The fixed dose combination (FDC) issue has been a contentious one for years and on March 10 came back to haunt pharma companies in India. A 288-page government notification listed 300-plus FDCs which were deemed to ‘have no therapeutic justification’ and therefore banned from manufacture, sale and distribution in the country.
What is the way forward? Do we throw the baby out with the bath water? The concept of FDCs does have its benefits. Patient compliance is better when there are fewer medicines to consume and FDCs are a practical way to achieve this. But there should be enough evidence that the FDCs are rational and safe. All regulators agree that the burden of proof is on the pharma company. Absence of ill effects should not be taken as proof of safety and efficacy, especially in a country like India where the pharmacovigilance framework is still very nascent.
SV Veerramani, National President, IDMA may be justified that a minimum of a year should be provided for phasing out such formulations unless they pose an imminent health risk. This time lag is to presumably allow stocks in circulation to be used up or called back. But IDMA’s stance that these FDCs have been in wide use for decades without any adverse reports, either with regards to efficacy or safety, will not hold for long.
Other countries’ regulators too undertake a periodic review of FDCs. For instance, in May 2015, the US FDA announced plans for a new regulation on FDCs and co-packaged drugs. The proposed rule would ‘create a single set of regulations for prescription and OTC combination drugs, and codify existing policy on what kinds of studies are needed to show that the combination drug requirements are met.’ FDA’s Transparency Initiative and FDA Transparency Results Accountability Credibility Knowledge Sharing (TRACK), which provides a list of FDA’s upcoming rulemakings, lists the projected publication date for this regulation (RIN0910-AF89 ) as April 30 this year.
Past guidances from the US FDA provide a clue to the agency’s views on FDCs. A Guidance dated May 2004 titled ‘Fixed Dose Combination and Co-Packaged Drug Products for Treatment of HIV’ is clearly motivated by concerns that the FDC concept is being abused and in fact singles out non-FDA evaluated FDCs ‘being promoted in resource poor nations where HIV-1 has reached epidemic proportions.’ Though the US FDA concedes that these FDCs ‘may offer cost advantages and allow simplified dosing because two or three drugs are combined in one pill’, the Guidance stresses that ‘products whose safety, efficacy, and quality do not conform to expected standards may pose a threat to individual patients by increasing the chances of substandard performance, which may lead to not only treatment failure, but also the development and spread of resistant virus.’
MSF makes the same distinction, between rational and irrational FDCs, when it hails the March 10 notification, pointing out that ‘the list of banned drugs includes several FDCs containing multiple antibiotics that have long been used injudiciously, contributing to the development of resistant strains of infection-causing bacteria.’ India’s increasing burden of drug-resistant tuberculosis (DR-TB) is due to the easy access to irrational FDCs containing anti TB drugs such as quinolones (ofloxacin and levofloxacin) and linezolid, says the MSF release.
The main grouse of the industry to the March 10 notification is that so many FDCs were banned in one go. But the current crackdown on FDCs by the Indian authorities has been on the cards for quite some time. The regulator has been trying to net irrational FDCs since 1988, when the Drugs and Cosmetics Rules, 1945 (Rules), were amended to mandate prior permission from the Licensing Authority i.e., DCG(I) before import or manufacture of FDCs (See article by Abhijeet Das, Senior Associate, Singhania and Partners which analyses the FDC bans in the past, and the various legal arguments open to pharma companies. http://www.expressbpd.com/article/pharma/latest-updates/dcgi-bans-344-drugs-constituting-fixed-dose-combinations-but-will-it-hold/228027/)
Clearly, the industry ignored the warning signals. Self regulation and a review by each company over the years would have prevented the proliferation of irrational FDCs. But it is tough to stay on the narrow path when it is easier to evade the regulator. Many companies have got stay orders on the ban, but pharma companies will incur increased litigation costs, while government will lose time, effort and resources attempting to enforce the ban. Courts too are giving contrary verdicts, with the Delhi High court staying the ban on while its Chennai counterpart refused to do so. On all sides, there is a further erosion of trust, which does not bode well for the future.
One hopes that this time around, there will be some closure, fast.