Medicines are an integral part of healthcare. More than one drug is frequently used
for treatment of either single ailment or multiple comorbid conditions. Sometimes,
two or more drugs are combined in a fixed ratio into a single dosage form, which is
termed as fixed dose combinations (FDCs). The FDCs are justified when they demonstrate
clear benefits in terms of (a) potentiating the therapeutic efficacy, (b) reducing
the incidence of adverse effect of drugs, (c) having pharmacokinetic advantage, (d)
better compliance by reducing the pill burden, (e) reducing dose of individual drugs,
(f) decreasing development of resistance, and (g) cheaper than individual drug because
of reduced cost from packaging to distribution. It is important that the above claims
are adequately supported by scientific evidence.
The Problems with Fixed Dose Combination
The FDCs formulated without due diligence can pose problems namely (a) pharmacodynamic
mismatch between the two components, one drug having additive/antagonistic effect
leading to reduced efficacy or enhanced toxicity, (b) pharmacokinetic mismatch and
having peak efficacy at different time, (c) chemical noncompatibility leading to decreased
shelf life, (d) drug interactions because of the common metabolizing pathways, and
(e) limitations of finer dosing titration of individual ingredients.
Although FDCs are available in almost all therapeutic categories, many of them are
bizarre combinations. The therapeutic categories having high number of FDCs are cough,
cold, and fever preparations; analgesics and muscle relaxants; antimicrobials; drugs
for hypertension, dyslipidemia, diabetes, and psychiatric disorders; and vitamins
and minerals. The FDC formulation may have up to 5 or even more ingredients with or
without rationality of their presence and in the quantity.
Very Few Fixed Dose Combinations in Essential List of Medicines
Essential medicines are those that satisfy the priority health care needs of the population
and intended to be available at all times, in adequate amount and at affordable price.
The list is prepared with due consideration to disease prevalence, efficacy, safety,
and comparative cost-effectiveness of medicines. Out of the 414 medicines included
in the 19th list of WHO List of Essential Medicines, 27 are FDCs. We included 24 FDCs
out of 376 entities in the National List of Essential Medicines of India (NLEM) 2015.
These FDCs were included after due deliberations in national consultations with scientific
justifications. Majority of the FDCs in both the lists belong to antimalarial, antitubercular,
antiretroviral drugs, which emphasize the importance of FDC use in treatment adherence
and prevention of drug resistance.
Problem of Plenty: Fixed Dose Combinations with Questionable Justifications in India
Notwithstanding with the basic principle of formulating FDC, the Indian medicine market
has become the world leader of FDCs. The estimated number of FDCs in India is over
6000. Time and again, studies, editorials have shown violation of scientific merits
in having many FDCs without adequate justification. Exploiting the liberal licensing
system, many times, bizarre FDCs find place. India today does not have the exact database
of currently available FDCs in the market, their sales turnover and use pattern. The
existence of unlimited brands of FDCs with different permutations and combinations
leads to confusion rather than guiding the prescribing doctor.
Fixed Dose Combinations are New Drugs but Permitted by State Licensing Authority:
An Example of Disconnect
As per the Rule 122E of Drugs and Cosmetics Act 1940, the FDCs are considered as New
Drugs and the Central Drugs Standard Control Organization (CDSCO), after due examination
of data on rationality, safety, and efficacy, issues approval. On the basis on this,
the State Licensing Authority (SLA) gives the manufacturing and marketing permission.
Incidentally, in the past, SLAs issued the license to manufacture and market without
asking for no-objection from CDSCO. Thus, the efficacy, safety, and rationality of
such FDCs remain questionable. This “disconnect” between the CDSCO and SLAs has precipitated
a roadblock in the action against irrational FDCs.
Role of Strong Marketing and Key Opinion Leaders in Legitimizing Fixed Dose Combination
The strong marketing pressure, inadequate time and attitude of critical analysis,
influences the prescribing habit toward these FDCs. Senior leaders in medicine from
academia and practice who are key opinion leaders influence the prescribing trend
of their juniors and have a cascading effect on the medical community. Thus, frequent
prescribing of FDCs and the near absence of adverse drug reaction reporting system
in India legitimize this faulty practice. The high sales turnover and high prescription
trend from Medical Colleges, Primary Health Centers, and general practitioners are
often projected as their rationality, safety, and efficacy.
The Good, the Bad, and the Ugly of the Fixed Dose Combination in India
On the basis of the rationality of available FDCs in India, we are tempted to classify
them as follows: The Good FDCs – having strong justification, for example, carbidopa
+ levodopa, sulfonamides + trimethoprim, antitubercular drugs, antiretroviral drugs,
some antihypertensives, and some antidiabetic medications; the Bad FDCs – are formulated
primarily with marketing interests and do not add any value to the therapeutic usefulness
and whose justification is debatable. Majority of the available FDCs fall in this
category. Some examples are combinations of dual nonsteroidal anti-inflammatory drugs
(NSAIDs), NSAIDs with muscle relaxant, and NSAIDs with H2 blockers; and the Ugly FDCs
– those that have neither evidence nor theoretical justifications. There could be
a possibility of adverse event because of wrongful administration of an unnecessary
component, or where the dose titration is required. Some examples of such bizarre
combinations are formulations having cough syrups with two or more antihistamines
+ decongestant + bronchodilator + cough suppressant + expectorant and antifungal +
antibiotic + steroid + topical local anesthetic.
