Come September 30, a new deadline that the Indian drugs regulator, Drugs Controller General of India, has set for state food and drug administrations to produce safety and efficacy data on scores of marketed fixed dose combinations – two or more molecules combined in specific ratios – from manufacturers, will lapse.
This is the latest effort by the DCGI to weed out a number of drug combos that, at best, have no scientific reason to exist and at worst, can cause harm. Will it work?
To those situated in better-regulated markets, the idea of a drugs authority beginning the process of data collection/analysis after a product has been on the market for some years might seem bizarre. But as those operating in the Indian pharma market will tell you, it’s not that simple.
In India, the responsibility of drug regulation is split between the DCGI (an authority reporting to the Union Ministry of Health) and the Food and Drug Administrations/health departments of states. A drug that is to be launched in the country for the first time needs approval from the DCGI. The manufacturer has to provide safety and efficacy data on Indian subjects. This first drug becomes a “reference” product and subsequent manufacturers of the drug have to demonstrate bioequivalence to this reference product for DCGI approval.
However, once a drug has been on the market for four years, a manufacturer can launch it by seeking a manufacturing licence from a state food and drug administration.
To all intents and purposes, an FDC is a “new” drug since it combines two or more different chemical substances. However, that is not how the states have viewed it. If each of the constituent drugs of an FDC has been approved by the DCGI, their combination is not considered “new.” States have issued licences with no safety and efficacy data deemed necessary to back up the approvals of such combinations. This has resulted in a plethora of so-called “irrational” FDCs – those that have no scientific justification – flooding the Indian market.
These approvals belie some widely-accepted truths about FDCs. One,they need a strong scientific justification backed up by data. A 2008 paper in the British Journal of Clinical Pharmacology (BJCP) observes that a drug combination is rational only if the constituent drugs have different mechanisms of action or ways of working in the body, are not released into, broken down, absorbed and eliminated by the body at widely different rates, and do not become more toxic when combined. (I have simplified the jargon in the paper for better understanding).
Two, as this would suggest they are nowhere as easy to develop as their numerosity in the Indian market might suggest. According to Bejon Misra, founder, Partnership for Safe Medicines India, some of the challenges include pre-clinical formulation development, keeping the drug stable throughout its shelf life, and matching the theoretical benefit of combining two drugs with actual clinical outcomes in efficacy and safety trials.
Ideally, FDCs should be preferred in two situations. One, when the combined effect of two or more drugs is better than any of the drugs on its own with acceptable side-effects. Two, when many drugs are to be taken over a long time by patients suffering from chronic conditions such as diabetes, combinations improve patient compliance and convenience. Sometimes, FDCs are also used to prevent resistance (such as in the case of malaria drug combos).
However, in all cases they have to meet the criteria spelt out earlier.
They’re lovin’ it
In India, manufacturers often gravitate towards FDCs for different reasons. Since India began rewarding drug patents only after 2005, the market continues to be overrun by me-toos or generics. Combinations help companies to differentiate.
Doctors appear to have been won over. Earlier this year, the International Journal of Basic and Clinical Pharmacology published a study of prescription patterns of doctors in tertiary hospitals in central India. The study found that out of 278 FDCs prescribed by various departments in the hospitals, just 5.4 per cent were “rational.”
And when the DCGI’s office first attempted to pull nearly 300 irrational FDCs from the market in 2007, manufacturers sued and obtained a stay from the Madras High Court that has yet to be lifted.
Foiled in its head-on attempt, the DCGI’s office has resorted to other methods. Earlier this year, it issued a notice to states asking them to license drugs by generic name and not brand name – a process that states complained would make it tougher to approve multi-ingredient drugs.
It is also upping its own standards. It issued a guidance note to manufacturers on FDCs and set up a committee of experts to spell out detailed policy guidelines to be followed while seeking approval for FDCs.
This expert report which combines elements of the DCGI’s guidance, the World Health Organisation’s guidelines and inputs from all stakeholders including manufacturers is awaiting comments. The report lists original data and/or data from scientific literature and/or a combination of the two (“hybrid”) as prerequisites to approve FDCs and suggests that most will require “hybrid” documentation.
This is important. For even some of the FDCs that experts have called irrational have been approved by the DCGI’s office in the past. One such instance cited in the BJCP is the FDC of anti-inflammatory drugs diclofenac and serratiopeptidase.
The authors point out that this combo does not offer any particular advantage over the individual drugs despite the claim that serratiopeptidase promotes more rapid resolution of inflammation. On the other hand, they observe that the patient is exposed to greater risk of gastrointestinal irritation and serious bleeding from unsuspected peptic ulceration.
This combination is listed as approved by the DCGI’s office since 2008. Medline lists over 30 such brands.
It is unclear what is to happen after September 30. There are many unanswered questions such as this one : if the state FDAs fail to collect the required safety and efficacy information on FDCs by September 30, 2013 what action can be taken by CDSCO and/or the states against the manufacturers? Or this one : whose responsibility is it to verify the quality and accuracy of the data that is submitted and also to ensure that it is bonafide and not fraudulent?
I asked these and other questions to the DCGI’s office 9 days ago. I have yet to receive an answer.
Pic sourced from http://www.dreamstime.com
This post has been edited to correct a small factual error in the second sentence under the sub-head ‘Uphill Battle.’ The DCGI issued a notice to states to “license” drugs by generic name and not “prescribe” drugs by generic name as stated in the original post. The author regrets the error.