Fixed-Dose Combination (FDC) Drugs - ECONOMY

Fixed-Dose Combination (FDC) Drugs - ECONOMY

NEWS: Recently, the Central Drugs Standard Control Organisation (CDSCO) has directed state and Union territory drug regulators to immediately halt the manufacture, sale, and distribution of 35 Fixed-Dose Combination (FDC) drugs. 

  • The directive follows an ongoing investigation into the approval of these drugs without the mandatory assessment of their safety, efficacy, and therapeutic justification, as required under the Drugs and Cosmetics Act, 1940, and New Drugs and Clinical Trial (NDCT) Rules, 2019.
  • The CDSCO emphasized that several such combinations had been approved at the state level without clearance from the Drugs Controller General of India (DCGI) , a violation that raises serious concerns about patient safety and regulatory integrity.

WHAT’S IN THE NEWS?

What are Fixed-Dose Combinations (FDCs)?

  1. Definition:

·         FDCs are pharmaceutical formulations that combine two or more active pharmaceutical ingredients (APIs) into a single dosage form.

·         The APIs are present in a fixed proportion, meaning each dose always contains the same ratio of drugs.

  1. Common Usage:

·         These combinations are frequently used in the treatment of conditions like pain (e.g., paracetamol + ibuprofen), diabetes (e.g., metformin + glimepiride), and as nutritional supplements (e.g., multivitamin + mineral tablets).

 

Benefits of Fixed-Dose Combinations:

  1. Improved Patient Compliance:

·         Patients are more likely to adhere to treatment regimens as they have to take fewer pills, especially helpful for those with chronic conditions requiring multiple drugs daily.

  1. Synergistic Effect and Enhanced Therapeutic Outcomes:

·         When two drugs with complementary actions are combined, their therapeutic effect can be enhanced (synergism), improving efficacy over individual drug use.

  1. Cost-Effectiveness:

·         Manufacturing and packaging costs are reduced by combining drugs, often leading to lower prices for patients.

·         Reduced need for multiple prescriptions and follow-ups also lowers overall treatment costs.

  1. Reduced Pill Burden:

·         Particularly beneficial for elderly patients and those on long-term medication, as managing fewer pills simplifies treatment.

 

Classification of FDCs:

Category I: Approved FDCs

  1. Definition:

·         These are combinations already approved for use either in India or other countries.

  1. Regulatory Requirements:

·         They have a proven record of safety and efficacy, so only minimal additional studies are needed for approval in India.

  1. Example:

·         A combination of amoxicillin and clavulanic acid used widely for bacterial infections.

 

Category II: Known Drugs with Potential Interactions

  1. Definition:

·         Combinations of drugs that are individually approved but may interact when taken together, either enhancing or diminishing their effect.

  1. Regulatory Needs:

·         New clinical studies may be required to assess safety and efficacy due to possible pharmacokinetic (absorption, distribution, metabolism, excretion) or pharmacodynamic (drug effect) changes.

  1. Example:

·         Combining two antihypertensive drugs at fixed doses not previously studied together.

 

Category III: Modified Release or New Route of Administration

  1. Definition:
    • These FDCs use drugs that are already approved but alter how or when they are released or delivered.
  2. Examples:
    • A once-daily slow-release pill replacing two doses taken separately.
    • A nasal spray form of two drugs previously available as oral tablets.
  3. Regulatory Requirement:
    • New pharmacokinetic studies are required to demonstrate that the new form behaves safely and effectively.

 

Category IV: FDCs Involving New Drugs

  1. Definition:
    • These combinations contain at least one new drug substance not previously approved for marketing in India.
  2. Regulatory Requirements:
    • Full clinical trials are mandated to establish safety and efficacy.
    • Must obtain approval from the Drug Controller General of India (DCGI).
  3. Legal Framework:
    • These are classified as “new drugs” under the New Drugs and Clinical Trials (NDCT) Rules, 2019.

 

About the Central Drugs Standard Control Organisation (CDSCO):

  1. Role and Identity:

·         CDSCO serves as India’s National Regulatory Authority (NRA) for pharmaceuticals and medical devices.

·         It functions under the Directorate General of Health Services, part of the Ministry of Health and Family Welfare.

  1. Headquarters:

·         Located in New Delhi, the CDSCO also operates zonal and sub-zonal offices throughout India.

Key Responsibilities of CDSCO:

  1. Ensuring Safety and Quality:

·         Oversees that drugs and devices meet national standards of quality, efficacy, and safety.

