India has been in the forefront of combination therapy. As early as 2001, Cipla, a pioneer in anti-retroviral therapy, introduced the world’s first ever 3 in 1 fixed dose combination (FDC) to fight AIDS. Combivir, Trizivir and many combinations and kits followed by globally with astonishing synergistic results. India had, all along, continued to work on combination drugs. Since ayurvedic formulations in ancient texts had extensively been based on synergistic combinations including use of TRIKATU and TRIBHALA, India had already inherited strong faith in combination therapy in its genes. Over the years, India had experimented on antibiotic combinations too. One of the early antibiotic combinations was streptopenicillin, of the sixties which was very effective for throat infections, but has since been banned as declared irrational. Many Indian pharma companies introduced oral formulations/dosage forms with 2 to 3 antibiotics with or without lactobacillus. In antibiotic resistant and persistent upper respiratory tract and lung infections, these combinations had been showing extra-ordinary beneficial results.
However, in recent times, partly because of PILs and NGO pressures and partly pushed by the judiciary, the regulators have come down heavily and “surprisingly irrationally” on the so called “irrational” FDCs. The origin of this initiative is still apparently unknown. But, the recent sweeping ban on FDC, which were in market for several years, appears to succeed in destroying the advantage and the lead that India had established over developed countries, who could very well have been beneficiary of the steam rolling against FDC in India.
In the meantime, antibiotic combination therapy has been found to be effective against drug resistant infections in recent research. A recent report in The Times of India dated July 25, 2016 have highlighted the research findings which astounding results. According to this report, combination of 3 antibiotics increases effectiveness against antibiotic resistant injections. It is reported that 700,000 or more patients die from antibiotic resistant injections. According to the UCLA Research paper, the researchers comment that the three drug combinations can have really beneficial results which is supporting much higher than those ever predicted from all pairs of antibiotics. As per the report “different classes of antibiotics use different mechanisms to fight bacteria. One class, which includes amoxicillin, kill bacteria by preventing them from making cell walls. Another disrupts their tightly coiled DNA. A third inhibits their ability to make proteins. But there had been little previous research indicating that combinations of three antibiotics might be more potent together than any two of them”. The research was published in the proceedings of the National Academy of Sciences.
Having been associated with the Indian pharma industry for nearly 50 years, the current FDC controversy has erupted abruptly causing serious problems for the Indian pharma industry, at a time when the Indian pharma is already reeling under the international non-tariff barrier pressures and hurdles. The intensity with which the “powers that be” at the helm of this “FDC ban” has steam-rolled the ban process reeks of external pressures to obliterate the advantages built up by Indian pharma over the last 30 to 40 years.
Regulatory systems such as FDA, CDSCO, DCG(I), FSSAI are bound and governed by respective laws, acts and rules. These have provisions to safeguard the interests of the consumer by providing for quality efficacious medicines for the patients. When more than one drug is combined rationally, this can lead to synergy, in which case, if novel, can lead to patentability. Even if not novel, inventive and devoid of synergy and hence not patentable, the combination drugs can lead to patient benefit by avoiding to have to take multiple drugs in independent doses. The expertise and experience gained by India on combination therapy is being deeply impacted negatively by this ban of FDCs. Need for existing FDCs in the market to freshly conduct clinical studies, at a time when the clinical trial options systems and infrastructure itself is similarly dented and disturbed, is further complicating and negatively being impacted. In spite of severe NGO pressures domestically the Indian pharma has been surviving from export-sales and profits. With pressures of US FDA inspections in the new formats, the NTBs such as PICs and TPPs like treaties from overseas markets, the Indian regulatory agencies and their lead ministries need to review the rationale behind multi-pronged attack on the Indian pharma industry, among which the “FDC ban” is the latest “bolt from the blue”.
As such, a more positive approach to the FDCs in India (past, present and future) need to be adopted by the Health Ministry, as well as whosoever is pushing this negative initiative intensively.
Jagat Prakash Nadda on behalf of Government of India, replied to the starred question No.172 in Rajya Sabha as follows: (a) & (b) The Government of India has so far prohibited/restricted/suspended 439 drugs for manufacture for sale, sale and distribution in the country. Out of these, 95 drugs (Annexure I) had been prohibited/suspended/restricted earlier. These are not being marketed in the country. However, in respect of one drug, the prohibition has been stayed by Madras High Court. Further, 344 drugs (Annexure II) which are FDCs had been prohibited by the Central govt on 10.03.2016. A large number of petitions have been filed in different High Courts in respect of most of these FDCs, and most of the notifications issued by the Central govt have been stayed. The matter is currently sub-judice. To avoid misuse of approved drugs in different parts of the country, concerned enforcement agencies take suitable action in the matter.
(c): The Government is committed to ensuring that the quality, safety and efficacy of drugs is not compromised and, has accordingly, taken action to prohibit/suspend/restrict the drugs that are not considered rational and safe for human use. In addition to this and to check that spurious, adulterated, misbranded, sub-standard and expired drugs are not marketed in the country and the quality of drugs is not compromised the government has taken a series of measures such as penalties including making certain offences cognizable and nonbailable; establishment of special designated Courts for trial of offences under the D&C Act for speedy disposal of cases; announcement of a Whistle Blower Scheme to encourage vigilant public participation for detection of movement of spurious drugs in the country; issuance of guidelines to the State drugs controllers for taking action on samples of drugs declared spurious, adulterated, misbranded or not of standard quality; instructions to the concerned staff to keep a vigil and draw samples of drugs for test and analysis for monitoring quality of drugs moving in the country; increase in the number of posts in the CDSCO; re-equipping Central drug testing labs with state-of-the-art equipment and their accreditation by NABL; undertaking a large scale nation-wide survey to determine the 'not of standard quality' drugs; conducting workshops and training programmes for skill enhancement in areas such as GMP, GLP, GDP, GCP and Good Storage and Distribution Practices to regulators and industry in partnership with other Departments, industry and regulators of other countries including USA and EU; conduct of training programmes for lab personnel of the State and Central labs to upgrade their analytical capabilities and skill sets; risk based inspection of manufacturing facilities after training of officials from the regulatory structures and laboratories both from the Centre and States together; and (xii) dissemination of information to all stakeholder about the measures required to ensure compliance with GMP and GLP through a simple check list.
The above measures will help in substantially reducing the incidence of not of standard quality drugs. The manufacture and marketing of prohibited drugs is a punishable offence under the D&C Act, 1940.
(Author is CEO, Gopakumar Nair Associates)