15 February 2014

Generics, Fakes and Regulatory Incapacity

Noting an item in today's New York Times on cross-border regulation and generic pharmaceuticals.

The Times reports that India’s pharmaceutical industry supplies 40% of over-the-counter and generic prescription drugs consumed in the US, so increased scrutiny could have profound implications for US consumers.
F.D.A. investigators are blitzing Indian drug plants, financing the inspections with some of the roughly $300 million in annual fees from generic drug makers collected as part of a 2012 law requiring increased scrutiny of overseas plants. The agency inspected 160 Indian drug plants last year, three times as many as in 2009. The increased scrutiny has led to a flood of new penalties, including half of the warning letters the agency issued last year to drug makers. 
Ranbaxy, one of India’s biggest drug manufacturers, pleaded guilty to felony charges and paid a $500 million fine last year. 
Indian officials and executives are reportedly shocked by recent FDA export bans over adulterated generic versions of popular medicines such as the pain drug Neurontin and antibiotic Cipro that the FDA determined were adulterated. Some reportedly "take a very sinister view" of US inspections, suspecting that the US is protecting its domestic industry from cheaper imports. The article regrettably does not refer to or unpack the international expansion of generic manufacturers.

The Financial Times rather mordantly commented earlier this month that
Arun Sawhney wanted to be clear. “Ranbaxy is a different company today”, the chief executive of the Indian drugs group said shortly after the US Department of Justice imposed a $500m fine in May [2013] for distribution of adulterated medicines between 2004 and 2007. 
Mr Sawhney was drawing a line under the scandal. “All Ranbaxy products currently in the global market are safe and effective,” he said. The company had a new code of conduct for staff and clear accountability.
Less than a year later, Mr Sawhney’s words ring hollow. The US Food and Drug Administration has banned imports from another Ranbaxy facility for violating quality standards. This is a serious blow for the company, which now has all four of its Indian plants subject to US restrictions. It was left to express its disappointment and apologise to stakeholders. A key question is how these lapses have persisted under Daiichi Sankyo, Ranbaxy’s Japanese majority owner, given that country’s reputation for high-quality, precision manufacturing? 
For Daiichi Sankyo, the acquisition of a 64% stake in Ranbaxy for $4.7bn in 2008 was to be the road to globalisation. Five years on, many Mumbai-based analysts are struggling to explain the new owner’s failure to turn things round and the Indian workers’ still lackadaisical attitude towards data integrity and quality standards. 
Notes from the most recent FDA inspections at Ranbaxy’s facilities in Toansa and Mohali, for example, found that ingredients and drugs were being retested until acceptable results were obtained. Hygiene was also inadequate. FDA inspectors noted in its “483 report”, used to cite observations that can lead to regulatory action, that there were flies too numerous to count in the sample preparation room, cupboards holding sensitive equipment and agents were broken, and the refrigerator that stored samples was not working well, with melting ice causing pools of water inside. 
“If you see the kind of observations the FDA has made, they look quite basic,” said one Indian pharmaceutical industry analyst. “It’s more about the mindset of the company in the past and the way it was handled. If the Japanese management are not able to make changes in the company, who else will be able to?”
Concerns regarding quality and counterfeiting are longstanding, highlighted in works such as 'Counterfeit pharmaceuticals: Murder by medicine' by Peter Aldhous in (2005) 434(7030) Nature 132, 'Counterfeit and substandard quality of drugs: the need for an effective and stringent regulatory control in India and other developing countries' by Azhar Yaqoob Khan and N. M. Ghilzai in (2007) 39(4) Indian Journal of Pharmacology 206, 'Counterfeit anti-infective drugs' by Paul Newton, Michael D. Green, Facundo M. Fernández, Nicholas PJ Day, and Nicholas J. White in (2006) 6(9) The Lancet infectious diseases 602, 'Counterfeit Pharmaceuticals in China: Could Changes Bring Stronger Protection for Intellectual Property Rights and Human Health' by Dina Bronshtein in (2008) 17 Pacific Rim Law & Policy Journal 439, 'The other global drugs crisis: Assessing the scope, impacts and drivers of the trade in dangerous counterfeit pharmaceuticals' by Y. A Majid in (2008) 1(1) International Journal of Social Inquiry 151 and 'Parallel trade in pharmaceuticals: injecting the counterfeit element into the public health' by Bryan Liang in (2006) 31 North Carolina Journal of International Law & Commercial Regulation 847.

