INTRODUCTION:

Fixed dose combination drugs (FDCs) can be defined as two or more drugs in a single formulation available in certain fixed doses, each drug having independent modes of action, the combination of which are synergistic or additive or complementary in their effect. A fixed-dose combination finished pharmaceutical product (FDC-FPP) is one in which two or more separate drug and/or biological active ingredients are combined in a single dosage form. Fixed dose combination drug products are developed to target a single disease (such as with antiretroviral FDCs used against Acquired Immunodeficiency Syndrome), or may also target multiple diseases, such as Caduet. Fixed dose combination drug products may improve medication compliance by reducing the pill burden of patients.

Fixed dose combination medicinal products are hot and becoming hotter. Recent United States Food and Drug Administration (USFDA) approval of several high-profile combination drugs is drawing increased attention to opportunities in this area. Pfizer introduced Caduet, a drug combining Norvasc (amlodipine besylate) for high blood pressure and Lipitor (atrovastatin calcium) for high cholesterol.

Extensive previous patient use of the drugs separately and in combination with no ill effects permitted use of existing preclinical studies to support the FDC product’s regulatory filing. AIDS combination therapies have gained the most notice in the recent years. In August 2004, FDA approved two FDC antiretrovirals for use in the United States as well as in the developing world.¹

Although FDCs are particularly suitable for providing less costly and simpler treatment regimens for AIDS, malaria, and other diseases plaguing the third world, manufacturers are enthusiastic about moving in this direction in the United States and other established markets as part of product life cycle management. A successful drug facing patent expiration may gain new life through transformation into FDC. The new formulation may enhance patient compliance not just through simplified treatment regimens but also by reducing toxicity and side effects or boosting drug bioavailability and increasing efficacy. Manufacturers are looking particularly at treatments for asthma, diabetes, hypertension, and infectious diseases as prime opportunities for developing more-effective combination products.^1,2

With few exceptions, regulators and the pharmaceutical industry has generally been wary of FDCs as an innovative delivery mechanism in this context, even though FDCs may be useful to improve adherence and can simplify procurement, storage and distribution of medicines. In 1978, the first expert committee dealing with the Essential Medicines List, developed criteria for FDCs for the World Health Organization based on the fact that there were too many irrational drug combinations being sold, particularly in developing countries. Indeed, the early WHO list of 250 essential drugs included only 7 combinations drugs. ³

However, FDCs are an important approach to address the management of both chronic and acute diseases and more attention and research should be paid to their use. The policy towards FDCs of the World Health Organization (WHO) has recently undergone a major shift. The total number of essential drugs mentioned in the 14th list of essential medicines by WHO is 312, out of which only 18 are fixed dose combinations.¹⁵ The WHO new Essential Medicines List now includes FDC anti-TB products and anti-retrovirals. Moreover, WHO now recommends use of arteminisin fixed dose combinations to treat malaria.² On the down side, the shift to FDCs may reduce the range of treatment options available to physicians and patients. In developing FDCs, manufacturers often drop less used dosage strengths and produce a more limited range of treatments, reducing prescribing choices.

There are a variety of reasons for this reluctance. The general lack of interest to use the FDCs with some notable exceptions can be traced to the long shadow cast by US policy in the 1970s with regard to FDCs. FDCs having various challenges like dose titration, allergies to one or more of the components, different pharmacokinetic and/or pharmacodynamic profiles, and pharmaceutical development.

To date, most FDCs pills involve already-approved components that a company combines into a new therapy. With a large number of suitable FDCs already on the market, manufacturers will be looking more to combine new therapies into new types of fixed dose combination products. These may be costly for manufacturers to develop but provide simplified dosing regimens and improved safety that may pay off in stronger market acceptance.

Available information suggests that compliance with European Union guidelines requires more extensive clinical evaluation than compliance with USFDA. Whereas in CDSCO, some clauses are present which are neither in USFDA nor in EMEA and in general seems to be less stringent.

Currently, there are no uniform principles, guidelines, or international standards addressing the development of FDCs and their potential benefits or disadvantages in treating the diseases.

