Compliance Requirement under the Rules

1. Bioavailability or bioequivalence study of new drug or investigational new drug (Rule 31, Rule 32)

No bioavailability or bioequivalence study on new or investigational drugs may be conducted in humans without compliance with the Act & rules. Such studies require approval from the CLA & an Ethics Committee registered under Rule 8. All participants must follow the guidelines in the First Schedule.

Rule 32:-

The work of every bioavailability or bioequivalence study centre shall be overseen by an Ethics Committee registered under rule 8, before initiation and throughout the duration of the conduct of such study.

3. Form CT-07: Permission to Conduct Bio Availability or Bioequivalence Study Of New Drug (Rule 34 (1), (2), (2A))

Central Licensing Authority shall review Form CT-05 applications and, within 90 working days, may grant permission in Form CT-07, seek request rectification of deficiencies, or reject the application with reasons.  If no response is given within 90 days, approval is deemed granted and legally valid.

(1) Any person or institution or organisation which intends to conduct bioavailability or bioequivalence study of a new drug or an investigational new drug in human subjects shall obtain permission for conducting bioavailability or bioequivalence study from the Central Licencing Authority by making an application in Form CT-05.

(2) An application for grant of permission to conduct bioavailability or bioequivalence study of any new drug or investigational new drug shall be accompanied by a fee as specified in Sixth Schedule and such other information and documents as specified in the Table 2 of the Fourth Schedule.

Further that no fee shall be payable for conducting a bioavailability or bioequivalence study by an institution or organisation owned or funded wholly and partially by the Central Government or a State Government.

4. Rectification and Appeal of Clinical Trial Application Decisions (Rule 34 (3), (4))

(1) The applicant, after being informed, regarding the deficiencies in application by the Central Licencing Authority, may:-

(i) rectify the deficiencies within a period specified by the Central Licencing Authority;

(ii) If the applicant rectifies the deficiency and submits the required documents, the Central

Licensing Authority will review the application and decide within 90 days, granting permission or rejecting the application.

If rejected, the applicant may request reconsideration by the Central Licensing Authority within 60 working days of the rejection, upon payment of the prescribed fee specified in the Sixth Schedule. and submission of required documents.

(2) An aggrieved applicant may appeal a decision of the Central Licensing Authority under sub-rule (1) or (3) to the Ministry of Health and Family Welfare within 45 days of receiving the decision. The Government shall, after due inquiry and a hearing, dispose of the appeal within 60 working days.

5. Conditions of permission for conduct of bioavailability or bioequivalence study (Rule 35)

Bioavailability or bioequivalence studies under Rule 34 need Ethics Committee approval (within 50 km), must be done at Central Licensing Authority-registered centres, reported to Central Licensing Authority, and Clinical Trial Registry of India-registered if involving investigational new drugs.

(i) Bioavailability or bioequivalence studies must follow the approved protocol, GCP guidelines, and regulatory provisions;

(ii) If a study is terminated, reasons must be submitted to the Central Licensing Authority (CLA) within 30 working days;

(iii) Serious adverse events must be analysed and reported to CLA, Ethics Committee Chairperson, and the study site within 14 days;

(iv) In case of injury during the study, full medical care and compensation must be provided per Chapter VI, with details reported to CLA within 30 days of receiving its order;

(v) In case of study-related death or permanent disability, compensation must be provided and reported to CLA within 30 days;

(vi) Sponsor and study site premises must be open for CLA inspections, including inspection, search, and seizure of records or materials;

(xiii) The first subject must be enrolled within one year of permission; otherwise, prior approval from CLA is required to initiate the study.

6. Suspension or cancellation of permission to conduct bioavailability or bioequivalence study (Rule 38)

On non-compliance by entities permission granted under rule 34 in Form CT-07, the Central Licensing Authority may take action after giving a chance to be heard.
Appeals against such orders can be made to the Central Government within 60 working days.