The New York Times continues that -
The F.D.A.’s increased enforcement has already cost Indian companies dearly — Ranbaxy, one of India’s biggest drug manufacturers, pleaded guilty to felony charges and paid a $500 million fine last year, the largest ever levied against a generic company. And many worry that worse is in store.
The unease culminated Tuesday when a top executive at Ranbaxy — which has repeatedly been caught lying to the F.D.A. and found to have conditions such as flies “too numerous to count” in critical plant areas — pleaded with Dr. Hamburg at a private meeting with other drug executives to allow his products into the United States so that the company could more easily pay for fixes.
In response to that delightful example of chutzpah the US representative "politely declined".
India’s drug industry is one of the country’s most important economic engines, exporting $15 billion in products annually, and some of its factories are world-class, virtually undistinguishable from their counterparts in the West. But others suffer from serious quality control problems. The World Health Organization estimated that one in five drugs made in India are fakes. A 2010 survey of Delhi pharmacies found that 12% of sampled drugs were spurious. 
In one recent example, counterfeit medicines at a pediatric hospital in Kashmir are now suspected of playing a role in hundreds of infant deaths there in recent years. 
One widely used antibiotic was found to contain no active ingredient after being randomly tested in a government lab. The test was kept secret for nearly a year while some 100,000 useless pills continued to be dispensed. 
More tests of hospital medicines found dozens more that were substandard, including a crucial intravenous antibiotic used in sick infants. … 
[C]onvictions of drug counterfeiters in India are extremely rare. ... Heather Bresch, chief executive of Mylan, which has plants in the United States and India, said regulatory scrutiny outside of the United States was long overdue. “If there were no cops around, would everyone drive the speed limit?” Ms. Bresch asked. “You get careless, start taking risks. Our government has enabled this.”
The US visit is
part of a long-running effort to create a global network of drug and food regulators to help scrutinize the growing flood of products coming into the United States, including 80% of the seafood consumed in the United States, 50% of the fresh fruit, 20% of the vegetables and the vast majority of drugs. 
She has gone to conclaves of regulators from Europe and elsewhere to coordinate policing, but Indian officials have so far not attended such meetings. 
Many of India’s drug manufacturing facilities are of top quality. Cipla, one of the industry’s giants, has 40 plants across the country that together can produce more than 21 billion tablets and capsules annually, and one of its plants in Goa appeared just as sterile, automated and high tech on a recent tour as those in the United States. 
Cipla follows F.D.A. guidelines at every plant and on every manufacturing line, and the company exports more than 55 percent of its production, said Yusuf Hamied, the company chairman. 
But Benjamin Mwesige, a pharmacist at the Uganda Cancer Institute in Kampala, said in an interview in July that the institute had stopped buying cancer drugs from India in 2011 because it had received shipments of drugs that turned out to be counterfeit and inactive, with Cipla labels that Mr. Mwesige believed were forged. ... Mr. Mwesige estimated that in 2011 about 20% of the drugs that the institute bought were counterfeit. 
Enforcement of regulations over all is very weak, analysts say, and India’s government does a poor job policing many of its industries. … India’s Central Drugs Standard Control Organization, the country’s drug regulator, has a staff of 323, about 2% the size of the F.D.A.’s, and its authority is limited to new drugs. The making of medicines that have been on the market at least four years is overseen by state health departments, many of which are corrupt or lack the expertise to oversee a sophisticated industry. Despite the flood of counterfeit drugs, Mr. Singh, India’s top drug regulator, warned in meetings with the F.D.A. of the risk of overregulation.
 This absence of oversight, however, is a central reason India’s pharmaceutical industry has been so profitable. Drug manufacturers estimate that routine F.D.A. inspections add about 25% to overall costs. In the wake of the 2012 law that requires the F.D.A. for the first time to equalize oversight of domestic and foreign plants, India’s cost advantage could shrink significantly.
What's striking is the comment that
“If I have to follow U.S. standards in inspecting facilities supplying to the Indian market,” G. N. Singh, India’s top drug regulator, said in a recent interview with an Indian newspaper, “we will have to shut almost all of those.” 
From an Australian perspective that comment embodies a regulator's misunderstanding of costs, i.e. non-recognition of the costs (potentially death rather than merely paying for substandard or fake drugs) to Indian consumers from inadequate regulation, manufacture and distribution. Indian consumers have a lesser right to health than their Australian peers or are, in the mind of Indian bureaucrats, just more expendable?