India's therapeutic jungle

On December 1, the Delhi High Court set aside a bunch of notifications prohibiting manufacture and sale of 344 fixed dose combinations (FDCs). In its ruling, the court found gross procedural violation on the part of the government and cancelled all the notifications, but importantly, said it could not adjudicate whether the FDCs are risky or not. The big question now is will the Centre move the Supreme Court?

The recent Delhi High Court judgement which set aside a bunch of central government notifications prohibiting manufacture and sale of 344 fixed dose combinations (FDCs) in India raises deep concerns. The fact that as many as 454 petitions were submitted shows how important FDCs are for the bottom line of the pharmaceutical industry.

India’s pharmaceutical industry is mighty, with over Rs 2 lakh crore worth of medicines and vaccines, produced and supplied by a strong 7,000 manufacturing units. It caters to not only the domestic market, but it also exports to over 200 countries. India is called the pharmacy of the global south.

At the same time, the Indian pharmaceutical industry carries a dubious distinction of producing and supplying the maximum number of irrational and inessential FDCs. The social costs and public health consequences of producing FDCs way exceed the profits it yields to the industry. Of the 34 million plus people who fall below the poverty line while paying for medicines, a good proportion gets impoverished due to consumption of quintessentially irrational FDCs.

Traditionally, allopathic drugs have been originally discovered, produced and consumed as single active pharmaceutical ingredient (API). These active pharmaceutical ingredient formulations are generally discovered after going through 12-15 years of clinical trials and introduced into the health systems when chemical/biological therapies satisfy stringent criteria for safety and efficacy. In recent years, pharmaceutical companies have discovered the art of combining more than one API to invent FDCs.

But such introductions in the well-regulated western world have been few and far between. When FDCs are introduced, the drug regulatory authorities in the western world ensure that the new formulation, created by combining two or more existing molecules, also go through the rigour of clinical trials for safety and efficacy. The stated objective of combining two or more molecules is to ensure the adherence to treatment regimen by the patient and to keep the costs down.

As per the current count, drawn from IMS data source, the number of branded medicines stands over 32,500, most of which are unregulated FDCs. Such a magnitude of brands is unheard of anywhere in the world.

In India, access to medicines and vaccines is not only hindered by the affordability factor but also by a large majority of prescriptions that are driven by industry influence, a well-oiled machinery and by its strong promotional tactics. Such prescriptions are often not only considered inessential but primarily irrational, by scientific standards. In addition, a poor regulatory mechanism coupled with a lack of clear authority between the Centre and the states’ drug regulatory systems have unleashed `therapeutic jungle raj’ in the country.

Pharmaceutical companies, both Indian and multinational, have perfected the art of supplying such FDCs without due regard to regulatory approvals. As a result, at present, 17,975 medicine brands in India are FDCs. By market value, half of the medicines sold in India are FDCs in nature. In volume terms, this works out to nearly two-third of all medicines sold in the country. By contrast, in the well-regulated markets of Europe, the US and other rich countries, FDCs accounted for less than 5% of the entire market.

Such combination products are approved but to a limited extent in well-regulated markets in recent years in certain therapeutic areas, including HIV/AIDS, CVD (Cardio Vascular Diseases), diabetes etc. In the World Health Organisation’s Essential Drug List (EDL), 2015 – a model therapeutic list of 480 medicines - 28 are FDCs. The EDL is currently adapted by several countries around the world, including the central and state governments, for use in government health facilities.

However, the menace of FDCs in India is found in most therapeutic groups. By value terms, the highest share of FDCs exists in the therapeutic segment for respiratory medicines (75%), followed by vitamins/minerals/nutrients (73%), anti-tuberculosis medicines (67%) and anti-diabetes (65%). One of the growing segments that is driving the Indian pharmaceutical market in recent years is the FDC market in the CVD segment. Among the anti-infective category, over 40% of drugs sold in the market are FDCs. While the safety and efficacy of most FDCs are in question, the growing threat of anti-microbial resistance in India is also exacerbated by the production and supply of FDCs in this segment.

Sold before approval?
Most FDCs are not tested for its safety and efficacy in clinical trials in any part of the world. It is found that several FDCs were marketed before the Central Drugs Standard Control Organisation (CDSCO) approval. The state drug regulatory agencies first permitted manufacture and sale of these drugs, and then subsequently, they were approved by CDSCO. It must be noted that CDSCO is the sole authority to approve a new drug, while state drug controllers have the authority to only approve manufacture and sale of medicines approved by CDSCO.

Recognising the irrationality of most FDCs, civil society groups, patient groups and academics have long argued the need for weeding them out from the market. Earlier, the Drug Controller General of India had attempted to ban 294 FDCs in 2007. But utilising the loopholes in legislation and multiplicity of authorities governing drug regulation, the pharmaceutical companies got together to stay the ban on FDCs, from the Madras High Court.

