Thursday, November 20, 2014

The biter bit?

Once again, Ranbaxy and its fraught relationship with the FDA are in the news, but for a very different reason this time - Ranbaxy is suing the US drug regulator. At issue are the approvals that the FDA granted to Ranbaxy in 2008 to manufacture generic versions of two drugs, Valcyte and Nexium. The FDA claims that these approvals were granted 'in error'; Ranbaxy claims that the FDA is acting in a manner 'arbitrary, capricious, and otherwise contrary to law' and has no authority to reverse a decision taken six years ago.

Thursday, October 30, 2014

The publication Hall of Fame

Here's a very cool effort by the people at Nature - to commemorate the 50th year of the Science Citation Index, the first tool to track citations in the scientific literature, they asked the current owners of the SCI, Thomson Reuters, to generate a list of the top 100 most cited papers. Personally, I found the results fascinating, especially for the biology side of things. First of all, the top 100 papers represent a miniscule sliver of all the papers out there:

"Thomson Reuter’s Web of Science holds some 58 million items. If that corpus were scaled to Mount Kilimanjaro, then the 100 most-cited papers would represent just 1 centimetre at the peak."

If someone had asked me what sorts of biology-related studies had made the cut, I would have thought maybe this one, or either of these. Turns out, I'd be totally wrong. The top papers in biology are largely methods papers, outlining a protocol for performing specific procedures - the top three are the papers describing the Lowry and Bradford methods of protein quantification, and a recipe for Laemmli buffer, used to prepare proteins for electrophoresis. While these are workhorse procedures in a molecular or cellular biology lab, explaining the sheer volume of citations, they're definitely not what would first come to mind as candidates for publishing glory.

When I was in grad school, I heard of many instances where so-called "methods" papers weren't considered particularly exciting; you were just building a tool, not discovering a cool new biological phenomenon that could land you on the cover of Nature. This study is conclusive proof that tool-building is exactly the way to go if you want your papers to live on in the literature.

"Still, there is one powerful lesson for researchers, notes Peter Moore, a chemist at Yale University in New Haven, Connecticut. “If citations are what you want,” he says, “devising a method that makes it possible for people to do the experiments they want at all, or more easily, will get you a lot further than, say, discovering the secret of the Universe”.

Wednesday, October 8, 2014

Quick links

From The Economist: A new study in Science traces the early spread of the HIV virus in Africa.

From Nature: A modified version of the anti-parasitic drug niclosamide reduces fat accumulation and insulin resistance in mouse models of type 2 diabetes and is a promising new lead for an anti-diabetic drug.

From Science: This year's Nobel Prize in Medicine goes to three scientists who discovered the brain's positioning system.

From Fierce Pharma: The Thiola pricing kerfuffle.

From Forbes: In the wake of the Thiola pricing kerfuffle, an interesting look at the way drug pricing works.

From Businessweek: Retrophin, the company marketing Thiola, and its many troubles.

From Vanity Fair: Tracking the origin of the current Ebola outbreak and why containment efforts have failed.

Thursday, September 4, 2014

Pharma R&D to start moving abroad?

Here's an interesting article describing how Indian pharma companies are starting to move their R&D operations abroad in a quest for bigger profits. There are a couple of reasons suggested for why companies are making the move:

  • Companies are switching focus from the embattled generics arena (See here, here and here) towards products that either serve a more niche area, or are harder to manufacture. People with the required expertise for this focus shift are harder to find in India in the absence of a robust R&D ecosystem. Some comments from the article:
          "Investing in research abroad is specific to companies that want to grow in certain areas for which the best talent and regulatory expertise is available abroad," said Shakti Chakraborty, group president at Lupin. 
"For Indian companies to set up R&D abroad is expensive, but it is necessary, because otherwise their ability to grow within the country is going to be limited," said Kavita Patel, a fellow in the Engelberg Center for Healthcare Reform at the Washington-based think tank Brookings Institution. 
Dhaval Patel, head of Novartis' European drug discovery unit, had this to say about India's research infrastructure:

"I visited India five or six years ago, looking to identify places for collaboration, to try to identify those hubs where such [research] activities occur. I travelled all over and came back more disappointed than excited."

Friday, August 29, 2014

Quick links

From Science: Genome sequencing from patient samples reveals how the Ebola virus spread in Sierra Leone, mutating along the way. Sadly, some authors who contributed to the study died after being infected with the virus.

