IMPORT OR MANUFACTURE OF NEW DRUG FOR CLINICAL TRIALS OR MARKETING

122-A. Application for permission to import New Drug

(1) (a) No new drug shall be imported, except under, and in accordance with, the permission granted by the Licensing Authority as defined in clause (b) of rule 21;

(b) An application for grant of permission to import a new drug shall be made in Form 44 to the Licensing Authority, accompanied by a fee of fifty thousand rupees:

Provided further that where a subsequent application by the same applicant for that drug, whether in modified dosage form or with new claims, is made, the fee to accompany such application shall be fifteen thousand rupees:

Provided further that any application received after one year of the grant of approval for the import and sale of new drug, shall be accompanied by a fee of fifteen thousand rupees and such information and data as required by Appendix 1 or Appendix 1 A of Schedule Y, as the case may be.” ;

(2) The importer of a new drug when applying for permission under sub-rule (1), shall submit data as given in Appendix 1 to Schedule Y including the results of local clinical trials carried out in accordance with the guidelines specified in that Schedule and submit the report of such clinical trials in the format given in Appendix II to the said Schedule:

Provided that the requirement of submitting the results of local clinical trials may not be necessary if the drug is of such a nature that the licensing authority may, in public interest decide to grant such permission on the basis of data available from other countries:

Provided further that the submission of requirements relating to Animal toxicology, Reproduction studies, Teratogenic studies, Perinatal studies, Mutagenicity and Carcinogenicity may be modified or relaxed in case of new drugs approved and marketed for several years in other countries if he is satisfied that there is adequate published evidence regarding the safety of the drug, subject to the other provisions of these rules.

(3) The Licensing Authority, after being satisfied that the drug if permitted to be imported as raw material (bulk drug substance) or as finished formulation shall be effective and safe for use in the country, may issue an import permission in Form 45 and/or Form 45 A, subject to the conditions stated therein:

Provided that the Licensing Authority shall, where the data provided or generated on the drug is inadequate, intimate the applicant in writing, and the conditions, which shall be satisfied before permission, could be considered.”

122-B. Application for approval to manufacture New Drug other than the drugs classifiable under Schedules C and C(1)

(1) (a) No new drug shall be manufactured for sale unless it is approved by the Licensing Authority as defined in clause (b) of rule 21.

(b) An application for grant of approval to manufacture the new drug and its formulations shall be made in Form 44 to the Licensing Authority as defined in clause (b) of rule 21 and shall be accompanied by a fee of fifty thousand rupees:

Provided that where the application is for permission to import a new drug (bulk drug substance) and grant of approval to manufacture its formulation/s, the fee to accompany such application shall be fifty thousand rupees only.

Provided further that where a subsequent application by the same applicant for that drug, whether in modified dosage form or with new claims, is made, the fee to accompany such subsequent application shall be fifteen thousand rupees:

Provided further also that any application received after one year of the grant of approval for the manufacture for sale of the new drug, shall be accompanied by a fee of fifteen thousand rupees and such information and data as required by Appendix I or Appendix I A of Schedule Y, as the case may be.”;

(2) The manufacturer of a new drug under sub-rule (1) when applying for approval to the licensing authority mentioned in the said sub-rule, shall submit data as given in Appendix I to Schedule Y including the results of clinical trials carried out in the country in accordance with the guidelines specified in Schedule Y and submit the report of such clinical trials in the format given in Appendix II to the said Schedule.

(2A) The Licensing Authority as defined in clause (b) of rule 21 after being satisfied that the drug if approved to be manufactured as raw material (bulk drug substance) or as finished formulation shall be effective and safe for use in the country, shall issue approval in Form 46 and/or Form 46 A, as the case may be, subject to the conditions stated therein:

(3) When applying for approval to manufacture of a new drug under sub-rule (1) or its preparations to the State licensing authority, an applicant shall produce along with his application, evidence that the drug for the manufacture of which application is made has already been approved by the licensing authority mentioned in Rule 21:

Provided that the requirement of submitting the result of local clinical trials may not be necessary if the drug is of such a nature that the licensing authority may, in public interest decide to grant such permission on the basis of data available from other countries:

Rule 122C has been omitted.