Difference between FDCs and Combination Products

Fixed dose combination is different from combination products as Combination Products. According to USA, the Federal Food, Drug, and Cosmetic Act, as defined in 21 CFR 3.2(e), a combination product is a product comprised of any combination of a drug and a device, a biological product and a device, a drug and a biological product, or a drug, device, and a biological product. ^6,7

Studies on Fixed Dose Combinations Drugs

Study done by Panda et al on “Evaluation of the rationality of some FDCs: Focus on antihypertensive drugs”⁸ have explained seven-point criteria for evaluating the rationality of FDCs. C. M. Gulhati (Title “Irrational Fixed-Dose Drug Combinations: A Sordid Story of Profits before Patients”) ¹⁰ have suggested that FDCs should be allowed only under exceptional circumstances.

Studies Related to Rationality and Irrationality in the Fixed Dose Combination Drugs:

The rationality of some FDCs is controversial and debated issue in today’s clinical practice. Evidence of safety and efficacy is of utmost importance when the two drugs are combined together as a single formulation. If a simultaneous administration of more than one pharmacologically active substance is justified, an administration in the form of a fixed combination product generally simplifies therapy; however, a fixed combination product cannot be justified by the simplification of treatment alone.¹¹ In the United States, an FDC is considered as a new drug, and it has to be approved by the USFDA before it can be marketed, even though the individual components are available for concurrent use.¹² In India Drugs and Cosmetic Act, 1940, also takes a similar stand on this issue. There are equal numbers of advantages and disadvantages of FDCs.¹³ The use of FDCs may lead to polypharmacy, dose of one ingredient alone cannot be altered, and in case of development of an adverse drug reaction and it is difficult to withdraw the suspected drug alone.^{14, 15}

Dose Combination Drug Regulations in United States, European Union and India:

United States of America: United States Food and Drug Administration (USFDA):

Earlier, lack of enthusiasm among regulatory agency for fixed dose combinations appears to stem from the late 1960s in the United States when the USFDA initiated a review of all medicines approved prior to 1962 and strongly encouraged monotherapy. The 1962 Kefauver-Harris amendments to the 1938 Food, Drug and Cosmetics Act were passed in the wake of the thalidomide birth defect tragedies.¹⁶ In the United States in 1970, combination drugs accounted for over 50% of pharmaceutical products and for 40% of the best selling drugs in the U.S. This evaluation, the Drug Efficacy Study Implementation (DESI), looked at the many fixed dose combinations that were being marketed. The DESI study found that only 45 of some 1200 FDC drugs were rated as effective. In 1970, the American Council on Drugs asserted that FDCs are “ … in most instances, not recommended”.¹⁷

The Food and Drug Administration's policy in administering the new-drug, antibiotic, and other regulatory provisions of the Federal Food, Drug, and Cosmetic Act regarding fixed combination dosage form prescription drugs for humans are specified in the section 300.50.

European Union (EU): European Medicines Agency (EMEA):

Fixed dose combination product: a single product created by the combination of two or more active components and in which each active component contributes to the benefit of the new product. FDCs are not simply two or more active constituents’ combination. Rather justification to the particular combination of active substances required. Potential advantages in the clinical situation against possible disadvantages are evaluated. The indications claimed for a fixed-combination medicinal product are such that the presence of each active substance makes a contribution to the claimed effect.¹⁸

When developing a fixed combination the non-clinical program will vary depending on the characteristics of the single components, on the existing non-clinical and clinical experience of their individual and concomitant use as well as the intended clinical use. When there is no experience from use of the combination, even if the individual components are known, bridging studies addressing expected and potential unexpected pharmacodynamic and toxicological interactions are in principle needed.¹⁹ Applicable for any non-clinical combination study, the dose selection should be based on considerations of interspecies differences in pharmacokinetic as well as pharmacodynamic.

INDIA: Central Drugs Standard Control Organization (CDSCO):

As per the Clause (c) of rule 122-E:²⁰

“A fixed dose combination of two or more drugs, individually approved earlier for certain claims, which are now proposed to be combined for the first time in a fixed ratio, or if the ratio of ingredients in an already marketed combination is proposed to be changed, with certain claims, viz. indications, dosage form (including sustained release dosage form) and route of administration.”

Several branded formulations are available in India which are either single or fixed dose combination drugs. Only a few drugs are lifesaving and essential; rests of the drugs are substitutes for each other. Irrational combinations are popular and widely prescribed by physicians in India. The combinations such as tetracycline and vitamin C, quinolones and nitroimidazoles and penicillins with sulfonamides are some of the examples of irrational FDCs. Such dubious FDCs entail financial burden, resistant strains of bacteria and increase in unwanted effects.

