REGULATORY DOSE

India makes a long overdue move to ensure better drug safety

The health ministry has made bioequivalence studies compulsory for some generic drugs.

In a long overdue move the Ministry of Health and Family Welfare has finally amended the law to make bioequivalence studies compulsory for certain classes of generic drugs manufactured in India. The government first advertised the draft amendments in early February for public comment and then formally amended the Drugs & Cosmetics Rules, 2017 through a notification on April 3 to incorporate the change.

Bioequivalence studies are studies conducted to establish that two medicines, normally the original patented drug and a generic version, have the same biological equivalence – that is, that they work the same way, to the same extent and for the same purpose. The new law required bioequivalence studies to be performed on drugs with low solubility. Although it is preferable to have a system of by which bioequivalence should be established for all drugs, this requirement is often waived for drugs that are highly water soluble as they are likely to with high solubility are considered to be more easily absorbed in the body.

In order to understand the significance of these amendments it is necessary to understand the history of modern drug regulation, especially in the context of generic medicines. The modern drug regulatory framework can be traced to the sixties when the United States amended its law to require drug manufacturers to demonstrate proof of efficacy of their new drugs. Until then the main policy objective of regulation was to ensure quality of drugs per the manufacturer’s specifications. Proof of efficacy required the conduct of extensive clinical trials, often requiring thousands of patients and the cost these days runs into hundreds of millions of dollars. The cost of clinical trials created a new entry barrier for competitors to enter the market after the patents over the original drug expired.

The United States Congress responded by enacting the Hatch Waxman Act in 1984 creating a new regulatory pathway that would enable competitors to introduce generic versions of the proprietary drugs without the requirement of repeating expensive clinical trials. The one mandatory requirement to gain approval for a generic under this new regulatory pathway was the conduct of bioequivalence studies. These studies are aimed at studying whether the generic drug behaves in the same manner as the innovator drug – that is, whether it dissolves at the same rate into the bloodstream thereby demonstrating similar therapeutic properties as the innovator.

Lower costs of generics

These studies are usually conducted on a much smaller group of healthy volunteers than is the case with clinical studies which are conducted on patients suffering from the disease in question. As a result, the cost of a bioequivalence study is only a small fraction of conducting full-fledged clinical trials. This practice of approving generics based on bioequivalence studies is one of the reasons that generic drugs are much more affordable than patented versions of the drugs.

The legal requirement in India under the Drugs & Cosmetics Rules, 1945 for conducting bioequivalence studies has, so far, been limited to only those generics that are approved by the Drug Controller General of India within the first four years of the innovator drug being approved in India. For example, if Pfizer has a new drug approved in 2012 after submitting clinical trial data, manufacturers of all generics versions for that drug to be launched in the market between 2012 and 2016 must seek permission from the Drug Controller General of India and submit data on bioequivalence studies in cases where there is no valid patent. For those generics entering the market after the four year process only require permission from state licensing authorities, who are not required to demand data on bioequivalence studies under the Drugs & Cosmetics Rules, 1945.

This distinction between generics approved within the first four years and those approved from the fifth year, has no basis in science and has without doubt jeopardised public health because state licensing authorities were in effect approving generics with absolutely no data on their performance. As a result doctors have been prescribing generics without having any data on the performance of these drugs. As a result most domestic manufacturers catering for the Indian market would wait till the fifth year and get approval to manufacture and sell generics without conducting bioequivalence studies.

Those manufacturers exporting to the US and the European Union would still be required to conduct these studies in order to gain marketing approval for those jurisdictions. In fact, even these companies have faced serious allegation of fraud regarding the manner in which these bioequivalence studies are conducted as exposed in the Ranbaxy scandal and more recently the GVK Bio scandal.

