Tuesday, April 29, 2014

A damning indictment of drug regulation in India - Drug safety in India versus the world, the CDSCO way

(This post is the fourth part of a series examining the functioning of India's drug regulatory authority, the CDSCO).

As mentioned earlier, there are several drugs that continue to be sold in the Indian market even though they have been withdrawn elsewhere. The Committee decided to look into allegations that some such drugs had been approved unlawfully, and found several cases where drugs had been approved in contravention of the existing laws.

  • Buclizine, an anti-histamine, was approved for appetite stimulation in children without any expert consultation or clinical trials. As per the law, if a drug approved for one condition is proposed for the treatment of a different condition, it must be treated as a new drug, following all the required procedures and meeting all regulatory requirements. This was not done for buclizine. The Ministry also claimed that buclizine had been previously approved in other countries, when in fact it had either been discontinued or banned in those countries.
  • Letrozole, an anti-cancer drug, is to be used for the treatment of breast cancer only in women of post-menopausal age. Yet, India was the only country where letrozole was approved for improving female fertility in women of reproductive age. No Phase II studies were conducted, an especially crucial requirement since this drug had not been tested for its impact on female fertility anywhere else in the world. Phase III trials were approved without any Phase II information being provided, and were conducted on a small group of women, far fewer than the number specified in Good Clinical Practice rules. No post-marketing surveillance reports were provided by the manufacturer to determine whether this novel use of letrozole had any adverse impact, either on the women taking the drug or the babies born to them. When the entire episode received negative coverage in the media, CDSCO took no action against any erring officials or the manufacturer, and instead referred the matter to experts to determine drug efficacy and safety. The drug has since been banned for use in improving female fertility, and the report sternly demands that the DGCI "...take action against those CDSCO functionaries who colluded with private interests and got the drug approved in violation of laws."

Saturday, April 26, 2014

A damning indictment of drug regulation in India - The CDSCO and expert opinions

(This post is the third part of a series examining the functioning of India's drug regulatory authority, the CDSCO).

One of the requirements to be completed for a new drug approval is to obtain opinions from several qualified experts as to whether the drug should receive approval or not. These experts, at least in India, are usually professors affiliated with medical colleges.

The Committee investigated the process by which these expert opinions are sought and submitted. And here I tip my hat to those Sherlockian committee members who painstakingly sifted through the records and gathered substantial evidence to suggest that many of the letters submitted were "...actually written by the invisible hands of drug manufacturers and experts merely obliged by putting their signatures." Copies of the letters in question have been attached to the report as annexures.

  • In one case, letters from three medical professors affiliated to colleges thousands of kilometres apart were identical, word for word.
  • A second case again had three such identical letters, with the added twist that all three had the same error in the DGCI's address.
  • Letters related to multiple other drugs were also found to be exact (or nearly exact) copies of each other.
  • In one case, a letter seeking an expert opinion was dispatched by an official from New Delhi on 9th August, 2010. By 11th August, not only had the letter reached Mumbai, but had been replied to as well, by an individual apparently capable of examining 131 pages of scientific documents and formulating an expert opinion within a few hours. In the case of this drug, all four expert letters had been dispatched with an incorrect version of the organization's name, no postal address, and no pin code. I salute the Indian postal service if they were apparently able to deduce from this fragmentary information that all four letters were meant for the Delhi office of the CDSCO.
  • Letters dispatched from four different cities (New Delhi, Chandigarh, Mumbai and Secunderabad, all of which are quite far from each other), somehow landed up at the DGCI's office on the same day. The Committee deduces, probably correctly, that someone personally collected these letters and delivered them to the DGCI's office, which means that "...it is obvious that the interested party was in the loop in the entire process of consultation with experts." 
  • In another case, a letter took two months to travel from New Delhi to...New Delhi. Both the hospital from which it was sent and the DGCI's office are in the same city, but it apparently took two months for the letter to be delivered.
  • In the case of one particular drug (a fixed dose combination which is not approved in any developed country), an official of the CDSCO was found to have written a letter to the manufacturer suggesting that they select experts themselves and have the letters delivered to the DGCI's office. Not surprisingly, many of the experts turned in identical letters which had probably been drafted by the manufacturer.

Friday, April 25, 2014

A damning indictment of drug regulation in India - How the CDSCO handled new drug approvals

(This post is the second part of a series examining the functioning of India's drug regulatory authority, the CDSCO).

Having examined the mandate, organization structure and operational procedures of the CDSCO, the Committee moved on to investigate one of the most important activities the CDSCO undertakes - New Drug Approvals. In order to do so, the CDSCO was asked to provide detailed reports on 42 new medicines that had received their approval - a mere 2% of all drugs approved by them from January 2001 to October 2010. And this is where things started to get very murky indeed.

Three of the drugs on the list (pefloxacin, lomefloxacin and sparfloxacinhappened to be somewhat controversial, having either never been marketed in Western countries, or withdrawn from the market due to serious side effects. They are still sold in India. Naturally, one would expect a higher level of monitoring of these medications. Instead, the Ministry had no files for them at all. That's right, nothing. In government-speak, the files were "untraceable". So there is no record of how such controversial drugs got approved, what kind of safety profile they had with regards to the Indian population, and whether any adverse effects were reported in clinical trials, if they were performed at all.