122D. Permission to import or manufacture fixed dose combination

(1) An application for permission to import or manufacture fixed dose combination of two or more drugs as defined in clause (c) of rule 122 E shall be made to the Licensing Authority as defined in clause (b) of rule 21 in Form 44, accompanied by a fee of fifteen thousand rupees and shall be accompanied by such information and data as is required in Appendix VI of Schedule Y.

(2) The Licensing Authority after being satisfied that the fixed dose combination, if approved to be imported or manufactured as finished formulation shall be effective and safe for use in the country, shall issue permission in Form 45 or Form 46, as the case may be, subject to the conditions stated therein:

Provided that the Licensing Authority shall where the data provided or generated on the fixed dose combination is inadequate, intimate the applicant in writing, and the conditions which shall be satisfied before grant of approval/permission could be considered:

122DA. – Application for permission to conduct clinical trials for New Drug/Investigational New Drug.-

(1) No clinical trial for a new drug, whether for clinical investigation or any clinical experiment by any Institution, shall be conducted except under, and in accordance with, the permission, in writing, of the Licensing Authority defined in clause (b) of rule 21.

(2) An application for grant of permission to conduct,-

(a) human clinical trials (Phase-I) on a new drug shall be made to the Licensing Authority in Form 44 accompanied by a fee of fifty thousand rupees and such information and data as required under Schedule Y;

(b) exploratory clinical trials (Phase-II) on a new drug shall be made on the basis of data emerging from Phase-I trial, accompanied by a fee of twenty-five thousand rupees;

(c) confirmatory clinical trials (Phase-III) on a new drug shall be made on the basis of the data emerging from Phase-II and where necessary, data emerging from Phase-I also, and shall be accompanied by a fee of twenty-five thousand rupees:

Provided that no separate fee shall be required to be paid along with application for import/manufacture of a new drug based on successful completion of phases of clinical trials by the applicant.

Provided further that no fee shall be required to be paid alongwith the application by Central Government or State Government Institutes involved in clinical research for conducting trials for academic or research purposes.

(3) The Licensing Authority after being satisfied with the clinical trials, shall grant permission in Form 45 or Form 45A or Form 46 or Form 46-A, as the case may be, subject to the conditions stated therein:

Provided that the Licensing Authority shall, where the data provided on the clinical trials is inadequate, intimate the applicant in writing, within six months, from the date of such intimation or such extended period, not exceeding a further period of six months, as the Licensing Authority may, for reasons to be recorded, in writing, permit, intimating the conditions which shall be satisfied before permission could be considered:

Explanation – For the purpose of these rules Investigational New Drug means a new chemical entity or a product having therapeutic indication but which have never been earlier tested on human being.

122DB, Suspension or cancellation of Permission / Approval.

If the importer or manufacturer under this Part fails to comply with any of the conditions of the permission or approval, the Licensing Authority may, after giving an opportunity to show cause why such an order should not be passed, by an order in writing stating the reasons therefor, suspend or cancel it.

122DC. Appeal.

Any person aggrieved by an order passed by the Licensing Authority under this Part, may within sixty days from the date of such order, appeal to the Central Government, and the Central Government may after such enquiry into the matter as is considered necessary, may pass such order in relation thereto as it thinks fit.”

122-E. Definition of new drug

For the purpose of this Part, ‘new drug’ shall mean and include-

(a) a new substance of chemical, biological or biotechnological origin; in bulk or prepared dosage form; used for prevention, diagnosis, or treatment of disease in man or animal; which, except during local clinical trials, has not been used in the country to any significant extent; and which, except during local clinical trials, has not been recognized in the country as effective and safe for the proposed claim;

(b) a drug already approved by the licensing authority mentioned in Rule 21 for certain claims, which is now proposed to be marketed with modified or new claims, namely, indications, dosage forms (including sustained release dosage form) and route of administration;

(c) a fixed dose combination of two or more drugs, individually approved earlier for certain claims, which are now proposed to be combined for the first time in a fixed ratio, or if the ratio of ingredients in an already marketed combination is proposed to be changed, with certain claims, viz. indications, dosage form (including sustained release dosage form) and route of administration. [See items (b) and (c) of Appendix VI to Schedule Y.]