From 'Tis the season for big-money buys in the pharma sector.

From Forbes: How Illumina became the leader in genome sequencing technology.

From Nature: The RIKEN research centre at the centre of the recent stem cell scandal (see here) is going to be renamed and downsized, after researchers around the world protested the initial plan of closing it down altogether. Throwing the baby out with the bathwater, perhaps?

From MarketWatch: XPRIZE announces the 10 finalists for the $10 million Qualcomm Tricorder XPRIZE. The Tricorder is meant to be a small, personal medicine device that fits in the palm of your hand, capable of monitoring your health parameters and instantly diagnosing selected illnesses. To learn more, see here.

Thursday, August 28, 2014

Patient, diagnose thyself

Here's another interesting genomics-related article I came across recently - a patient more or less diagnosed herself by identifying the gene mutation that was making her sick.

The subject of the article is Kim Goodsell, an extreme athlete and mainstream dropout, who in her forties was diagnosed with a genetic condition called Charcot Marie Tooth (CMT) disease, a neurological disorder. She was already suffering from a heart problem, and was surprised when doctors didn't seem to think they were related.

Monday, August 25, 2014

Personal genomics in India

Personal genomics - where a consumer directly gets his or her DNA sequenced through a private company to learn about their predispositions to various diseases as well as other lifestyle conditions - has been on the rise in the West, with companies springing up to offer direct-to-consumer genetic testing, and a McKinsey report anointing it as one of the 12 disruptive technologies of the future, with an estimated market value of around 1 trillion dollars in a decade from now.

In India, however, personal genomics is very much a nascent industry. Three years ago, I wrote about Acton Biotech, a company that at the time was planning to introduce India's first commercial genome scanning service. While that doesn't seem to have happened, I recently had a chance to speak with Anu Acharya, the CEO of Hyderabad-based Mapmygenome, which started offering large-scale genome tests to customers last year under the brand Genomepatri.

Saturday, August 23, 2014

Another setback for stem cell research

A few months ago, I wrote about two high profile papers in the field of stem cell research that were published with a great deal of fanfare, only to fall under a cloud of suspicion when other researchers were unable to replicate the initial findings. The story has taken a very sad turn indeed, so I thought a follow-up post was due.

The two papers were authored by a team from the RIKEN Institute in Japan - Dr. Haruka Obakata was the lead author - and attracted attention for demonstrating an extremely simple method of creating stem cells from normal ones, as simple as exposing cells to mechanical stimuli or bathing them in an acid solution. Elegant in their simplicity, these methods also bypassed many of the technical and ethical obstacles that stem cell researchers must contend with. Naturally, many researchers were eager to duplicate the method in their own labs, but as one lab after another failed in their attempts, scientists began to wonder if the published results were perhaps too good to be true.

Tuesday, August 19, 2014

Quick links

In the New Yorker: An in-depth profile of anti-GMO activist Vandana Shiva that explores both sides of the debate over genetically modified seeds. As always, I'm struck by the gap between the rhetoric of the experts and the reality on the ground.

From BuzzFeed: A professor at the University of British Columbia has designed a series of evening gowns that draw design inspiration from microscopic images of cancer cells.

From the New York Times: Some Ebola survivors are returning home to a less than warm welcome.

From the Economist: An unexpected link between HIV and multiple sclerosis may open new avenues of treatment.

Wednesday, August 6, 2014

More updates on the Ebola outbreak

Here are some more updates on the ongoing Ebola outbreak in West Africa.

The current state of the epidemic:

  • WHO confirms that the death toll currently stands at 932 and pledges $2 million to help the fight against the spread of the virus.
  • The US Centres for Disease Control (CDC) has issued a Level 3 travel warning, advising against non-essential travel to the countries of Guinea, Sierra Leone and Liberia, where the outbreak is at its worst. CDC Director Tom Frieden has called this the "biggest and most complicated Ebola outbreak in history."
  • There are now five confirmed cases of Ebola in Nigeria, all of whom were involved with caring for a Liberian-American man who flew into Lagos from Sierra Leone and ultimately died. A nurse involved in the man's treatment has also died after acquiring the virus from her patient.
  • A suspected Ebola victim in Saudi Arabia, a man who recently visited Sierra Leone, has now died. If the virus indeed caused the man's death, this will be the first Ebola-related death outside of Africa.