Thursday, April 24, 2014

A damning indictment of drug regulation in India - How the CDSCO works

A comment on a previous post asking about quality control of drug manufacturing in India led me on a search to try and understand how the process works in this country. The major regulatory body in India is the Central Drugs Standard Control Organization (CDSCO), headed by the Drug Controller General of India (DGCI) and under the Ministry of Health and Family Welfare. There are also state-level regulatory authorities. As per the CDSCO's website, "Under the Drug and Cosmetics Act, the regulation of manufacture, sale and distribution of Drugs is primarily the concern of the State authorities while the Central Authorities are responsible for approval of New Drugs, Clinical Trials in the country, laying down the standards for Drugs, control over the quality of imported Drugs, coordination of the activities of State Drug Control Organisations and providing expert advice.."

Given that the CDSCO's mandate places it on par with the FDA(USA), the EMA(European Union) and other such regulatory bodies, I was interested in learning more about the organization. That is what led me to this report, presented to the government in 2012. Although two years old, the findings detailed in this report are so alarming that I thought it well worth my while to devote a few posts to them. I'll be running these as a short series, and today's post is an overview of the report and some general findings regarding the setup and functioning of the CDSCO. Later posts will have more details of the specific findings discussed.

The report in question is the 59th report of the Department-related Parliamentary Standing Committee on Health and Family Welfare, examining the functioning of the CDSCO. The Committee was made up of members of the Rajya Sabha and the Lok Sabha as well as administrative officials, who solicited views and information from the Secretary, Department of Health and Family Welfare, as well as CDSCO officials. Committee members also visited state drug testing facilities in Chennai, as well as the private testing laboratories of Bangalore-based Biocon Pvt. Ltd.

I've read a few government reports in my time and they generally tend to be dry as dust. Not this one, which is both blunt and scathing in its documentation of the many, many problems besetting the CDSCO. Here's a list:

Monday, April 14, 2014

Lupin's turn

In this post, I predicted, "As FDA scrutiny of Indian generic manufacturers increases, we can expect many more such headlines to be made", in reference to Sun Pharma joining the list of companies whose generic drugs failed USFDA quality control standards.

Just call me Nostradamus, because Lupin Ltd. is the next generics manufacturer to fall foul of the FDA.  The company's US arm, Lupin Pharmaceuticals Inc, voluntarily withdrew nearly 10,000 bottles of the branded antibiotic Suprax (cefixime). Much like in Sun's case, the company claims that this is a "voluntary recall" which is of "no business consequence". Lupin also withdrew over 64,000 bottles of the drug last year, due to problems with discoloration.

Again, taken in isolation, the incident may indeed not be of much business consequence. But as pointed out on Fierce Pharma
"The laundry list of product bans, FDA warning letters and recalls at Ranbaxy and its Indian rivals have prompted new scrutiny not only by regulatory agencies around the world, but by pharmacology experts who worry that Indian-made generics aren't as effective as their brand-name counterparts." 
That is very bad news indeed for the Indian generics industry, and for drug development in India as a whole. There are companies who use the revenue generated from their generics business to bankroll their research operations. Generic drug manufacturers are also helping to build a pool of experienced pharma professionals in India, who could presumably apply their knowledge to developing new drugs as well. Cleaning up these negative perceptions is going to be a Herculean task, but one that all players in this market need to do in good faith if they plan to stay in business, not just to make money in the US market but to help drug discovery take root and flourish in India.

Thursday, April 10, 2014

Open source drug discovery in India

Here is an article in Forbes magazine that evaluates India's Open Source Drug Discovery programme, six years after it was founded. Started by India's Council for Scientific and Industrial Research (CSIR), the OSDD initiative is designed to focus on diseases of the developing world, such as tuberculosis and malaria. Those afflicted by such diseases are often too poor to pay for treatment, making drug development in these areas a financially unattractive proposition for pharma companies. Indeed, AstraZeneca Labs, one of the few companies in India that was working on TB and malaria, shut down its Bangalore-based R&D unit and halted all early-stage research efforts in these areas.

OSDD, as the name suggests, is intended to function as a not-for-profit, government-funded, open source platform integrating drug discovery efforts across academia, government institutes and private companies. All projects and research results are reported and collated on a web-based platform, allowing for greater collaboration between groups. In a previous discussion on Derek Lowe's blog In the Pipeline (which I also blogged about here), OSDD was mentioned as an example of innovative approaches to drug discovery that a country like India can adopt.

But as the Forbes article points out, the OSDD approach is not without its own pitfalls. The first and foremost is the limited talent pool of drug-discovery scientists available in India. This becomes a problem when there aren't enough trained people in fields like cheminformatics, who can carry out the kind of virtual screening and SAR analysis needed in the critical early stages of drug discovery. OSDD is trying to bridge the gap by creating training programmes for students and developing their own cheminformatics algorithms with help from other groups, such as the UK's Royal Society of Chemistry.

