Decades Old FDCs Under Review: DCGI Demands Proof of Efficacy
CDSCO has given manufacturers a final 3-month deadline to submit required data or face regulatory action, including license cancellation.
New Delhi: The Drugs Controller General of India (DCGI) has issued an important regulatory update regarding certain Fixed Dose Combinations (FDCs) that were approved for manufacturing and sale in India before 1988 without proper approval from the Central Licensing Authority. These FDCs, including Paracetamol IP 500mg + Phenylephrine Hydrochloride IP 10mg + Caffeine Anhydrous IP 32mg tablets and Caffeine Anhydrous IP + Paracetamol IP + Phenylephrine Hydrochloride IP + Chlorpheniramine Maleate IP, have been under review to ensure their safety and effectiveness.
Many manufacturers had obtained state-level licenses for these medicines before 2012 but had not submitted the required applications for further evaluation. To address this, the apex drug regulatory body, Central Drugs Standard Control Organization (CDSCO) has now provided a final opportunity for these manufacturers to submit the necessary data within three months from the date of the issued notice (24.02.2025). Failure to do so may lead to regulatory action, including cancellation of licenses.
This update follows previous communications, including the CDSCO notice dated 11.01.2024, which required manufacturers holding licenses from State Licensing Authorities (SLAs) before 01.10.2012 to submit applications for Phase IV Clinical Trials or Active Post Marketing Surveillance (PMS). The deadline for such submissions expired on 11.07.2024, and despite the lapse of nearly 12 months, a significant number of firms failed to comply. To address this non-compliance, the CDSCO has now extended a final opportunity for manufacturers to submit their applications within three months from the date of issuance of this letter (24.02.2025). Failure to comply will result in appropriate regulatory action.
The regulatory evaluation aligns with directives from the Hon’ble Supreme Court, dated 15.12.2017 and 14.02.2019. In response, the Ministry of Health & Family Welfare established an Expert Committee, chaired by Dr. M.S. Bhatia, Professor & Head, Department of Psychiatry, University College of Medical Sciences, New Delhi. The committee assessed 19 FDCs claimed to be pre-1988 and recommended further data generation for three specific combinations.
The committee provided recommendations for continued manufacturing and marketing of these combinations, subject to strict conditions. The first FDC, comprising Paracetamol IP 500mg + Phenylephrine Hydrochloride IP 10mg + Caffeine Anhydrous IP 32mg tablets, requires manufacturers to generate safety and efficacy data via a Phase IV Clinical Trial within one year.
The second FDC, containing Caffeine Anhydrous IP + Paracetamol IP + Phenylephrine Hydrochloride IP + Chlorpheniramine Maleate IP in various dosage combinations, must be sold only on prescription from a Registered Medical Practitioner (RMP). Additionally, package inserts must include a caution for cardiovascular patients, and a minimum dose of 500mg Paracetamol is required. A randomized comparative Phase IV Clinical Trial must be conducted within one year.
The third FDC, Paracetamol IP 250mg + Propyphenazone 150mg + Caffeine 30mg tablets, is recommended for mild to moderate headaches with conditions such as a restriction on usage for more than 5-7 days and availability only on prescription. Firms must also conduct an Active Post Marketing Surveillance (PMS) study within one year.
To comply with CDSCO’s directives, manufacturers must submit applications containing essential documents. Existing manufacturers licensed before 01.10.2012 must provide Form CT-21, applicable fees as per the sixth schedule of New Drugs and Clinical Trials Rules, 2019, name and composition of the FDC, product permission issued by SLA, a copy of the manufacturing license in Form 25/28, and a Phase IV trial protocol or Active PMS study protocol. New manufacturers must submit similar documents, including Form CT-21, applicable fees, product permission issued by SLA in Form 29, a copy of the manufacturing license in Form 25/28, stability study data (06 months accelerated conditions), test specifications of the FDC along with the method of analysis, and a Phase IV trial protocol or Active PMS study protocol.
Manufacturers failing to submit their applications within six months will not have their applications considered, and their licenses will be deemed invalid. Compliance with expert committee recommendations, including revisions to prescribing information and labeling, is also mandatory.
The CDSCO has emphasized adherence to this updated regulatory framework to ensure the safety and efficacy of FDCs permitted before 1988. All stakeholders, including manufacturers and state drug regulators, are asked to follow the prescribed procedures to prevent legal and commercial repercussions.
