Why is it in the News?

A group of academics from India, Qatar and the United Kingdom recently published a worrying new study in the Journal of Pharmaceutical Policy and Practice on the volume of unapproved and even banned fixed dose combinations (FDC) of antibiotics being sold in India.

News Summary:

• In the Journal of Pharmaceutical Policy and Practice, a group of academics from India, Qatar, and the United Kingdom recently released a concerning new study on the amount of antibiotics that are being sold in India that are not allowed or even prohibited as fixed dosage combinations (FDCs).
• The analysis, which makes use of pharmaceutical industry sales data, shows that in 2020, 60.5% of FDCs containing antibiotics (or 239 formulations) were unapproved, and another 9.9% containing 39 formulations were being distributed in the nation even though they were prohibited.
• The fact that antibiotics are present in so many of these illicit or prohibited FDCs is concerning given the rising incidence of antimicrobial microbial resistance (AMR) in India.

What are the Fixed Dose Combinations (FDCs) Drugs?

• FDCs are combinations of one or more known drugs and can be useful in treating some diseases since the combination can improve patient compliance.
  • For instance, if a patient has to take three different medications for a particular treatment, she may forget to take one.
  • But if all three medications are combined into one tablet or one syrup, the chance of her forgetting to take one or two of the drugs is reduced.
• For diseases such as AIDS, it is well documented that FDCs have proven to be very useful in improving patient compliance, which at the end of the day improves treatment outcomes.

Concerns with FDCs Drugs?

• Making FDCs is not an easy job, even though most consist of drugs with known safety and efficacy profiles.
• All drugs have side effects. When formulated together, there is a possibility that the active ingredient or excipients (inactive ingredients) may affect how each drug functions.
  • For example, the drugs may interact in a way to reduce the therapeutic efficacy of each active ingredient, or, worse, the drugs may interact with each other to create a more toxic element, often called metabolites.
• This is why all FDCs must go through a scientifically designed approval process where such interactions can be evaluated.

Advantages of Fixed Dose Combinations:

• FDCs increase patient adherence, streamline treatment, and optimize the advantages of the combined therapeutic actions of the two medications.
• Treatment for infectious diseases: A significant portion of India's population is afflicted with infectious diseases.
  • FDCs are very helpful in the treatment of infectious disorders when it is customary to administer numerous antimicrobial drugs, such as HIV, malaria, and tuberculosis.
  • Additionally useful in chronic diseases, FDCs are especially beneficial when co-occurring disorders are common.
• Affordability and accessibility: FDCs have particular benefits over single entity preparations, including improved efficacy, a lower likelihood of side effects, potentially lower costs, and easier distribution logistics that are pertinent to resource-constrained scenarios like those in India.

Challenges Associated with Fixed-Dose Combinations (FDCs):

• Increased Risk of Side Effects: Combining multiple active ingredients in FDC drugs heightens the risk of adverse drug interactions and increases susceptibility to side effects.
• Patients may exhibit heightened sensitivity or allergic reactions to specific components, posing challenges in identification and management due to the fixed combination.
  • For instance, a single FDC drug containing Paracetamol, Bromhexine, Phenylephrine, Chlorpheniramine, and Guaiphenesin may elevate the risk of side effects like drowsiness, dizziness, and increased blood pressure.
• Regulatory Challenges: Regulating FDC drugs prove challenging due to the complexities associated with evaluating the safety and efficacy of multiple active ingredients in a single formulation.
  • Maintaining quality control and standardization for FDC drugs becomes more demanding compared to single-component medications.
• Overuse and Misuse: FDC drugs can contribute to the overuse and misuse of medications.
  • Patients might unknowingly consume multiple active ingredients unnecessarily or in inappropriate combinations, leading to potential health risks.
• Lack of Evidence-based Clinical Data: Approval of some FDC drugs may be based on limited or insufficient clinical evidence supporting their efficacy and safety profiles.
  • The absence of robust scientific data raises concerns about the appropriateness and reliability of FDC drugs for specific medical conditions.

Why are FDCs banned in India?

