Compliance Requirement under the Rules

1. Conduct of BA/BE Studies Requires CLA Permission and Protocol Approval by Ethics Committee (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:-

Work of every BA/BE study centre shall be overseen by Ethics Committee registered under rule 8, before initiation and throughout the duration of conduct of such study.

No BA/BE study on new or investigational drugs may be conducted in humans without compliance with the Act and Rules, prior approval of the CLA, and protocol approval by a registered Ethics Committee.

For export-only, single-dose, two-period, two-sequence, two-treatment oral BA/BE studies in healthy adults (excluding cytotoxic, hormone, narcotic, psychotropic, NTI or highly variable drugs) already approved in India, USA, EU, Japan, Australia, Canada or UK, studies may proceed on prior intimation (Form CT-05) and CLA acknowledgement, subject to:

(i) EC approval under Rule 8;

(ii) separate EC records subject to CLA review;

(iii) minimum sample size of 18.

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

The Central Licensing Authority shall scrutinize Form CT-05 and grant or reject permission in Form CT-07, or seek deficiency clarification, within 90 working days. If no communication is issued within 90 working days, permission for BA/BE study shall be deemed granted and legally valid.

Any person or organisation intending to conduct a BA/BE study of a new or investigational drug in humans must obtain permission from the Central Licensing Authority (CLA) by applying in Form CT-05. For studies covered under Rule 31(2) proviso, online prior intimation in Form CT-05 is sufficient.

The application must be accompanied by the prescribed fee (Sixth Schedule) and required documents (Fourth Schedule, Table 2). No fee is payable by institutions wholly or partly funded by the Central or State Government.

Rule 36:-

(1) The permission or the acknowledgment of prior intimation to conduct bioavailability or bioequivalence study granted in Form CT-07 or the acknowledgment of prior intimation under the proviso of sub-rule (2) of rule 31, as the case may be shall remain valid for a period of one year from the date of its issue, unless suspended or cancelled by the Central Licencing Authority.

(2) In exceptional circumstances, where the Central Licencing Authority is satisfied about the necessity for an extension beyond one year, the said authority may, on the request of the applicant made in writing, extend the period of permission granted or the acknowledgment of prior intimation under the proviso to sub-rule (2) of rule 31 for a further period of one year

3. 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.

4. Conditions of permission/prior permission for conduct of bioavailability or bioequivalence study(Rule 35)

The permission granted by the Central Licencing Authority to conduct bioavailability or bioequivalence study under rule 34 or the acknowledgment of prior intimation under the proviso of sub-rule (2) of rule 31, as the case may be shall be subject to following conditions, namely:-

(i) bioavailability or bioequivalence study at each site shall be initiated after approval of bioavailability or bioequivalence study protocol, as the case may be, and other related documents by the Ethics Committee of that site, registered under rule 8;

(ii) where a bioavailability or bioequivalence study centre does not have its own Ethics Committee, bioavailability or bioequivalence study at that site may be initiated after obtaining approval of the protocol from the Ethics Committee registered under rule 8:If the approving Ethics Committee shall in such case be responsible for the study at the centre:If further that both the approving Ethics Committee and the centre, shall be located within the same city or within a radius of fifty kms of the bioavailability or bioequivalence study centre;

(iii) in case an Ethics Committee of a bioavailability or bioequivalence study centre rejects the approval of the protocol, the details of the same should be submitted to the Central Licensing Authority prior to seeking approval of another Ethics Committee for the protocol for conduct of the bioavailability or bioequivalence study at the same site;

(iv) the Central Licencing Authority shall be informed about the approval granted by the registered Ethics Committee within a period of 15 working days of the grant of such approval;

(v) bioavailability or bioequivalence study of new drug or investigational new drug shall be conducted only in the bioavailability or bioequivalence study centre registered with the Central Licencing Authority under rule 47;

(vi) bioavailability or bioequivalence study of investigational new drug 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 study

(vii) Studies shall follow the approved protocol, GCP, and applicable regulations

(viii) Study termination reasons shall be reported to the Central Licensing Authority within 30 working days

(ix) Serious adverse events shall be analysed and reported to the Central Licensing Authority, Ethics Committee, and study site within 14 days

(x) Study-related injury shall be provided medical care and compensation as per Chapter VI and reported to the Central Licensing Authority within 30 days

(xi) Study-related death or permanent disability shall be compensated and reported to the Central Licensing Authority within 30 days

(xii) Sponsor and study sites shall permit inspection, search, and seizure by the Central Licensing Authority

(xiii) first subject must be enrolled within one year from the date of grant of permission or the acknowledgment of prior intimation under the proviso of sub-rule (2) of rule 31, as the case may be; otherwise, prior approval from CLA is required to initiate the study.

5. Appeal against Suspension / Cancellation of Registration/acknowledgement under Form CT-07(Rule 38)

In case of non-compliance, the Central Licensing Authority may, after notice and hearing, take action by written order. Any aggrieved party may appeal to the Central Government within 60 days, which shall decide the appeal after due hearing
In case of non-compliance, the Central Licensing Authority may, after notice and hearing, take action by written order. Any aggrieved party may appeal to the Central Government within 60 days, which shall decide the appeal after due hearing.

6. 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.”

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. 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.

14. 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.

15. 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).

16. 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.

17. 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.

18. 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.”