified under rule 101, the application, shall be disposed of by way of grant of permission or rejection or processed by way of communication to rectify any deficiency, as the case may be, as specified in rule 22, by the Central Licensing Authority within a period of ninety working days from the date of the receipt of the application by the said Authority.

25. Conditions of permission for conduct of clinical trial

The permission granted by the Central Licensing Authority to conduct clinical trial under this Chapter shall be subject to the following conditions, namely: ―

• Clinical trial at each site shall be initiated after approval of the clinical trial protocol and other related documents by the Ethics Committee of that site, registered with the Central Licensing Authority under rule 8;
• Where a clinical trial site does not have its own Ethics Committee, clinical trial at that site may be initiated after obtaining approval of the protocol from the Ethics Committee of another trial site; or an independent Ethics Committee for clinical trial constituted in accordance with the provisions of rule 7:

Provided that the approving Ethics Committee for clinical trial shall in such case be responsible for the study at the trial site or the Center, as the case may be:

Provided further that the approving Ethics Committee and the clinical trial site or the bioavailability and bioequivalence Center, as the case may be, shall be located within the same city or within a radius of 50 kms of the clinical trial site;

• In case an ethics committee of a clinical trial site rejects the approval of the protocol, the details of the same shall be submitted to the Central Licensing Authority prior to seeking approval of another Ethics Committee for the protocol for conduct of the clinical trial at the same site;
• The Central Licensing Authority shall be informed about the approval granted by the Ethics Committee within a period of fifteen working days of the grant of such approval;
• Clinical trial shall be registered with the Clinical Trial Registry of India maintained by the Indian Council of Medical Research before enrolling the first subject for the trial;
• Clinical trial shall be conducted in accordance with the approved clinical trial protocol and other related documents and as per requirements of Good Clinical Practices Guidelines and the provisions of these rules;
• Status of enrollment  of the trial subjects shall be submitted to the Central Licensing Authority on quarterly basis or as appropriate as per the duration of treatment in accordance with the approved clinical trial protocol, whichever is earlier;
• Six monthly status reports of each clinical trial, as to whether it is ongoing, completed or terminated, shall be submitted to the Central Licensing Authority electronically in the SUGAM portal;
• In case of termination of any clinical trial the detailed reasons for such termination shall be communicated to the Central Licensing Authority within thirty working days of such termination;
• Any report of serious adverse event occurring during clinical trial to a subject of clinical trial, shall, after due analysis, be forwarded to the Central Licensing Authority, the chairperson of the Ethics Committee and the institute where the trial has been conducted within fourteen days of its occurrence as per Table 5 of the Third Schedule and in compliance with the procedures as specified in Chapter VI;
• In case of injury during clinical trial to the subject of such trial, complete medical management and compensation shall be provided in accordance with Chapter VI and details of compensation provided in such cases shall be intimated to the Central Licensing Authority within thirty working days of the receipt of order issued by Central Licensing Authority in accordance with the provisions of the said Chapter;
• In case of clinical trial related death or permanent disability of any subject of such trial during the trial, compensation shall be provided in accordance with Chapter VI and details of compensation provided in such cases shall be intimated to the Central Licensing Authority within thirty working days of receipt of the order issued by the Central Licensing Authority in accordance with the provisions of the said Chapter;
• The premises of the sponsor including his representatives and clinical trial sites shall be open for inspection by officers of the Central Licensing Authority who may be accompanied by officers of the State Licensing Authority or outside experts as authorized by the Central Licensing Authority, to verify compliance of the requirements of these rules and Good Clinical Practices Guidelines, to inspect, search and seize any record, result, document, investigational product, related to clinical trial and furnish reply to query raised by the said officer in relation to clinical trial;
• Where the new drug or investigational new drug is found to be useful in clinical development, the sponsor shall submit an application to the Central Licensing Authority for permission to import or manufacture for sale or for distribution of the new drug in India, in accordance with Chapter X of these rules, unless otherwise justified;
• The laboratory owned by any person or a company or any other legal entity and utilized by that person to whom permission for clinical trial has been granted used for research and development shall be deemed to be registered with the Central Licensing Authority and may be used for test or analysis of any drug for and on behalf of Central Licensing Authority;
• The Central Licensing Authority may, if considered necessary, impose any other condition in writing with justification, in respect of specific clinical trials, regarding the objective, design, subject population, subject eligibility, assessment, conduct and treatment of such specific clinical trial;
• The sponsor and the investigator shall maintain the data integrity of the data generated during clinical trial.