·         Promotes transparency and accountability in regulatory processes.

  1. Approval of New Drugs and Clinical Trials:

·         Evaluates data submitted by pharmaceutical companies before granting permission to market new drugs.

·         Monitors and regulates the conduct of clinical trials across the country.

  1. Setting Drug Standards:

·         Defines quality benchmarks for drugs, including parameters for strength, composition, purity, and packaging.

·         Regulates the import of pharmaceutical products to ensure they meet Indian standards.

 

Collaboration with State Regulators:

  1. Joint Licensing Functions:
    • CDSCO works in coordination with state drug control authorities to issue licenses for the manufacture and sale of certain critical medicines.
    • These include high-risk or essential items like blood products, vaccines, intravenous fluids, and sera (antitoxins or antibodies).
  2. Expert Advisory Role:
    • Provides technical and regulatory guidance to states to ensure consistent enforcement of the Drugs and Cosmetics Act, 1940.
    • Helps harmonize state-level drug regulation practices with national standards.

 

Fixed Dose Combinations (FDCs): Significance, and Challenges

  • Combination of Multiple Drugs: Fixed Dose Combinations combine multiple drugs into a single medication, which improves patient compliance as taking one tablet is easier than multiple pills.
  • Significance: For diseases such as AIDS, it is well documented that FDCs have proven to be very useful in improving patient compliance and hence improve treatment outcomes.
  • Challenges: FDCs need careful testing as combining drugs can reduce their efficacy or create toxic interactions (often called metabolites). Hence, regulatory approval is critical before marketing FDC

Why does the pharmaceutical industry promote the use of Fixed Dose Combinations (FDCs)?

  • Escape Price Control: Individual drugs face price caps but not combinations. Under the Drugs (Prices Control) Order, (by which the government fixes the prices of individual drugs), drug combinations were traditionally not covered, hence the pharmaceutical industry uses fixed dose combinations (FDCs) as an easy way to escape the price cap.
  • For Profit Making: It gives individual companies a reason to charge higher prices for their drugs. As to create an FDC, companies can claim it as a new unique product catering to a specific need, thereby allowing them to charge a higher price. 
  • Avoidance of Quality Testing: As Indian Pharmacopoeia Commission standards don’t exist for most FDCs. Hence, no risk of “not of standard quality” prosecution under the Drugs & Cosmetics Act, 1940. 

What rules and laws govern Fixed Dose Combinations (FDCs) in India?

  • Drugs and Cosmetics Act, 1940: The fixed dose combinations (FDCs) problem has been on the regulatory radar since 1978 when the first government committee studied the issue and admitted this problem. At the time, there was no system under the colonial-era Drugs and Cosmetics Act, 1940 to stop FDCs sale.
  • Provision of Prohibition: In 1982, Parliament changed the law to give the central government the power to “prohibit” the manufacture of specific drugs that lack therapeutic justification. 
  • Approval by DCGI: In 1988, the central government amended the rules to introduce a new requirement for manufacturers of all “new drugs”, including FDCs, to submit proof of safety and efficacy to the Drugs Controller General of India (DCGI) who heads the Central Drugs Standard Control Organization (CDSCO). 

·         It made clear that State drug controllers could not grant manufacturing licenses for new drugs that are not approved for safety and efficacy by the DCGI.

What are the concerns associated with the use of Fixed Dose Combinations (FDCs) in India?

  • Acceleration of Antimicrobial Resistance Cases: The widespread use of unapproved and irrational antibiotic fixed dose combinations (FDCs) can accelerate antimicrobial resistance in India, severely impacting the ability to treat infections.
  • Failure on Regulation: The decades-long failure to curb this practice reveals glaring gaps and incompetence in India’s drug regulatory framework.
  • Not Strict on License Approval: State drug controllers openly flout laws and continue giving manufacturing licenses for FDCs not cleared by DCGI.

·         Sporadic banning of specific FDCs plays whack-a-mole as manufacturers then promote similar alternate FDCs.

  • Judicial Inconsistencies: Inconsistencies in interpreting DCGI’s FDC banning authority under Section 26A also enable manufacturers to sell more FDCs.

Source: https://economictimes.indiatimes.com/industry/healthcare/biotech/pharmaceuticals/in-major-development-in-pharma-halt-order-enforced-on-production-and-sale-of-35-fixed-dose-combination-drugs/articleshow/120336524.cms?from=mdr