One FDC Declared Rational, 6 Require Phase IV Data: CDSCO Issues Fresh Guidelines
New Delhi: The Central Drugs Standard Control Organisation (CDSCO), under the Ministry of Health and Family Welfare, has issued a detailed directive outlining the procedures for State Licensing Authorities (SLAs) to grant product licenses for specific Fixed Dose Combinations (FDCs). The latest guidance recommends data generation for six FDCs and deems one combination rational, subject to specific conditions.
The apex drug regulatory body has issued a pathway for the grant of the product license by State Licensing Authorities (SLAs) for the FDC of chloroxylenol 4.80% w/v + terpinol 9.0% v/v + absolute alcohol 13.1% v/v (denatured) gel.
Furthermore, the Central Drugs Standard Control Organization has also produced pathways for clearance of subsequent applications required for generating data with respect to 6 FDCs.
The list of 6 FDCs that need generating data includes Heparin Sodium IP 50 IU + Benzyl Nicotinate 2mg + Sorbic Acid 1.97 mg (Preservative) per gm ointment, Ketoconazole IP 2.00 % w/v + Shale Oil Sulfonate (Ichthyol pale) 0.50%w/v + D-PanthenoI BP 0.2%w/v + Aloevera 1% w/v Shampoo, Propranolol hydrochloride 20mg/20mg/40mg + Etizolam 0.25mg/0.5mg/0.5mg Tablets, Glucosamine sulphate (added as glucosamine sulphate sodium chloride) 500mg + Chondroitin Sulphate 400mg (added as chondroitin sulphate sodium) film coated tablets, Taurine 500mg + N-Acetylcysteine 150mg film-coated tablets, Flupirtine maleate + Thiocolchicoside IP (100mg + 4mg and 100mg + 8mg) film-coated tablets.
In addition, the committee declared the FDC of chloroxylenol 4.80% w/v + terpinol 9.0% v/v + absolute alcohol 13.1% v/v (denatured) gel as rational with the following specific condition: “The firm should clearly mention do's and don'ts for use of the formulation in the package insert and accordingly the revised package insert shall be submitted."
This is with reference to this office letter dated 15.01.2013, whereby all the State/UT Drugs Controllers were requested to ask the concerned manufacturers in their state to prove the safety and efficacy of FDCs within 18 months that were permitted by State Licensing Authorities without due approval from the office of DCG(I).
The Prof. Kokate Committee submitted its 2nd assessment report to the Central Government on the remaining FDCs that could not be assessed in the first lot. Based on the recommendations of the Kokate Committee, the FDCs declared as irrational were referred to the Sub-Committee of DTAB through the DGHS, Chairperson DTAB vide order no. 18-04/2019-DC dated 12.04.2019.
The DTAB Sub-Committee under the Chairmanship of Dr. Nilima Kshirsagar submitted its report on 28.12.2021 after holding a series of meetings as well as by providing hearing to the stakeholders, which was placed before DTAB in the 88th meeting held on 26.09.2022, wherein the Committee after detailed deliberation, considered following 01 FDC as rational with certain conditions:
Sr. No. | Name of FDC as per the public notice | Recommendations |
1. | Chlorxylenol 4.80 % w/v +Terpinol 9.0% v/v + Absolute Alcohol 13.1% v/v (Denatured) Gel | After detailed deliberation, the Committee declared the FDC of Chlorxylenol 4.80 % w/v +TerpinoI 9.0% v/v + Absolute Alcohol 13.1% v/v (Denatured) Gel as rational with the following specific condition that : “Firm should clearly mention do's and dont's for use of the formulation in the package insert and accordingly the revised package insert shall be submitted.” |
Accordingly, with the approval of the Ministry of Health and Family Welfare, the expert committee has decided to follow the following pathway for grant of a Chloroxylenol 4.80% w/v + Terpinol 9.0% v/v + Absolute Alcohol 13.1% v/v (Denatured) Gel license by State Licensing Authoritys (SLAs) for the above-mentioned FDC:
1. Applicants shall submit the requisite fees preferably through Bharatkosh for FDC to CDSCO as specified in Sixth Schedule of New Drugs and Clinical Trial Rules, 2019.2. The applicant shall submit application to the concerned State Licensing Authorities (SLA) as per the provisions of Drugs and Cosmetics Rules 1945 for grant of product manufacturing license giving the details of FDC, stability studies data (06 months accelerated), Test Specification of the FDC along with Method of Analysis as well as label and other documents as required for grant of product license under Drugs and Cosmetics Rules.3 State Licensing Authority (SLA) shall grant the product license of such FDC without NOC from DCG (I), if conditions of license under the Drugs and Cosmetics Rules, which need to be verified by SLA, are found to have been fulfilled. The SLAs shall verified the quality of such FDC of each applicant/manufacturer, before grant of license.4. Every manufacturer permitted to manufacture said FDC shall submit the periodic safety update reports (PSURs) as per New Drugs and Clinical Trial Rules, 2019 to the Central Licensing Authority as defined in Rule ‘3' i.e. DCG(I). Failure to submit the PSURs shall be considered as contravention of these Rules.5. Manufacturers shall comply with the recommendation of the expert committee w.r.t. revision of the prescribing information/label.