The Indian debate

In 2013, an expert committee headed by Dr Ranjit Roy Choudhary had recommended making bioequivalence studies compulsory for all generics irrespective of when they were approved. Surprisingly when this recommendation was discussed by the Drug Consultative Committee, which has all state drug controllers and the Drug Controller General of India as members, the recommendation was rejected not on the basis of science but on commercial feasibility. At its 47th meeting held in July, 2014 the Drug Consultative Committee stated the following while rejecting the Choudhary Committee recommendation:

“The recommendations of the Prof Ranjit Roy Chaudhury Committee in respect of Bioavailability or Bioequivalence (BA / BE) studies conducted in India were deliberated in detail. The members were of the view that BA / BE studies in respect of drugs manufactured in the country shall be insisted whenever there are issues relating to patient safety and variable bioavailability. As the infrastructure for conduct of such studies is not uniformly available in the country it cannot be implemented as a rule.”

The rejection of this view that bioequivalence studies should be undertaken on case by case basis was yet another egregious example of how decisions related to patient safety are guided by the commercial interests of the Indian pharmaceutical industry rather than public health. Even more egregious perhaps was the Drug Consultative Committee’s claim that India lacked the infrastructure to conduct such studies. At that point in time India had one of the largest clinical research establishments in the world.

Last year, Ranbaxy whistleblower Dinesh Thakur had filed two PILs before the Supreme Court seeking, amongst other prayers, that the government make bioequivalence studies mandatory for the approval of all generics (full disclosure: I was his lawyer in the case). A bench headed by the then Chief Justice TS Thakur dismissed the PILs as raising issues of mere “academic interest”. The same judge however did admit a PIL on banning sardar jokes.

Thereafter, Thakur and I prepared a comprehensive report and submitted the same to the Ministry of Health where we specifically highlighted the issue of bioequivalence studies.

It is not clear what influenced the government to change its mind and make bioequivalence studies compulsory but the health ministry certainly deserves credit for making the decision.

The challenge for the future will be to ensure that clinical research organisations that conduct bioequivalence studies do not commit fraud. This is a daunting task given the list of organisations that have been caught red-handed by foreign regulators.

The writer is a research associate at the School of Law, Singapore Management University.

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Swara Bhasker: Sharp objects has to be on the radar of every woman who is tired of being “nice”

The actress weighs in on what she loves about the show.

This article has been written by award-winning actor Swara Bhasker.

All women growing up in India, South Asia, or anywhere in the world frankly; will remember in some form or the other that gentle girlhood admonishing, “Nice girls don’t do that.” I kept recalling that gently reasoned reproach as I watched Sharp Objects (you can catch it on Hotstar Premium). Adapted from the author of Gone Girl, Gillian Flynn’s debut novel Sharp Objects has been directed by Jean-Marc Vallée, who has my heart since he gave us Big Little Lies. It stars the multiple-Oscar nominee Amy Adams, who delivers a searing performance as Camille Preaker; and Patricia Clarkson, who is magnetic as the dominating and dark Adora Crellin. As an actress myself, it felt great to watch a show driven by its female performers.

The series is woven around a troubled, alcohol-dependent, self-harming, female journalist Camille (single and in her thirties incidentally) who returns to the small town of her birth and childhood, Wind Gap, Missouri, to report on two similarly gruesome murders of teenage girls. While the series is a murder mystery, it equally delves into the psychology, not just of the principal characters, but also of the town, and thus a culture as a whole.

There is a lot that impresses in Sharp Objects — the manner in which the storytelling gently unwraps a plot that is dark, disturbing and shocking, the stellar and crafty control that Jean-Marc Vallée exercises on his narrative, the cinematography that is fluid and still manages to suggest that something sinister lurks within Wind Gap, the editing which keeps this narrative languid yet sharp and consistently evokes a haunting sensation.

Sharp Objects is also liberating (apart from its positive performance on Bechdel parameters) as content — for female actors and for audiences in giving us female centric and female driven shows that do not bear the burden of providing either role-models or even uplifting messages. 

