It has been reported that the expert committee panel constituted by the Government of India so far cleared 236 combination medicines out of 294 identified fixed dose combination (FDC) medicines which require further assessment for their rationality. It may be recalled that in 2007 the Government of India, through a national workshop, identified these 294 fixed dose combinations requiring attention and action. Consequently the then Drugs Controller General of India (DCGI asked the state licensing authorities (Drugs Controller of States) not to issue licence further on these combinations. Though the FDCs are treated as new drugs, the state licensing authorities used to issue licence for their manufacture. As per our statute, only Drugs Controller General of India has the authority for approving FDCs.
The World Health Organization (WHO) defines FDC medicine (FDC finished pharmaceutical product) a combination of two or more active drugs in a fixed ratio of doses intended for administration as one product. It describes four scenarios for FDCs:
● Scenario 1: The new FDC has the same composition as that of an already approved FDC. The quality, safety and efficacy of the already approved product have been established.
● Scenario 2: The new FDC contains the same active drugs in the same doses and dosage regimen as an established regime of single drug products. It includes combination of another single drug with an approved FDC (which has already two active drugs) too. The established regime as well as approved FDC have well characterised safety and efficacy profile and good clinical evidence.
● Scenario 3: The new FDC intends to combine the active drugs that are of established safety and efficacy but have not been previously used in combination for this indication. Also, it includes the new FDC comprising a combination for which safety and efficacy have been established, but they are intended in a different dosage regimen.
● Scenario 4: The new FDC contains one or more new drugs
The FDCs offer several advantages over single ingredient products. These include convenience for prescribers and patients, better patient adherence, simplified logistics for procurement and distribution, and lower cost. At the same time they have many concerns: difficult to meet every patient's need as dose of each component differ from patient to patient; dose of one component can not be altered; chances of therapeutic incompatibility; difficulty for the physicians to keep themselves aware of details of combination; difficulty of withdrawal of a suspected component for Adverse Drug Event; leads to polypharmacy; increasing financial burden on patients with unnecessary drug; no possibility of individual components dosage adjustment in renal or hepatic impaired cases; and increasing chance of duplication.
The FDCs are recommended in the following conditions (WHO):
● There is a rationale for combining the ingredients.
● There is availability of identifiable patient group for intended combination.
● The combination has a greater efficacy than any of the component used alone.
● The combination has lower incidence of adverse reaction than that response to any of the component given alone.
● The antimicrobial combination results in a reduced incidence of resistance.
● One drug acts as booster for another.
● The ingredients have compatible pharmacokinetic and pharmacodynamic profile.
● The combination results a simplified therapy while existing is complex or onerous.
One of the ingredients is intended to minimise abuse of the other ingredient.
In short, the FDCs are acceptable when the dosage of each ingredient meets the requirements of a defined population group and when the combination has proven advantages over single ingredients administered separately in therapeutic effect, safety or compliance.
The issue of fixed dose combination is not new. As early as in 1975, the Hathi Committee too raised concern for multi-ingredient preparations. The particular concern was raised on products sold as 'tonics' containing vitamins in excessive quantities. The committee observed that multiple drug combinations in amounts far excess of what is required result in colossal national wastage of drugs. The committee went further ahead and recommended that this problem could be substantially reduced if the brand names are eliminated. Brand names have been responsible for putting up of large number of unnecessary and often irrational formulations in the market. The Hathi Committee Report, though not implemented, has been recognised as an important milestone in the pharmaceutical scenario of the country.
The step initiated by the Government of India during 2007 was a significant step in weeding out or at least reducing the irrational combinations in the Indian pharmaceutical market. These combinations are often dangerous. In fact the expert committee had identified a group as irrational and unjustified. While the expert group appointed by the government looked into this FDCs freshly and cleared majority of the combinations. Some are still under consideration. The expert committee and the government should look the combination issue from public health point. Often the claim as have long standing use and no adverse effects is not justifiable as we have very poor records of documentary practice.
The use of FDCs is becoming increasingly important from public health perspective. They are proved to have immense benefits in the treatment of a wide range of conditions. The use of FDCs especially in the management of the biggest threatening infectious diseases: Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS), Malaria and tuberculosis (TB), are widely accepted. While regulation requires that the time consuming clinical trial data are necessary for approval, the unnecessary delay of approval limits the access to new useful FDC. At the same time the government should not only ensure a thorough study before approval but also act firmly to ban the unapproved and irrational drug combinations still available in the market in public interest.
(The authors are with Division of Pharmacy Practice, Department of Pharmacy, Annamalai University, Annamalai Nagar - 608 002)