After consideration of the facts and reply given by the Ethics Committee, the Central Licencing Authority, may take one or more of the following actions, namely:-

(i) Issue warning in writing describing the deficiency or defect observed during inspection or otherwise, which may affect adversely the rights, or well- being of a subject enrolled in the study or the validity of bioavailability or bioequivalence study conducted;

(ii) Reject the results of bioavailability or bioequivalence study, as the case may be;

(iii) Suspend for such period as considered appropriate or cancel the permission granted under rule 34 in Form CT-07;

(iv) debar the investigator or the sponsor including his representatives, to conduct any bioavailability or bioequivalence study in future for such period as considered appropriate by the Central Licencing Authority.

7. Compensation for injury or death in clinical trial or bioavailability or bioequivalence study (Rule 39)

(1) In case of death during a clinical trial or bioavailability/bioequivalence study, the sponsor must provide financial compensation to the legal heir, as per Rule 42.

(2) For permanent disability or injury, the trial subject receives compensation from the sponsor as per Rule 42.

(3) Compensation is in addition to medical expenses.

(4) For non-permanent injury, compensation equals the subject’s loss of wages as per the Seventh Schedule.

(5) The sponsor or its representative must provide an undertaking along with the application for clinical trial permission to the Central Licensing Authority for compensation in case of injury or death.

(6) If the sponsor or its representative fails to provide compensation, the Central Licensing Authority may suspend, cancel, or restrict further trials or studies after a hearing.”

8. Medical Management in clinical trial or bioavailability and bioequivalence study (Rule 40)

(1) If a subject is injured during a clinical trial or bioavailability/bioequivalence study, the sponsor must provide free medical care until the injury is confirmed unrelated to the study or as advised by the investigator.

(2) The sponsor or authorized person is responsible for medical management.

(3) Failure to provide medical care may result in suspension, cancellation, or restriction of further studies by the Central Licensing Authority after a hearing.

9. Consideration of injury or death or permanent disability (Rule 41)

Any injury or death or permanent disability of a trial subject occurring during clinical trial or bioavailability or bioequivalence study due to any of the following reasons shall be considered as clinical trial or bioavailability or bioequivalence study related injury or death or permanent disability, namely:—

(a) Adverse effects of the investigational product;

(b) Protocol violation, scientific misconduct, or negligence by the sponsor or investigator causing a serious adverse event;

(c) Failure of the investigational product to provide the intended effect, where standard care or rescue medication was not provided as per protocol;

(d) Withholding of available standard care in a placebo-controlled trial, as per protocol;

(e) Adverse effects from protocol-mandated concomitant medication (excluding standard care);

(f) Adverse effects on a child in-utero due to parental participation;

(g) Study procedures causing a serious adverse event.

10. Reporting of Serious Adverse Events by Investigator (Rule 42 (1))

The investigator must report all serious adverse events within 24 hours of occurrence to the Central Licensing Authority, the sponsor or its representative, and the approving Ethics Committee.
Any delay must be justified to the Central Licensing Authority along with the event report.

Adverse event means:  any untoward medical occurrence (including a symptom or disease or an abnormal laboratory finding) during treatment with an investigational drug or a pharmaceutical product in a patient or a trial subject that does not necessarily have a relationship with the treatment being given.

11. Reporting of Serious Adverse Event in case of death by sponsor or representative and the investigator (Rule 42 (2) (ii))

The sponsor or representative and the investigator must submit analysed reports of any serious adverse event resulting in death to the Central Licensing Authority and the institution head within 14 days of becoming aware of the event.

12. Ethics Committee Reporting of Serious Adverse Event in case of Death and Compensation Recommendation (Rule 42 (2) (ix))

The Ethics Committee must submit its analysed report on a serious adverse event resulting in death, along with its opinion on financial compensation as per the Seventh Schedule, to the Central Licensing Authority within 30 days of receiving the investigator’s report.