Explanation: For the purpose of this rule-

(i) all vaccines shall be new drugs unless certified otherwise by the licensing authority under Rule 21;

(ii) a new drug shall continue to be considered as new drug for a period of four years from the date of its first approval or its inclusion in the Indian Pharmacopoeia, whichever is earlier.

‘Form 44

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

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

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I/we ________________________________________________________ of M/s. _________________________________________________ (address) hereby apply for grant of permission for import of and/or clinical trial or for approval to manufacture a new drug or fixed dose combination or subsequent permission for already approved new drug. The necessary information / data is given below:

1. Particulars of New Drug:

(1) Name of the drug:

(2) Dosage Form:

(3) Composition of the formulation:

(4) Test specification:

(i) active ingredients:

(ii) inactive ingredients:

(5) Pharmacological classification of the drug:

(6) Indications for which proposed to be used:

(7) Manufacturer of the raw material (bulk drug substances):

(8) Patent status of the drug:

2. Data submitted along with the application (as per Schedule Y with indexing and page nos.)

A. Permission to market a new drug :-

(1) Chemical and Pharmaceutical information

(2) Animal Pharmacology

(3) Animal Toxicology

(4) Human/Clinical Pharmacology (Phase I)

(5) Exploratory Clinical Trials (Phase II)

(6) Confirmatory Clinical Trials (Phase III) (including published review articles)

(7) Bio-availability, dissolution and stability study Data

(8) Regulatory status in other countries

(9) Marketing information:

(a) Proposed product monograph

(b) Drafts of labels and cartons

(10) Application for test license

B. Subsequent approval / permission for manufacture of already approved new drug:

(a) Formulation:

(1) Bio-availability/ bio-equivalence protocol

(2) Name of the investigator/center

(3) Source of raw material (bulk drug substances) and stability study data.

(b) Raw material (bulk drug substances)

(1) Manufacturing method

(2) Quality control parameters and/or analytical specification, stability report.

(3) Animal toxicity data

C. Approval / Permission for fixed dose combination:

(1) Therapeutic Justification

(authentic literature in pre-reviewed journals/text books)

(2) Data on pharmacokinetics / pharmacodynamics combination

(3) Any other data generated by the applicant on the safety and efficacy of the combination.

D. Subsequent Approval or approval for new indication – new dosage form:

(1) Number and date of Approval/permission already granted.

(2) Therapeutic Justification for new claim / modified dosage form.

(3) Data generated on safety, efficacy and quality parameters.

A total fee of rupees __________________________________________ (in words). ____________________________) has been credited to the Government under the Head of Account ________________________ (Photocopy of receipt is enclosed).

Date:____________ Signature:____________

Designation:____________

Note- Delete, whichever is not applicable.

FORM 45

(See rules 122 A, 122 D and 122 DA)

Permission to import Finished Formulation of a New Drug

Number of the permission and date of issue _______________________M/s_____________________________ of ______________________________________________________ (address) is hereby permitted to import the following new drug formulation under rule 122 A/ 122 D/ 122 DA of the Drugs and Cosmetics Rules 1945.

(1) Name of the New Drug:

(2) Dosage form:

(3) Composition:

(4) Indications:

Date:...................... Signature:____________

Name and Designation of the Licensing Authority

Conditions for Grant of Approval / Permission

1. The formulation shall conform to the specifications approved by the Licensing Authority.

2. The proper name of the drug shall be printed or written in indelible ink and shall appear in a more conspicuous manner than the trade name, if any, which shall be shown immediately after or under the proper name on the label of the innermost container of the drug or every other covering in which the container is packed.