Interestingly, a particular pharmaceutical company has decided to withdraw one of its FDCs from the market despite stay on the ban. While a voluntary withdrawal is certainly a good beginning, multinational drug companies need more soul searching. It is unfair that while multinational pharmaceutical companies do not produce such irrational drugs for regulated markets, they have flooded the Indian pharmaceutical market with FDCs. The ethical nature of such business proposition must be questioned.

The need of the hour is to scientifically obtain data and information about the magnitude and extent of irrationality of medicines in the market. While evidence is certainly critical, regulatory authorities, both at the Central and state levels, must be adequately given powers and independence to weed out medicines that are inefficacious and pose public health risks. Political support at the highest level is even more critical to supplement regulatory reach.

(The writer is senior health economist,  Public Health Foundation of India)

A rational FDC
1. The combination of ingredients meets the requirements of a defined population group
2. The FDC has proved to be definitely advantageous over single compounds.
3. The drug in the combination should act by different mechanisms
4. The mix should not result in toxicity.
5. Examples: sulfamethoxazole + trimethoprim; rifampicin + isoniazid, isoniazid + ethambutol (used for Tuberculosis) and levodopa + carbidopa (used for Parkinson’s disease).
6. When the above criteria are not met, the FDCs would be termed irrational.
7. One example is nimesulide + paracetamol formulations for children
8. WHO’s model list of Essential Medicines includes only 24 FDCs (out of 358)
9. India’s National List of Essential Medicines includes only 16 FDCs (out of 348).
10. But an estimated 40% of the Indian market for drugs comprises of FDCs, generating thousands of crores of rupees for pharma companies

The rule
FDCs containing drugs combined together for the first time are treated as ‘New Drugs’. These require permission from the Drugs Controller General of India before they could be licensed by the state licensing authorities for manufacture and sale in the country.

The violation
In 2012, a parliamentary committee reported that manufacturing licences for large numbers of FDCs had been issued by state authorities without prior approval of the Central Drugs Standard Control Organisation.

The action
*The Centre issued 344 Gazette Notifications on March 10, 2016, prohibiting manufacture, sale and distribution of FDCs for human use in public interest as they were likely to involve risk to human beings, and safer alternatives were available.

*The notifications were issued after a detailed scientific assessment and examination of all pertinent issues. This was done by a nine-member panel headed by C K Kokate, former president of Pharmacy Council of India, presently vice-chancellor of KLE University, Belagavi.

*Some well-known medicines which were banned include Pfizer’s Corex cough syrup, P&G’s Vicks Action 500 Extra; Reckitt Benckiser’s D’Cold, Piramal’s Saridon and Glenmark’s Ascoril and Alex cough syrups.

*Drug companies challenged the notifications before the Delhi High Court, which heard 454 petitions. They obtained a stay from the court allowing the sale to continue.

The Verdict
*The Delhi High Court quashed these notifications on December 1, 2016

*Justice Rajiv Sahai Endlaw said the court could not adjudicate whether the FDCs are risky to consumers or not. These aspects are to be considered by DTAB (Drugs Technology Advisory Board) and DCC (Drugs Consultative Committee)

*Justice Endlaw looked at the legal procedures followed for issuing these notifications and found that all the 344 notifications were issued without following the procedure statutorily prescribed. The government also did not consult the DTAB and DCC before issuing them.

*The judge said he found no merit in contention that DTAB was not involved in the approval of the drugs. He differed with the Additional Solicitor General’s opinion that DTAB-DCC were incapable of rendering the service as given by an expert panel (Kokate committee)

*He found violation of procedures as the central government invoked Section 26A of the Drugs and Cosmetics Act without involving DTAB and DCC.

*The technical sub-committee of DTAB had found guidelines on ingredients of cough matrix in order. Also the FDC for dry cough are alright as per the DTAB. The DCC, too, found therapeutic justification. Justice Endlaw said a non-statutory panel cannot disregard those opinions without carrying out any test.

The Reprimand (from the judgement)
“To say the least, the Central Government, though acting in public interest, seems to have gone about it in a haphazard manner. It claims that the FDCs for manufacture of which licences were issued by SLAs between September, 1988 and 1st October, 2012 without the same having approval of the Drugs Controller were wrongly granted such licences. However instead of taking action for cancellation of said licences, the manufactures were asked to apply for licences to be Drugs Controller, while continuing to manufacture the drugs for which according to the Central Government licence was wrongly given.

When such applications were received, instead of the same being considered by the Drugs Controller, who is vested with the power of approval, 10 committees were constituted for considering the applications.

After the said committees failed to examine all the applications, the Kokate Committee was constituted. The Kokate Committee, instead of considering the applications for approval, went into the aspects of risk to consumers and therapeutic value and therapeutic justification and on receiving report whereof impugned Notifications were issued.”