26. Validity period of permission to initiate a clinical trial

The permission to initiate clinical trial granted under rule 22 in Form CT-06 or automatic approval under rule 23 in Form CT 4A shall remain valid for a period of two years from the date of its issue, unless extended by the Central Licensing Authority.

27. Post-trial access of investigational new drug or new drug

Where any investigator of a clinical trial of investigational new drug or new drug has recommended post-trial access of the said drug after completion of clinical trial to any trial subject and the same has been approved by the Ethics Committee for clinical trial, the post-trial access shall be provided by the sponsor of such clinical trial to the trial subject free of cost,-

• If the clinical trial is being conducted for an indication for which no alternative therapy is available and the investigational new drug or new drug has been found to be beneficial to the trial subject by the investigator; and
• The trial subject or legal heir of such subject, as the case may be, has consented in writing to use post-trial investigational new drug or new drug; and the investigator has certified and the trial subject or his legal heir, as the case may be, has declared in writing that the sponsor shall have no liability for posttrial use of investigational new drug or new drug.

28. Academic clinical trial

(1) No permission for conducting an academic clinical trial shall be required for any drug from the Central Licensing Authority where, ―

• The clinical trial in respect of the permitted drug formulation is intended solely for academic research purposes for a new indication or new route of administration or new dose or new dosage form; and
• The clinical trial referred to in clause (i) has been initiated after prior approval by the Ethics Committee for clinical trial; and
• The observations generated from such clinical trial are not required to be submitted to the Central Licensing Authority; and
• The observations of such clinical trial are not used for promotional purposes.

(2) In the event of possible overlap between the academic clinical trial and clinical trial or a doubt on the nature of study, the Ethics Committee concerned shall inform the Central Licensing Authority in writing indicating its views within thirty working days from the receipt of application to that effect.

(3) The Central Licensing Authority shall, after receiving the communication from the Ethics Committee referred to in sub-rule (2), examine it and issue necessary clarification, in writing, within thirty working days from the date of receipt of such communication: Provided that where the Central Licensing Authority does not send the required communication to such Ethics Committee within thirty working days from the date of receipt of communication from the said Ethics Committee, it shall be presumed that no permission from the Central Licensing Authority is required.

(4) The approved academic clinical trial shall be conducted in accordance with the approved clinical trial protocol, ethical principles specified in National Ethical Guidelines for Biomedical and Health Research Involving Human Participants, notified by the Indian Council of Medical Research with a view to ensuring protection of rights, safety and wellbeing of trial subject during conduct of clinical trial of licensed and approved drug or drug formulation for any new indication or new route of administration or new dose or new dosage form for academic research purposes.

29. Inspection of premises relating to clinical trial

The person or the institution or the organization permitted to conduct clinical trial under rule 22 in Form CT-06 or rule 23 in  Form CT -4A including his representatives and investigator, shall allow any officer authorized by the Central Licensing Authority, who may, if considered necessary, be accompanied by an officer authorized by the State Licensing Authority, to enter the premises and clinical trial site with or without prior notice to inspect, search or seize, any record, statistical result, document, investigational drug and other related material; and reply to queries raised by the inspecting authority in relation to conduct of such clinical trial.

30. Suspension or cancellation of permission to conduct clinical trial

(1) Where any person or institution or organization to whom permission has been granted under rule 22 in Form CT-06 or rule 23 in Form CT-4A fails to comply with any provision of the Act and these rules, the Central Licensing Authority may, after giving an opportunity to show cause and after affording an opportunity of being heard, by an order in writing, take one or more of the following actions, namely:―

• Issue warning in writing describing the deficiency or defect observed during inspection or otherwise, which may affect adversely the right, or well-being of a trial subject or the validity of clinical trial conducted;
• Reject the results of clinical trial;
• Suspend for such period as considered appropriate or cancel the permission granted under rule 22 in Form CT-06 or rule 23 in Form CT-4A;
• Debar the investigator or the sponsor including his representatives to conduct any clinical trial in future for such period as considered appropriate by the Central Licensing Authority.

(2) Where a person or an institution or an organization to whom permission has been granted under rule 22 in Form CT06 or rule 23 in Form CT-4A or the sponsor is aggrieved by the order of the Central Licensing Authority, the person or the institution or the organization may, within a period of sixty working days of the receipt of the order, make an appeal to the Central Government and that Government may, after such inquiry, as deemed necessary, and after affording an opportunity of being heard, pass such order in relation thereto as may be considered appropriate in the facts and circumstances of the case.

