Conditional Approval to 5 FDCs for Continued Manufacturing and Marketing: CDSCO
New Delhi: Through a recent notification, the Indian drug regulator, Central Drug Standard Control Organisation has notified the continued manufacturing and marketing of five pre-1988 permitted fixed Dose Combinations (FDCs) that were previously under review for prohibition.
These five FDCs include Paracetamol plus Phenylephrine Hydrochloride plus Caffeine Anhydrous tablets, Caffeine Anhydrous plus Paracetamol plus Phenylephrine Hydrochloride plus Chlorpheniramine Maleate, Paracetamol plus Propyphenazone plus Caffeine, Imipramine Hydrochloride plus Diazepam, and Chlorpheniramine Maleate plus Ammonium Chloride plus Sodium Citrate.
This recommendation of continued manufacturing and marketing of some FDCs came with the condition of generating safety and efficacy data by way of conducting a Phase IV Clinical Trial.
Major brands including D Cold Total, Saridon Triple Action, Piriton Syrup, and Dolo Cold are expected to benefit from this decision.
Furthermore, the notice defined the procedures for obtaining a product license from State licensing authorities for these FDCs.
This came in reference to the office letter dated 15-1-2013 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 which were permitted by State Licensing Authorities without due approval from the office of DCGI.
In continuation to Hon'ble Supreme Court orders dated 15.12.2017 and 14.02.2019, Accordingly, the Ministry of Health & Family Welfare vide order No. X11035/53/2014-DFQC (Part-IV) dated 02.02.2021 constituted an Expert Committee under the Chairmanship of Dr. M. S. Bhatia, Professor & Head, D/o Psychiatry, University College of Medical Sciences, New Delhi for examining certain pre-1988 FDCs de novo licensed for manufacturing for sale in the country without due approval from Central Licensing Authority.
The Expert Committee submitted its report accordingly on these 19 FDCs claimed to be pre-1988 after holding a series of meetings as well as by providing a hearing to the stakeholders wherein, the Committee after detailed deliberation. recommended for generation of data with respect to the following 03 FDCs:-
Sr.No | Name of FDC as per the public notice | Recommendations |
1. | Paracetamol IP 500mg+Phenylephrine Hydrochloride IP 10 mg + Caffeine Anhydrous IP 32mg tablets. | The committee recommended continued manufacturing and marketing of the FDC with the condition to generate safety and efficacy data by way of conducting Phase IV Clinical Trial. Accordingly, a Phase IV Clinical Trial is required to be conducted to generate the data within the time frame of one year. |
2 | Caffeine Anhydrous IP + Paracetamol IP + Phenylephrine Hydrochloride IP + Chlorpheniramine Maleate IP (15mg 500mg + 5mg + 2mg, 30mg 500mg+ 5mg + 2mg, 30mg + 500mg +10mg+ 2mg, 30mg+ 500mg+10mg + 4mg & 30mg+ 650mg + 10mg + 2mg) tablets | The committee recommended continued manufacturing and marketing of FDC with the following conditions: a. FDC shall be sold by retail on the prescription of an R.M.P. only. b. Package insert should also mention caution for patients suffering from cardiovascular diseases. c. Dose of Paracetamol in the FDC should be a minimum 500mgThe Committee also recommended conducting a Randomized comparative, Phase IV Clinical Trial comparing the FDC with the individual ingredients present in the FDC. Accordingly, a Phase IV Clinical Trial is required to be conducted to generate the data within the time frame of one year. |
3 | Paracetamol IP 250mg + Propyphenazone 150mg Caffeine 30mg tablets | The committee recommended continued manufacturing and marketing of the FDC for mild to moderate Headaches with the following conditions: a. FDC shall not be taken more than 5 to 7 days b. FDC to be sold by retail on the prescription of an R.M.P. only c. Further, the firm(s) shall conduct an Active PMS study to generate safety and efficacy data on the FDC. Accordingly, Active Post Marketing Surveillance is required to be conducted to generate the data within the time frame of one year |
Furthermore, the notice added that with the the approval of Ministry, it has been decided to follow the pathway for clearance of such subsequent applications as under:-
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 contain:-
a) Form CT-21 (duly filled, signed and stamped)
b) Fees as specified in the sixth schedule of New Drugs and Clinical Trials Rules 2019 through Bharatkosh.
c) Name and composition of the FDC
d) Product Permission issued by SLA
e) Copy of Manufacturing license in Form 25/28
f) 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 contain:-
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.)
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 ) Phase IV trial protocol/commitment for conducting Active Post
h) Marketing Surveillance study protocol, as the case may be.
3. all manufacturers who held FDC licenses from State Licencing Authorities prior to October 1, 2012, and who did not apply to DCGI, must submit their applications to this Directorate as soon as possible, but no later than six months, failing which their applications will not be considered.
4. Manufacturers shall comply with the recommendations of the expert committee with respect to the revision of the prescribing information/label.
Additionally, after an extensive review, the Committee decided that the following two FDCs could be justified under certain guidelines:-
Sr.No | Name of FDC as per the public notice | Recommendations |
1 | Imipramine Hydrochloride IP Diazepam IP (25mg 2mg & 25mg 5mg) tablets. | The committee recommended continued manufacturing and marketing of the FDC. FDC shall be indicated for co-morbid anxiety conditions and the duration of the treatment should not exceed 6 to 8 weeks |
2 | Chlorpheniramine Maleate IP Ammonium Chloride IP Sodium Citrate IP (2mg 100mg 50mg/5ml & 2.5mg + 125mg + 55mg/5ml Syrup | The committee noted that the firms are manufacturing the FDC in different strengths. The committee also noted that as per the literature available, Sodium Citrate is administered 0.3gm to 1gm in divided doses in a day and Chlorpheniramine Maleate is administered 4mg to 16mg in divided doses in a day. After detailed deliberation, the committee recommended for continued manufacturing and marketing of the FDC with the condition that the firm should modify the prescribing information/label by clearly mentioning the dosing schedule for adults and children keeping in view of the above-stated dose range without exceeding the maximum permissible. dose |
Accordingly, with the approval of the Ministry of Health and Family Welfare, the notice declared the following pathway for the grant of product license by SLAs for these FDCS
1. Applicants shall submit the requisite fees preferably through Bharatkosh for each FDC to CDSCO as specified under the Drugs and Cosmetics Act, 1940, and existing Rules thereunder
2. The applicant shall submit the application to the concerned SLA as per the provisions of Drugs and Cosmetics Rules 1945 for the grant of a product manufacturing license giving the details of FDCs, 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 shall grant the product license of such FDCs without NOC from DCG (1), 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 verify the quality of such FDCs of each applicant/manufacturer, before granting of license.
4. Every manufacturer permitted to manufacture these FDCs 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
To view the notice click the link below:
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