After amendment of the Drugs Act in 1982, the Government has acquired the power to prohibit manufacture and sale of certain drugs and irrational FDCs. The government, subsequently, issued a first gazette notification in July 1983 banning several drugs and their FDCs after due consideration. Since then the government has been notifying the list of banned drugs on a regular basis. The Drugs Controller General of India (DCGI) had issued an order in May 2002 to State drug-controlling authorities not to grant any manufacturing or marketing approvals for new drugs. Since then DCGI has become the centralized authority for granting new drug approvals.²

When compared to the approvals given by the USFDA, there are relatively less approvals given by EMEA. It may be due the companies have not filed for such combinations or may be the EMEA is not that convinced about the FDCs of the selected therapeutic categories.

India is not lagging behind in approving FDCs, it is on par with USFDA. There are definitely large number of FDCs approved by DCGI, which may be due the less stringent rules and regulations. Approvals in the antihypertensive and antidiabetic FDCs were given mostly to β Adrenergic Blockers with Amlodipine and Metformin with sulphonylureas (glibenclamide, gliclazide, Glimepiride etc) combinations respectively.

Large numbers of FDCs were approved in USA, followed by India and least number of FDCs approvals found in Europe. But when comes to types of FDC, study shows that DCGI approved antihypertensive FDCs from 2000 to 2006 are more then USFDA, followed by EMEA. Whereas in case of antidiabetic FDCs, higher number of approvals by USFDA, then EMEA, and finally DCGI. It shows that USA and Indian pharmaceutical market are more encouraging to FDCs.

Comparison of Non clinical guidelines of FDCs among US FDA, EMEA and CDSCO:

Certain issues generally apply when determining whether components are suitable for combining. The medical and scientific rationale supports the combined use of the active components if they have following effects:

§ Increased efficacy (additive or synergistic)

§ Reduced toxicity

§ Increased drug levels

§ Prevention of antimicrobial resistance

§ Increased Stability

§ Assurance of reproducible drug release from the dosage form

§ Appropriate quality standards for each active ingredient and for the dosage form

§ Data showing lack of interactions between active ingredients

US FDA v/s EMEA

US FDA’s non clinical guidance for Fixed Dose Combinations consists of 3 major categories:

1) Two or more previously marketed drugs or biologics;

2) One or more new molecular entities (NMEs) and one or more previously marketed drugs or biologics; or

3) More than one NME.

Whereas in EMEA, non clinical guidance is divided into 4 different scenarios

1) A fixed combination of compounds already approved as free combination therapy.

2) A fixed combination of approved compounds not approved as combination therapy.

3) A fixed combination of one or more New Chemical Entities (NCEs) with one or more approved /well know compound.

4) A fixed combination of two or more NCEs

In United States, for assessment of general toxicity, a bridging study may be appropriate, provided the duration is sufficient to elicit the toxicity of concern. For example, a general toxicity bridging study of 3 month’s duration could be considered for a chronic indication. Studies of shorter duration could be appropriate for shorter clinical studies or for nonchronic indications, as per International committee on Harmonization (ICH M3).

Whereas in European Union, combinations for long term use (long term treatment of non-life-threatening conditions), safety data on 300-600 patients for six months or longer is usually required. But for a fixed combination containing approved compounds indicated for long term use where experience of concomitant use is lacking, a 3-month repeat dose toxicity study in one appropriate species, supported by toxicokinetic data is generally recommended. In US FDA, guidance for nonclinical safety evaluation of drug or biologic combinations have no information about immunotoxicity or dependence, but agency may recommend that targeted toxicity studies (like local tolerance studies) be conducted, depending upon the nature of toxicities seen in animals and humans with the drug products or drug class, whereas in EMEA special and/or mechanistic studies may be warranted, e.g. studies addressing immunotoxicity or dependence, depending on the properties of the individual components in the combination.

