Urban women who hit puberty in the late 1980s will probably be familiar with Baralgan. A popular brand made up of analgin and two other drugs, Baralgan provided relief from the pain of menstrual cramps that countless young women experience. To my adolescent self, Baralgan was a magic charm; just one tablet had me on my feet and ready to face the day, instead of curling up in bed, wallowing in pain and self-pity.
In 1996, the Indian government banned the combination of the drug analgin with any other drugs. Apparently, even as I was merrily popping it for pain, the scientific and regulatory community had been discussing whether analgin could send people to the emergency room.
The ban was the result of global concerns about the safety of analgin. The drug was linked to serious side-effects such as a severely compromised immune system. Regulators the world over were grappling with whether these occurred often enough to entirely discredit the drug. Indian activists called for an outright ban.
Instead, the Indian government banned the combination of analgin with other drugs. Globally, such combinations were panned for being less safe than analgin by itself, without adding substantial benefit.
But even today, analgin on its own can be legally sold in India. While the government did get around to banning it last year, it reversed its own order earlier this year making it legal to sell analgin once again. True, its use has been severely restricted to “severe pain, or pain due to tumour and as a final option for bringing down fever when other anti-pyretics fail.” But India has acted contrary to over a dozen countries including the US, France and Australia who no longer allow it on their market.
Analgin is just one among many such drugs—sold in India, banned elsewhere. Last year, the newspaper Mint reported that there were at least 13 such medicines.
To most people, this might sound plain wrong. Either a drug is safe or it’s not, right? Unfortunately, the answer is not a simple yes or no.
How it works
The first thing to understand: A country’s drug regulator is well within its rights to decide which medicines are suitable for its population and which ones aren’t. Indeed, that is what it is there for. What matters is whether it has systems in place to discharge its responsibilities.
In what pharmaceutical companies call “established” markets—such as western Europe and the US—where new drugs are almost always launched first, regulatory agencies approve a drug based on the results of safety and efficacy trials on human volunteers. As no drug is entirely free of side-effects, agencies take a decision based on the risk-benefit ratio. It is the regulator who decides that certain risks are acceptable when compared with the drug’s benefit. That is why, for example, chemotherapy drugs—which have some severe side-effects—are approved for launch.
Regulators in so-called emerging markets such as India take their cues from the West. They usually prescribe a safety and efficacy trial on roughly 100 Indian volunteers so long as the drug is approved in its home country or a major market. Since India is predominantly an off-patent drugs market, a number of companies other than the drug’s innovator have traditionally made their copies of the drug available here, sometimes before the innovator.
Since the regulatory barriers to entry are relatively low, India has hundreds of companies selling thousands of drug formulations.
A second opinion
This approach has pitfalls. First, while in most cases drugs pass muster with all major regulators, in some cases that does not happen. So one country may approve a new drug, another might not for any number of reasons, including politics. Or there may be a considerable lag between approvals. Whose call should India heed?
Second, more relevant to the issue of banned drugs is that a medicine may prove unsafe after it has been marketed. When all is said and done, a trial is still, well, a trial. It is limited in its scope. Even a drug approved after rigorous clinical trials might throw up unacceptable risks when given to a larger population. New side-effects may come to light or known ones might occur more frequently than anticipated. The most famous case in recent history is Merck’s anti-inflammatory drug Vioxx which raked in millions of dollars in revenues before being withdrawn for cardiovascular side-effects.
That is why well-regulated markets have systems to monitor new drugs post-approval. This is usually a combination of post-market surveillance of new drugs and regulatory activity to get information about side-effects from doctors, hospitals, patients etc. The system works imperfectly, but it does work. Not only does this help to take dangerous drugs off the market, it also helps to keep the safe ones firmly in by proving that the drug is safe and effective to the larger community.
Experts including the World Health Organisation believe that every country should have its own such system, known as pharmacovigilance. After all, there could be genetic or racial differences in the way humans react to a medicine. For instance, a drug might be toxic at a high dose but most Indians might need only a small dose (for reasons such as lower average body weight). Also, the richer the data, the better it is for decision-making the world over.
For the longest time, India did not have such a system in spite of its stature as a large producer and consumer of drugs. Drug companies flouted post-market surveillance rules. A system, which involves a network of doctors, hospitals and pharmacies that can feed information into a database, is now being rolled out after several abandoned efforts.
However, even now India relies heavily on the West even for post-market safety signals. This tends to get sticky. If two major market regulators take contradictory positions, what should India do?
The most recent instance is pioglitazone. The anti-diabetes drug is widely prescribed in India. Around 3 million patients were estimated to be on it last year. France banned it in 2011 for its potential to cause bladder cancer. India reacted last year with its own ban. There was an uproar among companies, doctors, patient groups. Many observed that the US still allows it to be sold with a warning and panned the decision as anti-consumer.
Guess what happened? Pioglitazone was put back within a couple of months albeit with updated warnings. The government caved in to the argument that a ban would force patients to move to pricier options or insulin (which being an injection would impact patient compliance).
Here’s the irony. The ban was not based on India-specific pharmacovigilance data, nor was its reversal. While a few studies were referred to by Indian doctors, these are merely a drop in the ocean of patients on pioglitazone and therefore hugely inadequate. The same was the case with analgin. So which of the two actions was right? The ban or its reversal? You will get vehement views on both sides of the debate.
Read the minutes of the meeting of the expert board that advised the regulator on these two drugs here. The tell-all sentence: “The need for having detailed pharmacovigilance data for arriving at such a conclusion cannot be overemphasised.”
India needs its own facts
This is not the first such case and it won’t be the last. India’s ministry of health knows this is an untenable situation. Last year, it appointed a committee of experts to advise it on the best way to tackle drugs that get banned elsewhere. Based on its recommendations, the Indian drugs regulatory agency said recently that, “if two or more countries remove a drug from their market on grounds of efficacy and safety, then the continued marketing of the drug in the country will be considered for examination and appropriate action.”
Reviewing is good if the reviewer has solid, representative data of the drug’s use in the country. For that, India’s pharmacovigilance effort has to be scaled up rapidly. Note that last year, it captured over 33,000 side-effects but in contrast China’s database had a record of over 600,000. (Again, side-effects by themselves are not grounds for a ban unless they adversely skew risk vs benefit).
Intuitively, I believe that in most cases drugs work like they’re supposed to and no one’s the worse for it. But then I also think of Baralgan with fondness, not dread. The truth is that safety cannot be based on intuition nor, beyond a point, on borrowed facts. Definitely not in the world’s fourth-largest pharma market by volume. To protect its citizens, India needs its own facts and it needs to put them to work.