Schedule: 2, Table: 1 – Data to be Submitted Along with the Application to Conduct Clinical Trials or Import or Manufacturing of New Drugs for Sale in the Country

1. Introduction: A brief description of the drug and the therapeutic class to which it belongs

2. Chemical and pharmaceutical information

2.1.  Information on active ingredients- Drug information (Generic Name, Chemical Name or International Nonproprietary Names (INN))

2.2.  Physicochemical data–

(a) Chemical name and Structure Empirical formula Molecular weight (b) Physical properties

• Description
• Solubility
• Rotation
• Partition coefficient
• Dissociation constant.

2.3. Analytical data

• Elemental analysis
• Mass spectrum
• NMR spectra
• IR spectra
• UV spectra
• Polymorphic identification.

2.4.  Complete monograph specification including

• Identification
• Identity or quantification of impurities
• Enantiomeric purity

2.5. Validations

• Assay method
• Impurity estimation method
• Residual solvent/other volatile impurities (OVI) estimation method.

2.6. Stability studies

• Final release specification
• Reference standard characterization
• Material safety data sheet.

2.7.  Data on the formulation

• Dosage form
• Composition
• Master manufacturing formula
• Details of the formulation (including inactive ingredients)
• In-process quality control check
• Finished product specification
• Excipient compatibility study
• Validation of the analytical method
• Comparative evaluation with international brand or approved Indian brands, if applicable.
• Pack presentation
• Dissolution assay
• Impurities
• Content uniformity pH
• Force degradation study
• Stability evaluation in market intended pack at proposed storage   conditions
• Packing specifications
• Process validation

When the application is for clinical trials only, the international nonproprietary name (INN) or generic name, drug category, dosage form and data supporting stability in the intended container-closure system for the duration of the clinical trial

3.1. Summary

3.2. Specific pharmacological actions

3.3. General pharmacological actions

3.4. Follow-up and supplemental safety pharmacology studies

3.5. Pharmacokinetics: absorption, distribution; metabolism; excretion

4. Animal toxicology (for details refer clause 2 of this Schedule)

4.1. General aspects

4.2. Systemic toxicity studies

4.3. Male fertility study

4.4. Female reproduction and developmental toxicity studies

4.5. Local toxicity

4.6. Allergenicity or Hypersensitivity

4.7. Genotoxicity

4.8. Carcinogenicity

Note: Where the data on animal toxicity as per the specifications of clause 2has been submitted and the same has been considered by the regulatory authority of the country which had earlier approved the drug, the animal toxicity studies shall not be required to be conducted in India except in cases where there are specific concerns recorded in writing.

5. Human or Clinical pharmacology (Phase I)

5.1. Summary

5.2. Specific Pharmacological effects

5.3. General Pharmacological effects

5.4. Pharmacokinetics, absorption, distribution, metabolism, excretion

5.5. Pharmacodynamics / early measurement of drug activity

6. Therapeutic exploratory trials (Phase II)

6.1. Summary

6.2.  Study report as given in Table 6 of Third Schedule

7. Therapeutic confirmatory trials (Phase III)  

7.1. Summary

7.2. Individual study reports with listing of sites and investigators.

8. Special studies

8.1. Summary

8.2. Bio-availability or Bio-equivalence.

8.3. Other studies e.g. geriatrics, pediatrics, pregnant or nursing women

9. Regulatory status in other countries

9.1. Countries where the drug is

(a) Marketed

(b) Approved

(c) Approved as Investigational New Drug (IND)

(d) Withdrawn, if any, with reasons

9.2. Restrictions on use, if any, in countries where marketed/approved

9.3. Free sale certificate or certificate of analysis, as appropriate.

10. Prescribing information

10.1. Proposed full prescribing information

10.2. Drafts of labels and cartons

11. Samples and Testing protocol/s

11.1. Samples of pure drug substance and finished product (an equivalent of 50 clinical doses, or a greater number of clinical doses if prescribed by the Central Licensing Authority), with testing protocols, full impurity profile and release specifications.

12. New chemical entity and Global clinical trial:

12.1Assessment of risk versus benefit to the patients

12.2Innovation vis-à-vis existing therapeutic option

12.3 Unmet medical need in the country.

13. Copy of license to manufacture any drug for sale granted by State Licensing Authority (in case the application is for manufacture for sale of new drug)

Schedule XIII: New Drugs and Clinical Trial Application Related Forms

Read More :

Medical device clinical trials & regulations in India

Reference –

1. file:///C:/Users/HP/Downloads/NewDrugs_CTRules_2019%20-%20Copy.pdf