3. The label of the innermost container of the drug and every other covering in which the container is packed shall bear a conspicuous red vertical line on the left side running throughout the body of the label which shall not be less than 1 mm in width and without disturbing the other conditions printed on the label to depict it is prescription drug.

4. The label on the immediate container of the drug as well as the packing in which the container is enclosed should contain the following warning :

“WARNING: To be sold by retail on the prescription of a ________ only.”

5. Post marketing surveillance study shall be conducted during initial period of two years of marketing of the new drug formulation, after getting the protocol and the names of the investigator duly approved by the Licensing Authority.

6. All reported adverse reactions related to the drug shall be intimated to the Drugs Controller, India and Licensing Authority and regulatory action resulting from their review should be complied with.

7. No claims except those mentioned above shall be made for the drug without the prior approval of the Licensing Authority.

8. Specimen of the carton, labels, package insert that will be adopted for marketing the drug in the country shall be got approved from the Licensing Authority before the drug is marketed.

9. Each consignment of imported drug shall be accompanied by a test/analysis report.

FORM 45 A

(See rules 122 A and 122 DA)

Permission to import raw material (new bulk drug substance)

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Number of the permission and date of issue _____________________________M/s. __________________________________________________________ of ______________________________________________________ (address) is hereby permitted to import the following raw material (new bulk drug substances) under rule 122 A / 122 DA of the Drugs and Cosmetics Rules, 1945, namely:-

Name of the raw material (new bulk drug substances):

(1) ___________________

(2) ___________________

(3) ___________________

Date:____________ Signature:____________

Name and Designation of the Licensing Authority

Conditions for Grant of Approval / Permission

(1) The raw material (new bulk drug substance) shall conform to the test specifications as approved by the Licensing Authority.

(2) For manufacture of raw material (new bulk drug substance) or its formulations in the country, separate approval under 122-B shall be obtained from the Licensing Authority.

(3) The permission to import shall not be used to convey or imply that the raw material (new bulk drug) is categorized as “life saving or essential drug.”

FORM 46

(See rules 122 B, 122 D and 122 DA)

Permission/Approval for manufacture of a new drug formulation

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Number of permission and date of issue _______________________________ M/s. _________________________________________________________ of ______________________________________________________ (address) is hereby granted Permission/Approval to manufacture following new drug formulation under rule 122 B / 122 D / 122 DA of the Drugs and Cosmetics Rules, 1945, namely:-

(1) Name of the formulation:

(2) Dosage form:

(3) Composition:

(4) Indications:

Date:...................... Signature:____________

Name and designation of Licensing Authority

Conditions for Grant of Approval / Permission

1. The formulation shall conform to the specifications approved by the Licensing Authority.

4. The label on the immediate container of the drug as well as the packing in which the container is enclosed should contain the following warning :

“WARNING: To be sold by retail on the prescription of a ________ only.”

7. No claims except those mentioned above shall be made for the drug without the prior approval of the Licensing Authority.

8. Specimen of the carton, labels, package insert that will be adopted for marketing the drug in the country, shall be got approved from the Licensing Authority before the drug is marketed.

FORM 46 A

(See rules 122 B and 122 DA)

Number of the permission and date of issue _____________________________

Permission / Approval for manufacture of raw material (new bulk drug substance)

M/s. __________________________________________________________ of ______________________________________________________ (address) is hereby granted Permission / Approval to manufacture the following raw material (new bulk drug substance) under rule 122 B / 122 DA of the Drugs and Cosmetics Rules, 1945:

Name of the raw material (new bulk drug substance):

(1) ___________________

(2) ___________________

(3) ___________________

Date:____________ Signature:____________

Name and Designation of the Licensing Authority …………………

Conditions for Grant of Approval / Permission

1. The raw material (new bulk drug substance) shall conform to the specifications approved by the Licensing Authority.

2. The raw material (new bulk drug substance) can be sold to only those manufacturers who have permission, in writing, from Licensing Authority, either to use the drug for development purpose/clinical trial/bio-equivalence study or to manufacture the formulation.

3. For manufacture of the formulation in the country, separate approval under rule 122-B shall be obtained from the Licensing Authority.