13. Reporting of Serious Adverse Events by Investigator in case of disability or injury other than death (Rule 42 (3) (i))

The sponsor or its representative and the Investigator must analyse and submit reports of serious adverse events to the Central Licensing Authority, the Chairperson of the Ethics Committee, and the Head of the Institution where the clinical trial or bioavailability/bioequivalence study was conducted, within 14 days of serious adverse events reporting.

14. Ethics Committee Report on Serious Adverse Events and Compensation Opinion (Rule 42 (3) (ii))

Ethics Committee must submit its report on serious adverse events resulting in permanent disability or other injuries (excluding death), along with its opinion on financial compensation (if applicable, based on the Seventh Schedule formula), to the sponsor or representative within 30 days of receiving the serious adverse events report.

15. Compensation for Clinical Trial or Bioavailability or Bioequivalence Study- Related to disability or Injury (Rule 42 (3) (v))

The sponsor or its representative, authorized to conduct the clinical trial or bioavailability/bioequivalence study, shall pay compensation for any injury related to the study, as specified in the Central Licensing Authority’s order. Payment must be made within 30 days of receiving the order.

16. Form CT-09: Grant of registration of bioavailability and bioequivalence study centre (Rule 47 (1), (2), (3))

The Central Licensing Authority shall review Form CT-08 and grant or reject registration in Form CT-09 within 90 working days. Deficiencies must be rectified within a specified time.
Rejection can be appealed within 60 days with required documents and fees.

Rule 45:- A bioavailability or bioequivalence study centre must conduct studies of new or investigational drugs only after obtaining registration from the Central Licensing Authority. The application for registration should be made in Form CT-08, accompanied by the required fee (Sixth Schedule) and necessary documents (Fourth Schedule).

17. Appeal in case of rejection of an application (Rule 47 (4))

An applicant who is aggrieved by the decision of the Central Licencing Authority, may file an appeal within forty-five days from the date of receipt of such rejection before the Central Government and that Government may, after such enquiry and after giving an opportunity of being heard to the appellant, dispose of the appeal within a period of sixty days.

18. Conditions of registration of bioavailability and bioequivalence study centre (Rule 49)

Registration under Rule 47 (Form CT-09) mandates bioavailability or bioequivalence centres to maintain qualified personnel, secure Ethics Committee and Central Licensing Authority approvals, report serious adverse events within 14 days, and comply with Good Clinical Practices.

(i) Medical management and compensation for study-related injury shall be provided per Chapter VI; details must be reported to the Central Licensing Authority (CLA) within 30 days of order receipt.

(ii) In case of death, permanent disability, or other injury, compensation per Chapter VI must be paid and reported to the CLA within 30 days.

(iii) Any change in ownership or constitution of the study centre must be notified to the CLA in writing within 30 days.

(iv) Study data and records must be retained for 5 years post-study or 2 years post-expiry of the study drug batch, whichever is later.

(v) The centre must permit authorized CLA officers (with or without notice), possibly with State Authority officers, to inspect premises and study documents.

(vi) CLA may impose additional justified conditions on specific studies regarding design, objectives, population, eligibility, and conduct.

19. Suspension or cancellation of registration of bioavailability and bioequivalence study centre (Rule 51)

On non-compliance by entities permission granted under rule 47 in Form CT-09, the Central Licensing Authority may take action after giving a chance to be heard.
Appeals against such orders can be made to the Central Government within 60 working days.

After consideration of the facts and reply given by the Ethics Committee, the Central Licencing Authority, may take one or more of the following actions, namely:—

(a) issue warning in writing describing the deficiency or defect observed during inspection or otherwise, which may affect adversely the right or wellbeing of trial subject or the validity of any study conducted;

(b) reject the results of the study;

(c) suspend the conduct of a study;

(d) suspend for such period as considered appropriate or cancel the registration granted under rule 47 in Form CT-09; and

(e) debar the centre including its representatives to conduct any bioavailability and bioequivalence study in future for such period as considered appropriate by the Central Licencing Authority.”