Trouble in Sierra Leone:

  • An official from Doctors Without Borders has appealed for help from international organizations, claiming that the Sierra Leone government is unable to deal with the outbreak.
  • Quarantine measures imposed by the Sierra Leone government are not being strictly enforced, making it harder to control the spread of the virus. This is due in part to decades of antipathy towards the state. Many also believe that the present outbreak has been caused by witchcraft and sorcery, and place greater faith in witch doctors and traditional healers. A deep-rooted distrust of Western medicine and its emissaries, doctors and foreign aid workers, is making things worse.
  • Author Richard Preston tracks Ebola in Kenema, Sierra Leone.

The latest in treatments being developed for Ebola:

  • The BBC covers the current state of experimental treatments.
  • Two Americans who contracted Ebola in Liberia have been flown back to the US to receive an experimental monoclonal antibody-based treatment on an emergency basis. The therapy has not yet been tested in humans or received official sanction from the FDA. Nonetheless, unhappy Liberians are demanding to know why they are being told that there is no cure for Ebola, when the Americans seem to have one.
  • The co-discoverer of the Ebola virus, Peter Piot, argues in an opinion piece that experimental treatments should be tested in affected countries with support from the WHO.

And finally:

  • The threat of an Ebola outbreak in the developed world is still low, despite all the furore. This is largely because Ebola is not transmitted via the airborne route, only through direct contact with the bodily fluids of an infected person. Quarantine, if correctly enforced, should be effective at halting the virus in its tracks.
  • Malaysian glove manufacturers are anticipating a boom in business thanks to Ebola. Tellingly, they anticipate the main consumers to be from the developed world,  "rather than from developing countries like Africa (sic) where glove consumption is low.” Low glove consumption can help to explain how Ebola is spreading so rapidly.
  • Author Laurie Garrett (do read her book The Coming Plague, if you haven't done so already) profiled the 1995 Ebola outbreak in Zaire, and it still makes for relevant reading.

Tuesday, July 29, 2014

Ebola strikes again

"Ebola virus virion" by CDC/Cynthia Goldsmith - Public Health Image Library, #10816

In alarming news, an outbreak of the Ebola virus that started in West Africa is now being called the worst in history. The three affected countries - Sierra Leone, Liberia and Guinea - are reporting over 670 deaths. Worse still, medical personnel now number among the victims. The health minister of Guinea said that the virus probably spread from local communities eating infected bats; bats serve as the animal host for the virus. People have also been advised to stay away from eating rats and monkeys.

The Ebola virus is highly infectious, with a mortality rate of upto 90 percent. Patients with Ebola often have severe internal and external hemorrhaging - they're basically bleeding to death. (If you want to know more, Ebola and its other deadly cousins, like the Lassa and Marburg viruses, are profiled in Richard Preston's The Hot Zone, a book I read and loved as an undergraduate. And when I say loved, I mean it scared the daylights out of me. No, really. I challenge you to read it and look a coughing man in the face without flinching).

Sunday, July 27, 2014

Can genomics save a struggling town?

 Like many manufacturing centres across the United States, the town of Kannapolis in North Carolina took a massive hit to its economy when the textile mill around which the town revolved downed its shutters. This article describes Kannapolis's unlikely re-invention as a centre for genomics research, thanks to an elderly billionaire named David Murdock, who is a fervent believer in longevity expansion through better nutrition (Here's a fun profile of Murdock in the New York Times that takes the term "health nut" to a whole new level).

The article raises a lot of interesting questions - can the biotech industry really revive a faded mill town? And more importantly, do the residents have a chance of profiting from any diagnostic tests or other inventions developed by using their biological materials? Right now the answers seem to be "Maybe" and "No". What is also not clear to me are the reasons why the residents of Kannapolis would make good candidates for recruitment into a biobank - what kind of population are they representative of? Nonetheless, it's interesting to think of this as a glimpse into a "brave new economy", where the residents are now literally the lifeblood of their town.

Saturday, July 26, 2014

A well-handled retraction

Recently, the Institute of Microbial Technology (IMTECH) made headlines for a rather unfortunate reason: data fraud. Three papers published by a research group at IMTECH in the journal PLoS ONE were retracted earlier this month for "fabrication of data", and now another four are being retracted as well. The first author on these studies (Dr. Fazlurrahman Khan) has reportedly resigned from the institution.