Due to the difficulties in developing new chemical entities, the pharmaceutical industry
finds it easier to develop FDCs. India is primarily the market of generic drugs. As
the patent expires, the intense competition among multiple manufacturers tempts them
to give the product a new look claiming multiple advantages without scientific validation.
By the Drug Price Control Orders 2013, the drugs included in the NLEM were brought
under price control by the National Pharmaceutical Pricing Authority of India. To
evade the price control, some companies reformulate the individual drugs into an FDC.
This loophole has since been checked.
The Regulatory Response to Proliferating Irrational Fixed Dose Combinations
Many articles in print media and Nongovernmental Organizations questioned the rationality
of FDCs. Drug regulator of India (CDSCO) came out with the policy guidelines for the
approval of FDCs in 2013.[1] CDSCO has periodically banned various FDCs due to reasons
such as lack of rationale or evidence and potential safety concern. In 2007, the Drugs
Controller General of India (DCG [I]) issued edicts to all SLAs to withdraw 294 FDCs
which were not approved by CDSCO. However, the industry disputed the ban and the matter
is currently subjudice.[2]
The Parliamentary Standing Committee on Health and Family Welfare in its 59th report
pointed out that some SLAs have been issuing manufacturing licenses for FDCs without
prior clearance from DCG (I).[3] Subsequently, the DCG (I) issued a circular on January
15, 2013, directing the manufacturers to prove the safety and efficacy of FDCs licensed
by the SLAs prior to October 1, 2012, within 18 months, failing which they would be
considered for being prohibited from manufacture and marketing in India.[4] The FDCs
approved before year 1988 were exempted. In response, 6220 applications were received
from the industry.[2]
In September 16, 2014, Ministry of Health and Family Welfare (MOH and FW) constituted
a committee for examining the applications for rationality, safety, and efficacy of
the FDCs.[2] The committee submitted its report to the MOH and FW on April 16, 2015.
It classified FDCs into 4 categories: (i) Category “a” – FDCs considered as irrational
and the show-cause notices were issued to the manufacturers; (ii) Category “b” – FDCs
requiring further deliberations with subject experts; (iii) Category “c” – FDCs considered
as rational and letter of approval was sent; (iv) Category “d” – FDCs requiring further
generation of data. Accordingly, letters were sent to submit phase four trial protocol
to the manufacturers. Replies from manufacturers against show-cause notices with respect
to 1083 irrational FDCs under category “a” were examined and the recommendations were
submitted on February 10, 2016.[5] Based on findings of the expert panel, on March
10, 2016, 344 FDCs were prohibited under Section 26A of Drugs and Cosmetics Act, 1940.[6]
The industry moved the Hon’ble Delhi High Court seeking a stay on the ban notification
citing the lack of regulatory power of the CDSCO to ban the manufacture of FDCs without
revoking the license to manufacture given by the SLAs. Questions were raised on the
procedure adopted by the DCG (I) such as not consulting Drugs Technical Advisory Board
and Drugs Consultative Committee to decide on the prohibition.[7] The Government defended
saying that the step of prohibition of the irrational FDCs was taken considering the
public interest and the delay in administrative procedures in revoking the license.[8]
A notification issued by DCGI on June 17, 2016, CDSCO has requested the concerned
pharmaceutical manufacturers to furnish the Phase IV clinical trial protocol for the
FDCs.[9] Despite all these, the original question of regulating and weeding out irrational
the Bad FDCs and the Ugly FDCs is left in limbo among these technical and procedural
convolutions.
What Interventions are Needed to Prevent Use of Irrational Fixed Dose Combinations?
To curb the irrational use of FDC in India, a multistep approach involving all stakeholders,
for example, consumers, physicians, regulatory authority, industry, and the academicians,
is needed. The enforcement mechanism by the regulators needs to be strengthened. Both
the central and state regulators must harmonize their procedures for licensing FDCs.
Good pharmacovigilance should be ensured to assess the performance of the product
in clinical practice. Industry should act responsibly, ensuring the adequate rationale
to develop FDC and generating robust efficacy and safety data. National Formulary
of India, NLEM, and Standard Treatment Guidelines should be adopted across different
levels of health services. CMEs on drug information, training medical and pharmacy
students with an orientation toward the public health implications of FDCs misuse
and good prescribing and pharmacy practices will go a long way in addressing the knowledge,
attitude, and practice gap of practicing physicians and pharmacists. A multipronged
corrective approach involving regulator, academia, industry, physicians, and public
is needed to correct the dismal FDC scenario in the country.