Instead, it presents a world where women are dangerous and dysfunctional but very real — a world where women are neither pure victims, nor pure aggressors. A world where they occupy the grey areas, complex and contradictory as agents in a power play, in which they control some reigns too.

But to me personally, and perhaps to many young women viewers across the world, what makes Sharp Objects particularly impactful, perhaps almost poignant, is the manner in which it unravels the whole idea, the culture, the entire psychology of that childhood admonishment “Nice girls don’t do that.” Sharp Objects explores the sinister and dark possibilities of what the corollary of that thinking could be.

“Nice girls don’t do that.”

“Who does?”

“Bad girls.”

“So I’m a bad girl.”

“You shouldn’t be a bad girl.”

“Why not?”

“Bad girls get in trouble.”

“What trouble? What happens to bad girls?”

“Bad things.”

“What bad things?”

“Very bad things.”

“How bad?”

“Terrible!!!”

“Like what?”

“Like….”

A point the show makes early on is that both the victims of the introductory brutal murders were not your typically nice girly-girls. Camille, the traumatised protagonist carrying a burden from her past was herself not a nice girl. Amma, her deceptive half-sister manipulates the nice girl act to defy her controlling mother. But perhaps the most incisive critique on the whole ‘Be a nice girl’ culture, in fact the whole ‘nice’ culture — nice folks, nice manners, nice homes, nice towns — comes in the form of Adora’s character and the manner in which beneath the whole veneer of nice, a whole town is complicit in damning secrets and not-so-nice acts. At one point early on in the show, Adora tells her firstborn Camille, with whom she has a strained relationship (to put it mildly), “I just want things to be nice with us but maybe I don’t know how..” Interestingly it is this very notion of ‘nice’ that becomes the most oppressive and deceptive experience of young Camille, and later Amma’s growing years.

This ‘Culture of Nice’ is in fact the pervasive ‘Culture of Silence’ that women all over the world, particularly in India, are all too familiar with. 

It takes different forms, but always towards the same goal — to silence the not-so-nice details of what the experiences; sometimes intimate experiences of women might be. This Culture of Silence is propagated from the child’s earliest experience of being parented by society in general. Amongst the values that girls receive in our early years — apart from those of being obedient, dutiful, respectful, homely — we also receive the twin headed Chimera in the form of shame and guilt.

“Have some shame!”

“Oh for shame!”

“Shameless!”

“Shameful!”

“Ashamed.”

“Do not bring shame upon…”

Different phrases in different languages, but always with the same implication. Shameful things happen to girls who are not nice and that brings ‘shame’ on the family or everyone associated with the girl. And nice folks do not talk about these things. Nice folks go on as if nothing has happened.

It is this culture of silence that women across the world today, are calling out in many different ways. Whether it is the #MeToo movement or a show like Sharp Objects; or on a lighter and happier note, even a film like Veere Di Wedding punctures this culture of silence, quite simply by refusing to be silenced and saying the not-nice things, or depicting the so called ‘unspeakable’ things that could happen to girls. By talking about the unspeakable, you rob it of the power to shame you; you disallow the ‘Culture of Nice’ to erase your experience. You stand up for yourself and you build your own identity.

And this to me is the most liberating aspect of being an actor, and even just a girl at a time when shows like Sharp Objects and Big Little Lies (another great show on Hotstar Premium), and films like Veere Di Wedding and Anaarkali Of Aarah are being made.

The next time I hear someone say, “Nice girls don’t do that!”, I know what I’m going to say — I don’t give a shit about nice. I’m just a girl! And that’s okay!

Swara is a an award winning actor of the Hindi film industry. Her last few films, including Veere Di Wedding, Anaarkali of Aaraah and Nil Battey Sannata have earned her both critical and commercial success. Swara is an occasional writer of articles and opinion pieces. The occasions are frequent :).

Watch the trailer of Sharp Objects here:

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This article was published by the Scroll marketing team with Swara Bhasker on behalf of Hotstar Premium and not by the Scroll editorial team.