PLoS ONE, an open access journal, is considered both prestigious and rigorous; in a Science paper that used a fake article to expose abysmal peer review standards in open-access journals, PLoS ONE was commended for its "rigorous peer review" and for being "the only journal that called attention to the paper's potential ethical problems", eventually rejecting the fake study for lack of scientific quality. Even so, the review process for the first three papers had failed to catch any of the manipulated data; Willem van Schaik, editor of one of the papers, later told the blog Retraction Watch that three separate reviewers had edited the papers, making it harder to notice any glaring errors, and that "even with hindsight, I find it difficult to find which data have been fabricated."

 It was Dr. Khan's former post-doc boss at Georgia Tech who, noticing some similarities between the published data and the work that Dr. Khan had done during his postdoc, contacted the Director of IMTECH, Dr. Girish Sahni. Commendably, an inquiry committee was immediately set up to investigate the matter, and found that "there are no data available underlying this study and thus that the published results are fabricated". The Council of Scientific and Industrial Research (CSIR), with which IMTECH is affiliated, immediately requested a retraction of the three papers in question.

Sunday, July 20, 2014

One is a lonely number

I recently came across a very interesting feature article in the New Yorker, "One of a Kind", which describes the dizzying journey parents undertake when their child is identified as the only person known to be affected by a particular genetic condition. The article focuses on one family, the Mights, whose son Bertrand was born with a previously unknown double mutation in one gene, NGLY1, involved in the deglycosylation of proteins - the product of the gene is an enzyme that helps in protein recycling by removing sugar molecules linked to these proteins. It took the Mights several years to learn what exactly was wrong with their son, during which they shuttled from one specialist to the next, trying desperately to map their son's illness while worrying about the damage all the poking and prodding was doing to him.

The conclusion from all these tests was that Bertrand was a complete medical novelty - whatever he suffered from was a disease unknown to medical science at the time. Rather than giving up the battle, the Mights chose to enroll Bertrand in a study designed to test whether genetic sequencing could be used to identify unknown conditions. Genetic sequencing, as most of us are familiar with, is usually designed to test a specific gene for mutations that would explain a medical condition. This only works if you already know that a mutation in gene X causes disease Y. What do you do in a case like Bertrand's, where you have absolutely no idea where in the genome you should be looking?

Sunday, May 4, 2014

A damning indictment of drug regulation in India - After a drug reaches the market

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

In the final part of their report, the Committee took a closer look at what happens once a drug is approved and reaches the market. For one thing, it needs a brand name. This is usually decided upon by the manufacturer and conveyed to the state authorities, which do not share this information with authorities in other states. As a result, asking for Lona at a chemist's shop could either get you low-sodium salt or the sedative clonazepam. Similarly, a drug with the brand name AZ could either be used to treat a worm infestation, a bacterial infection or anxiety - all very different medical indications. Such a situation is highly dangerous, since patients may end up taking the wrong medicine, with potentially serious consequences. There needs to be better coordination between State authorities, and the Committee recommended that "...a data bank of all branded pharmaceutical products along with their ingredients should be uploaded on the CDSCO website and regularly updated."

The Committee had earlier uncovered multiple instances where Post-Marketing Surveillance Reports (PSURs) had either been submitted incorrectly, or not at all. A total of 42 new drugs were randomly selected to check whether the rules regarding submissions of PSURs were being followed. Of these, PSURs for only 8 drugs were submitted. The Ministry claimed that 14 of these drugs were either new launches or not being sold and hence PSURs could be expected later. This turned out to be a lie since at least 2 of the 14 had been in the market long enough for manufacturers to submit PSURs. For another 17 drugs, the Ministry was unable to explain why there were no PSUR records.

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 " 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.

Saturday, March 22, 2014

Sun Pharma's turn

Sun Pharma joins the list of Indian generic drug makers to face sanctions from the US FDA. The plant whose products have been barred from import into the US is a Gujarat based manufacturer of the antibiotic cephalosporin. Not surprisingly, the news has sent Sun Pharma's share price into a dive, even though company spokespersons and analysts both downplay the significance of the ban, stating that it will have little impact on Sun Pharma's overall sales in the US.

As FDA scrutiny of Indian generic manufacturers increases, we can expect many more such headlines to be made. However, it's important to note that the FDA has not yet specified the nature of the violations found at the plant. They may very well turn out to be minor issues that do not materially affect the quality of the drugs being made. Unless of course, we have Ranbaxy-style falsification of records and contamination of drugs, in which case any panic is entirely justified.