In case of reproductive toxicity, in EMEA, study is not required if individual components are free from such risks, otherwise further evaluation should be done (e.g. the possibility of a potentiation of the identified effect may be needed), But in US FDA Embryo-fetal development studies of the combination should be conducted as per the timing specified in ICH M3, unless the marketed products are already known to have significant risk for developmental toxicity (e.g., one of the marketed drugs has been assigned a pregnancy category “D” or “X”). If combination studies are needed, a single study could be conducted in the appropriate species, based on what is known about the individual drugs or biologics.

In both US FDA and EMEA, carcenogenicy and genotoxicity is not required if combination having individual component free from such risks, but If there is any concern related to one compound in the combination then the risk of that compound and interactions with the other component, should be carefully assessed.

The regulatory requirements of both US FDA and EMEA require that two or more components of a combination product must contribute to an increased overall effect. Available information suggests that compliance with EMEA guidelines requires more extensive clinical evaluation than compliance with United States Food and Drug Administrations (US FDA) recommendations.

US FDA v/s CDSCO:

In US FDA, FDCs are categories in 3 main categories whereas, in CDSCO, they are described in four major categories:-

1. FDC having one or more of the active ingredients is a new drug.

2. FDC having active ingredients already approved/marketed individually are combined for the first time, for a particular claim and where the ingredients are likely to have significant interaction of a pharmacodynamic or pharmacokinetic nature.

3. FDC is already marketed, but in which it is proposed either to change the ratio of active ingredients or to make a new therapeutic claim.

4. FDC whose individual active ingredients have been widely used in a particular indication(s) for years, their concomitant use is often necessary and no claim is proposed to be made other than convenience.

In USFDA, for assessment of general toxicity, a bridging study may require, provided the duration is sufficient to elicit the toxicity of concern. For example, a general toxicity bridging study of 3 months’ duration could be considered for a chronic indication. But no such bridging studies are required in CDSCO.

In India, FDC having category 4, in which have no claim other then patient convenience. This may be the reason behind more number of FDCs get approval from DCGI. Pharma companies may find this clause for putting one more brand in the market, on the name of patient convenience though it may not have significant number of patients for consumption. In EMEA such clause is restricted to only non prescription products, whereas in US FDA, there is no such clause.

For FDCs in the category 3 of CDSCO, the appropriate rationale including published reports (if any) are the only requirements to obtain marketing permission and the permission would be granted depending upon the nature of the claim and data submitted. Hence all that one need to get approval from CDSCO is change the ratio of constituents or claim new therapeutic use. Whereas no such clause in US FDA or EMEA.

In CDSCO, category 2 FDCs, where individual drugs were approved and marketed but used for the first time in a FDC, marketing permission may be granted based on just chemical and pharmaceutical data. Data showing the stability of the proposed dosage form will also have to be submitted. But such clause neither exists in USFDA nor in EMEA. There has been an alarming increase in Fixed Dose Combinations (FDCs) in various therapeutic categories in the recent years. Hence, the development of FDCs is becoming increasingly important from a public health perspective. They are being used in the treatment of a wide range of conditions other than human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), malaria and tuberculosis, which are considered to be the foremost infectious disease threats in the world today.

Regulatory authorities also are convinced of some FDCs and have approved certain combinations. However, some unapproved FDCs are prevailing in developing countries. FDCs have advantages when there is an identifiable patient population for whom treatment with a particular combination of active components in a fixed ratio of doses has been shown to be safe and effective, and when all of the active components contribute to the overall therapeutic effect. In addition there can be real clinical benefit in the form of increased efficacy and/or a reduced incidence of adverse effects, but such claims should be supported by evidence. Additionally, in a situation of limited resources, the cost of an FDC finished pharmaceutical product (FDC-FPP) may be less than that of single active component products and there can be a considerable reduction in the cost of logistics.

In developing FDCs, it is necessary to consider three major factors namely a) the safety and efficacy of the individual active components, b) the simultaneous use of all the active components, and c) the possible interaction between active components in a single formulation by the administration of a simultaneous fixed combination. Therefore, the risk-benefit assessment is very essential before choosing a combination for therapy. It should not be assumed that benefits outweigh risks.

It was observed that there are no specific guidelines prescribed by the regulatory authorities. However, they have the guidance’s regarding non clinical and clinical studies; it was observed that there were some differences in the guidence’s of USFDA, EMEA and CDSCO.