Medicinal chemistry is the second area where there aren't enough experienced scientists in academia. Most medicinal chemists tend to gain experience as they work in large pharma companies. This is a talent pool that OSDD is finding it hard to access. Firstly, as OSDD head Dr. T.S. Balganesh points out, he can't match the incentives that industry offers - "The only incentive OSDD can give them is emotional - I  can't give them high salaries or glamour", he says. Secondly, researchers who are part of OSDD work in research groups scattered throughout the country, which makes it hard to foster the kind of close collaborations that are needed for training new recruits. Says Bheemarao Ugarkar, a former AstraZeneca India employee who is now a principal investigator for medicinal chemistry at OSDD, "A lot of the training in the industry happens in a group environment with biologists, computational chemists, synthetic chemists, etc. sitting in one room day in and day out, discussing the project."

Although the OSDD uses open-access compound libraries for their analyses, investigators believe that real drug-like compounds can only be found if they prevail upon big pharma to make their compound libraries public. This is where India's troublesome intellectual property environment comes into play. Companies may be reluctant to hand over such databases knowing that they may stand to make no profit whatsoever if one of their compounds is ultimately developed into a drug.

But the biggest hurdle that OSDD needs to surmount is probably the same one that any such initiative anywhere in the world would need to overcome: What's in it for academia? Developing a cancer drug to treat humans is infinitely more complex than publishing a paper about a compound that kills cancer cells in vitro and shrinks mouse tumours. The publish-or-perish mentality that exists in academic institutions today heavily favours the latter approach. An investigator who decided to put in a good 15 or 20 years to come up with a market-ready drug would find herself out of academia long before she accomplished that goal.

OSDD has had some successes, such as generating the annotated genome of Mycobacterium tuberculosis through a collaborative platform called Connect2Decode. Although their methodology came under fire from some researchers, the results were eventually published in peer-reviewed journals. While OSDD doesn't yet have any internally-generated molecules ready for clinical trials, they have received approval to conduct clinical trials on a promising TB molecule, PA 824, which was developed elsewhere.

However, some people still believe that drug discovery is too complex a problem to be solved by an open-source approach. Probably the most realistic assessment of OSDD comes from the consultancy firm Frost and Sullivan's Jayant Singh. His take is that OSDD will serve more as a training ground for drug discovery professionals, who can then transition to the private sector.
Just creating a strong research ecosystem is “a good endpoint”, Singh says. “After all, that is the role of the government: To act as a facilitator, not a provider.”
 I think that initiatives like OSDD are laudable, and a much-needed attempt to start transforming the drug discovery ecosystem in India. We need to build collaborative, inter-disciplinary groups that can bridge the academia-industry divide and allow for free sharing of knowledge and experience. But as it stands, do I think OSDD can produce a new drug molecule within the next 5 years? I'm afraid the answer is no.

Monday, April 7, 2014

A problem shared is a problem halved?

In a move that should come as no surprise, Daiichi Sankyo, the Japanese owners of the embattled generics manufacturer Ranbaxy, have offloaded their problematic affiliate onto Sun Pharma. The deal, valued at $3.2 billion, will create the fifth-largest generic drug maker in the world, both of whom have been hit with bans from the USFDA for quality control violations.

Ranbaxy's low valuation is a testament to the struggles the company has undergone in recent times, leading to a steep decline in its share prices. Malvinder Singh, the former owner of Ranbaxy, lays the blame squarely at Daiichi Sankyo's door, saying that they "failed to harness and assimilate the complexities of running a strong generics business".

Ajay Piramal, the billionaire owner of the Piramal Group, which includes the pharmaceutical company Piramal Healthcare, has also been quoted as saying that "(Daiichi) has not been able to handle all the quality and FDA issues. I think that Sun is much more competent to do that." Oddly enough, he also looks upon the deal as "one company which has not had any issues, trying to correct another one."

I find these comments to be disingenous at best, and dishonest at worst. The Fortune article that took the lid off Ranbaxy's woes described a well-entrenched, institution-wide culture of playing fast and loose with the rules, with predictably disastrous consequences. In the face of such widespread flouting of ethical norms, Daiichi would have had to do a massive cleanup, assuming they were ever apprised of the full extent of the problem. Of course, it may suit Ranbaxy's former owner to blame anyone but himself. But I fail to understand why someone of Ajay Piramal's standing in the pharma community would blandly gloss over Sun's regulatory troubles, and make the entire deal seem like a benign takeover that can only be good for Indian pharma.

This is not to say that any pharma company running into regulatory issues should be tarred and feathered. If they are able to address such problems in a satisfactory manner, there isn't anything to be concerned about. The real problem is when industry leaders bury their heads in the sand and are so busy pointing fingers at others that they fail to acknowledge the very real problems besetting the Indian pharma industry, and the growing global perception that Indian-made generics are unsafe and dangerous for public consumption. Once that image sticks, it's very hard to shake off.