Friday, March 14, 2014

On the problem of irreproducible data

Given the potential that stem cells hold for curing a number of human diseases, it's no surprise that two high-profile papers published in the January edition of Nature garnered a great deal of attention. The papers basically suggested that creating stem cells from normal ones could be as simple as exposing them to acid or mechanical stress, such as forcing cells through glass tubes. Even more, these STAP (stimulus-triggered acquistion of pluripotency) cells seemed to be some sort of "super stem cell", capable of forming not only any body tissue but also the placenta, something that other pluripotent cells normally cannot do.

Most stem cell biologists were taken aback at the simplicity of the method. George Daley, a leading stem cell biologist at Harvard, called the findings "fascinating", "perplexing" and "begging to be replicated". Another researcher, Dieter Egli, bluntly said that if he described the method to his colleagues, they would think he was kidding.

Turns out they called it right. Several researchers now report that they are unable to replicate the original findings. Qi-Long Ying (whose lab was one building over from mine at USC), an original supporter of the method, was one of the unsuccessful ones. There's also a blog keeping record of other failed attempts. When the original author, Haruko Obokata (RIKEN/Harvard) and her colleagues shared the methodology they used, it turns out the process wasn't as simple as it initially sounded, and in fact was technically quite challenging. Subsequently, some of the data in the papers has also come under question, and calls for retraction have already been issued. (Edited to add: Uh oh.)

This isn't the first high-profile set of experiments that have failed the independent replication test, nor will they be the last. But this ties in very neatly to one of the things that frustrated me most during my Ph.D. - being able to reproduce the same set of data multiple times, until you're absolutely sure that your findings are real. Some of my work was performed in primary endothelial cells, and as any life scientist can tell you, working with primary cells is never easy. They can be terribly finicky creatures, and two different batches of cells may give completely different results in the same experiment. The number of repeats you have to run to get statistically significant data keeps increasing, and when you're repeating an experiment for the nth time, it can get really annoying.

Or when you're a grad student, trying to repeat a supposedly very easy protocol published in a journal like Nature (so it must be true!) and you can't get it to work, it's easy to ask yourself whether you're the one with the problem. Maybe you're not doing it right, or you just have bad hands, or you need to stand on one leg and recite the Lord's prayer backwards when performing the fifth step in the protocol. Who knows? Enough to drive even the most even-keeled of people slightly mad.

This is an issue that I am sure a lot of other life scientists struggle with, and something that I plan to revisit over the course of a few blog posts. In the meantime, I leave you with a fabulous compendium of articles on this issue published as a special issue by Nature a few years ago. Excellent, and very thought-provoking indeed. As we perform increasingly technically sophisticated experiments using better and bigger equipment, issues of reliability and reproducibility become all the more important. If we want to uphold the high ethical standards that all research is supposed to meet, these are things that we need to think, talk and debate about just as keenly as we discuss which lab got published on Nature's cover page last week.

Sunday, March 9, 2014

And the saga continues...

Per this news report, Ranbaxy has now withdrawn over 64,000 bottles of atorvastatin, the generic form of Lipitor, due to a mix-up in dosages. According to the FDA, a pharmacist found a 20 milligram tablet of atorvastatin in a sealed bottle meant to contain 10 milligram tablets of the drug. This, after all of Ranbaxy's India-based manufacturing plants have been shut down, and their only plant now supplying generic drugs to the US market is the New Jersey-based Ohm Laboratories Inc.

The error has been classified by the FDA as a Class II recall, which means that it most probably would not result in any adverse events - people are not likely to get very sick or die by taking twice as much of the drug as they should. Also, the recall was voluntary, and not imposed by the FDA or any other regulatory body.

Nonetheless, this kind of mistake still looks bad for a company hit with very serious questions about its quality control process. Ranbaxy is already under a cloud, and news of this sort is certainly not helping to restore consumer faith.

Wednesday, February 26, 2014

More trouble for Ranbaxy

Ranbaxy Laboratories, once one of India's great pharma success stories, continues to be in trouble. Shipments of active pharmaceutical ingredients (APIs) from all four of its Indian plants, meant for export to foreign markets, have now been suspended. In effect, Ranbaxy can no longer export drugs to its biggest market, the US.