It is high time that regulatory authorities, healthcare professionals, researchers and pharmaceutical companies have to join hands together to formulate guidelines for the FDCs to provide effective and safer drugs to the patients.

Improvements in FDC use:

The hit and trial method of combining drugs should be replaced by a rational and logical basis for bringing out a fixed dose drug formulation. Operational, statistical and mathematical models constitute a highly versatile framework for mechanism-based modeling (pharmacokinetic/pharmacodynamic) by taking signal transduction properties of the drug combination into account. There is a need to carefully monitor and censor misleading claims by the pharmaceutical companies. Some degree of irresponsibility on the part of the pharmaceutical industry and lack of vigilance of government agencies underlies the increased popularity of irrational drug combinations. Most advertisements in many of the medical journals published from India fail to mention important details pertaining to correct usage of drug combinations. Adverse Drug Reaction (ADR) reporting should be made mandatory as they are in developed countries. Pharmacovigilance should be more effective. Pharmaceutical companies should understand ill effects due to irresponsibility on their part. They should not make misleading claims and should follow the ethics. They have to fulfill their duties by imparting quality drugs and not irrational ones. For any individual fixed combination product, drug regulatory authority must assess the potential advantages in the clinical situation against possible disadvantages in order to determine whether the particular combination of active ingredients is justified and whether the product meets the requirements of the state of the art with respect to efficacy and safety. Only in exceptional cases should fixed combination products be used in the treatment of diseases in which a careful individual titration is required.

Clinical pharmacists can play an important role in guiding and imparting knowledge to the public. Hospitals should constitute drugs and therapeutics review committees to rationalize prescribing. There is a need to strengthen the mechanism for continuing professional development of practitioners to ensure that they have the necessary knowledge and skills to prescribe rationally. Perhaps the insistence that prescribers, especially those in private practice should undergo a continuing medical education (CME) course once in two years on newer drug combinations, new drug molecules introduced into the market and adverse drug reactions which may help in eradicating the irrational combinations. Medical colleges must take the responsibility of training young doctors how to assess new drug combinations more logically. Health care professionals should keep themselves updated with the list of drugs which are irrational and banned by the regulatory bodies. Government should provide incentives to the private sector, so that they can invest in research and development of FDCs for those pathogenic conditions where FDCs may prove useful, particularly in relationship to slowing down or eliminating antimicrobial resistance (AMR). Governments should fund research and development on FDCs using tax breaks and other subsidies. This will allow the private sector to extend market share and recoup RandD expenses in the developed countries, and the less developed nations will receive a low-cost FDC drug. Uniform Regulatory guidelines are required with respect to FDCs which can be followed by pharmaceutical companies worldwide. It would be appropriate for the Indian regulatory authority to open a new office like USFDA’s office of combination products to look into all the matters pertaining to combination products. The so formed office may work on the various aspects of combination products.

REFERENCES:

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4. Scientific and technical principles for fixed dose combination drug products. Botswana, Available at: www.globalhealth.gov Accessed on April 22, 2008

5. WHO Technical Report Series, No. 929, Annex 5: Guidelines for registration of FDCs medicinal Products. Available at: www.who.int Accessed on March 30, 2008.

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10. C. M. Gulhati, “Irrational Fixed-Dose Drug Combinations: A Sordid Story of Profits before Patients”, Ind J Med Eth. 2003; (11) 1: 5.

11. FDCs information as on www.medscape.com Accessed on May 12, 2008.

12. Steven B. L., Stephanie T., “Combination Medications in Diabetes Care: An Opportunity That Merits More Attention”, Clin Diabet. 2003; 21(4): 175-178.

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14. T Stanton, J. L. Reid, Fixed dose combination therapy in the treatment of hypertension, J Humn Hypert. 2002; (16) 2: 75-78.

15. FDCs information as on www.mednet3.who.int accessed on March 28, 2008.

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17. Guidance for Industry Nonclinical Safety Evaluation of Drug or Biologic Combinations, USFDA, March 2006. Available at: www.fda.gov accessed on March 28, 2007.

18. Note for Guidance on Fixed-Dose Combination Medicinal Products,” April 1996, Available at: www.emea.europa.eu accessed on Jan 12, 2008.

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Received on 24.03.2009 Modified on 02.05.2009

Research J. Pharm. and Tech.2 (3): July-Sept. 2009,;Page 433-438