In view of above, all State/UT Drugs Controllers/All Zonal/Sub Zonal offices of CDSCO are requested to ask the concerned stakeholders to follow the above procedure for obtaining the manufacturing license with respect to above FDC declared as rational.
Following a series of meetings and a meeting on September 26, 2022, the DTAB Sub-Committee, chaired by Dr. Nilima Kshirsagar, gave its report on December 28, 2021. Following a thorough discussion, the committee suggested that data be generated for the following 06 FDCs:
S.No. | Name of FDC, Product and Dosage form | Recommendations of Expert Committee |
1. | Heparin Sodium IP 50 IU + Benzyl Nicotinate 2mg + Sorbic Acid 1.97 mg (Preservative) per gm ointment | To conduct Phase-IV Clinical trial to show efficacy and safety of the product, with efficacy as the primary objective in statistically significant number of patients. Protocol should be approved by SEC and study should be completed within one year |
2. | Ketoconazole IP 2.00 %w/v + Shale Oil Sulfonate (Ichthyol pale) 0.50%w/v + D-PanthenoI BP 0.2%w/v + Aloevera 1% w/v Shampoo | To conduct double blind clinical trial comparing Ketoconazole alone with this FDC to show superiority of FDC over Ketoconazole alone for treatment of condition mentioned in the indication and thus providing therapeutic justification for the ingredients contained in this FDC. Protocol should be approved by the SEC and study should be completed within one year. |
3. | Propranolol hydrochloride 20mg/20mg/40mg + Etizolam 0.25mg/0.5mg/0.Smg Tablets | To conduct Phase IV Clinical Trial to evaluate efficacy and safety of the FDC in comparison with Etizolam, with efficacy as the primary objective in statistically significant number of patients for the indication as approved by SEC. The Clinical Trial protocol must receive approval of the SEC and the study must be completed within one year. | |
4. | Glucosamine sulphate (added as glucosamine sulphate sodium chloride) 500mg + Chondroitin Sulphate 400mg (added as chondroitin sulphate sodium) film coated tablets | To conduct non-inferiority, double blind, comparative Phase IV Study wherein, efficacy of this FDC (Glucosamine Sulphate potassium chloride 500mg +Chondroitin Sulphate 400mg gelatin coated tablet) given three times a day should be compared with FDC of Glucosamine Sulphate potassium chloride 750mg + Chondroitin Sulphate 600mg gelatin coated tablet given twice a day. The Protocol should be approved by the SEC and study should be completed within one year | |
5. | Taurine 500mg + N- Acetylcysteine 150mg film coated tablets | After detailed deliberation, the Committee recommended that firms in the current scenario while continuing the manufacturing and marketing are required to conduct a well-designed structured Phase IV Clinical trial in adequate sample size keeping efficacv as orimarv obiective and studv should be completed within one year. | |
6. | Flupirtine maleate + Thiocolchicoside IP (100mg +4mg & 100mg +8mg) film coated tablets | To conduct Active PMS Study on this FDC. The study should be completed within one year. |
Accordingly, the CDSCO has decided to proceed with the following procedure for approving such follow-up applications:
1. Documents required in case of manufacturers already holding licenses from State Licensing Authority (SLA) before 01.10.2012 for the proposed FDCs shall at least contains: -
a) Form CT-21 (duly filled, signed and stamped)
b) Fees as specified in sixth schedule of New Drugs and Clinical Trials Rules 2019 through Bharatkosh Name and composition of the FDC
c) Product Permission issued by SLA
d) Copy of Manufacturing license in Form 25/28
e) Phase IV trial protocol / commitment for conducting Active Post Marketing Surveillance study protocol, as the case may be.
2. Documents required in case of new manufacturers for the proposed FDCs shall at least contains: -
a) Form CT-21 (duly filled, signed and stamped)
b) Fees as specified in sixth schedule of New Drugs and Clinical Rules 2019 through Bharatkosh.
c) Name and composition of the FDC
d) Product Permission issued by SLA in Form 29
e) Copy of Manufacturing license in Form 25/28
f) Stability studies data (06 months accelerated)
g) Test Specifications of the FDC along with Method of Analysis
h) Phase IV trial protocol/commitment for conducting an active post-marketing surveillance study protocol, as the case may be.
3. All the manufacturers who are already holding licenses from State Licensing Authorities for such FDCs before 01.10.2012 and did not apply to DCG(I) are required to submit their applications to this Directorate at the earliest but not later than 6 months, failing which their applications will not be considered and their licenses will be considered as without legal validity.
In view of the above, the CDSCO has stated that all concerned stakeholders are required to follow the above procedure for clearance of such cases.
To view the official notice, click the link below:
https://medicaldialogues.in/pdf_upload/pathwayfdc-283806.pdf