The bans were put in place by the US Food and Drug Administration (FDA), after Ranbaxy failed to meet FDA quality standards for their products. On a recent visit to India, FDA commissioner Margaret Hamburg made it clear that Indian pharma companies wanting to do business with the US will have to play by their rules. 
"If Indian pharmaceutical companies want to sell in the US, they need to comply with our standards, practices and expectations."
In case anyone thinks the FDA's being unnecessarily harsh, let me direct you to this excellent and painstakingly researched article that explains, in frightening detail, exactly what was going wrong at Ranbaxy's manufacturing plants.
"...Ranbaxy had to recall millions of pills after tiny glass particles were discovered in some of them."
"...the company culture was for management to dictate the results it wanted and for those beneath to bend the process to achieve it." 
"Lying to regulators and backdating and forgery were commonplace..." 
"The company not only invented data but also fraudulently mixed and matched data..." 
If these statements are true (and given the amount of research that's gone into the article, I think they are), I'm not touching a Ranbaxy-made tablet with a ten-foot barge pole until they clean up their act.

Sadly, this attitude of "regulations are meant to be bent and/or broken" is something I've come across before. When you're making medicines that are meant to cure sick people, those regulations are there for a reason. There are plenty of Indian pharma companies who rigorously follow all the rules relating to good manufacturing practices. But bad apples like Ranbaxy, who not only break the rules but thumb their noses at them, make the Indian generics industry look very bad indeed, and that's the kind of negative publicity we really don't need.

Thursday, February 20, 2014

An accelerator for genomics startups?

This week, the sequencing company Illumina announced a tie-up with Russian billionaire Yuri Milner to fund an accelerator for genomics startups. Illumina will provide lab space, sequencing equipment and $100,000 for initial costs of operation. Milner will provide additional financial support.

Seems like it's a win-win for both partners; Illumina builds the machines, and gets young entrepreneurs to discover cool things to do with them, in turn fueling demand for their product. Both Illumina and Milner will get good press as well. Milner, in particular, is already funding prizes for breakthroughs in physics and the life sciences, although the life sciences prizes, in particular, have so far largely been awarded to scientists who are already big names in their fields and are well funded.

The challenge in genomics, unlike some other areas of biology, is not so much the generation of data as figuring out what to do with it. It lends itself well to the current trend of "big data" and network analytics, and is definitely cheaper and faster than, say, generating a transgenic animal model to study a specific disease.  It'll be interesting to see what comes out of this collaboration, and whether there is potential for more such tie-ups between companies and private investors.

Thursday, February 13, 2014

Spurring innovation in Indian pharma-where do we start?

I had an interesting email discussion with well-known pharma blogger Derek Lowe, about the state of innovation in Indian pharma, and what kind of drug discovery model would work best for us.

The post itself, as well as the comments to this post are quite thought-provoking, and generally touch on two major points:

1. It's a bad idea to try and adopt the same pharma model as the big Western companies.
This should be pretty obvious, given that the global pharma industry is in a downturn, with empty pipelines, expensive failures and expiring patents. Which is not to say that a company run along those lines would definitely fail, but it's probably not the best use of our money. What should our model be, in that case? Suggestions ranged from having government-funded initiatives (like the Open Source Drug Discovery programme), to focusing on traditional Indian medicine like Ayurveda, soliciting funds from NGOs, working on disease areas most relevant to our country, and so on. Another more radical solution was that we stop looking at small molecules altogether, and focus on biologics instead. All of these approaches have their own merits, and it would probably need a combination of all of these and more to develop a flourishing drug discovery ecosystem in India.

2. It's too risky a business for Indians, who aren't very entrepreneurial anyway.
This is one argument I don't completely buy. Yes, in practical terms, it makes a lot more sense to try and build a software startup, since you don't need much by way of startup capital, and the chances of quickly building a revenue-generating product are higher. But there's no shortage of entrepreneurs here, and I've personally heard of several interesting start-ups in the life sciences space. What they really need, however, is solid financial support, whether it's from venture capitalists or even from the government. Drug discovery is an inherently risky, time-consuming and capital-intensive business which requires long-term vision from investors. Perhaps the way to make it more attractive an investment is to start small, with more modest goals-pick a small but relevant problem to solve. R&D can be balanced with, say, a generic drug/biologics production programme (Biocon is probably the best-known example) to offset risk.

To me, the idea that India continues to largely depend on foreign companies to do all the messy work of drug discovery is a dangerous one. There are so many contentious issues to deal with - drug pricing and patent validity being two big ones - that this relationship cannot continue to remain one-sided. We already have several big players in the pharma space, which is good news. But rather than letting the status quo continue undisturbed, it's a good time to start thinking about what we can do with our resources to allow more drugs to be developed in India.