• Patients may not need that many drugs; thus, they are subjected to additional side effects.
• Some drug doses have to be individualized based on the patient's condition.
  • This is not possible when using FDCs.
• Some companies have been selling FDCs in India under this pretext without consulting the central government, as seen with the cefixime-azithromycin combination, which has already been banned.
• These non-essential FDCs, therefore, do more harm than good by encouraging irrational and indiscriminate prescribing of multiple drugs than necessary.

Some Examples of (Banned Fixed-Dose Combination) Drugs in India:

• Fixed dose combination of Aceclofenac + Paracetamol + Rabeprazole
• Fixed dose combination of Nimesulide + Diclofenac
• Fixed dose combination of Nimesulide + Cetirizine + Caffeine

How is the Pharmaceutical Industry Exploiting Loopholes in India's Legal Framework?

• Pharmaceutical companies in India use these FDCs to escape liability under multiple laws without much concern for public health.
  • One such law is the Drugs (Prices Control) Order (DPCO), under which the government fixes the prices of individual drugs.
  • Since drug combinations were traditionally not covered under the DPCO, the pharmaceutical industry decided that making FDCs provided an easy way to escape the remit of the DPCO.
• Motivated solely by market-driven pragmatism rather than a commitment to public health, the Indian pharmaceutical industry introduced an extensive array of FDCs lacking any discernible medical rationale.
  • For example, anti-inflammatory drugs were combined with vitamins, anti-histamines were combined with anti-diarrhoeal agents, penicillin was combined with sulphonamides, and vitamins were combined with analgesics.
• These were combinations not found in any other country.

The pharmaceutical industry benefited in two ways.

• Firstly, the wide range of FDCs in the market meant no standards were set by bodies like the Indian Pharmacopoeia Commission, shielding manufacturers from quality testing and potential legal consequences.
  • Essentially, the pharmaceutical industry could dictate its testing standards when FDCs were sampled for government testing.
• Second, the FDC approach provides companies with a justification for higher drug prices. For instance, if multiple companies sell azithromycin individually, they must compete and lower prices.
  • However, combining it with another drug in an FDC allows them to market it as a unique solution, justifying higher prices until competitors introduce similar products.
  • This system rewards pseudo-innovation rather than true medical breakthroughs, allowing dubious FDCs to command elevated prices, supported by doctors who may presume regulatory oversight.

Is there any Regulatory Framework Addressing the Issue of FDCs?

• The FDC problem has been on the regulatory radar since 1978 when the first government committee studied the issue and admitted that we had a problem on our hands.
• At the time, there was no system under the colonial-era Drugs and Cosmetics Act, 1940 to vet drugs for safety and efficacy before their sale in India.
• This meant that each State drug controller could hand out manufacturing licences for any drug formulation and there was little that the central government could do to stop their sale.
• In 1982, Parliament changed the law to give the central government the power to “prohibit” the manufacture of specific drugs that lack therapeutic value or justification.
• Later 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).
• These amendments also made it clear that State drug controllers could not grant “manufacturing licences” for “new drugs” that are not approved for safety and efficacy by the DCGI.

Is Unabated Licensing Undermining FDC Regulation in India?

• Despite clear legal provisions, State drug controllers continue to overlook regulations, issuing manufacturing licenses for Fixed-Dose Combinations (FDCs) not approved by the DCGI with impunity.
  • Manufacturers selling these unapproved FDCs technically expose themselves to prosecution by the Central government for violating the law.
• Rather than pursuing criminal prosecutions, the Ministry of Health is engaged in a reactive approach, frequently utilizing its powers under Section 26A to prohibit the manufacturing of specific FDCs.
  • Since 1983, 444 orders have been issued under this provision, primarily targeting FDCs. Many of these orders have become entangled in intricate legal disputes, with inconsistent court decisions further complicating the regulatory landscape.

Conclusion

The fact that these academics have discovered 239 unapproved FDCs being sold in 2020 in just one category of FDCs more than 42 years after the problem was first flagged is an astonishing indictment of the incompetence of the drug regulatory framework in India. As they point out in their paper, unregulated FDCs may end up contributing to the AMR problem in India. The Ministry of Health needs to take immediate action.