Glaring contradictions between the US FDA's stance and the Indian regulator's rules on drug safety norms have doctors and patients flummoxed
R Anantharaman, an endocrinologist at Bangalore’s Apollo Hospitals, has been wary of prescribing Indian biological drugs ever since he learnt about the quality problems surrounding some of them. He often prescribes recombinant human insulin—insulin that bacteria produce when the human insulin gene is introduced inside them. This diabetes drug is prepared by a complex method, and minor manufacturing defects can make a big difference to its efficacy.
This is why, when the US Food and Drug Administration (FDA) banned three facilities of the Mumbai-based Wockhardt Limited—the firm that manufactures the Indian version of this drug—from exporting to the United States because of major lapses in quality control, Anantharaman switched to foreign brands.
While Wockhardt reported a drop of 78 percent in its profit for the March quarter because of the ban, it continues to sell its products in India. And though there is no government edict preventing the drug from being sold in India, Anantharaman is not taking any chances.
The endocrinologist isn’t alone in his concerns about the quality of Indian drugs. Many doctors, citing absence of rigour on the part of the Indian drug regulatory body, Central Drugs Standard Control Organization (CDSCO), are being cautious just like him. A case in point is the varied reaction to Ranbaxy, which was engulfed in regulatory problems last year when four of its plants were banned from exporting to the US.
Several doctors and major hospitals such as Jaslok in Mumbai have misgivings about Ranbaxy’s products. Jaslok Hospital has a policy against Ranbaxy drugs.
“We are not using them, except a few drugs, where we have no substitutes. When there is speculation over the quality of a drug anywhere in the world, unless we are hundred percent convinced otherwise, we have to take some steps,” says Tarang Gianchandani, the CEO of Jaslok Hospitals.
On the other hand, other hospitals such as Apollo and Medanta eventually decided to continue prescribing the drugs. When asked if he was worried about the quality of Ranbaxy drugs, Naresh Trehan, chairman of Gurgaon-based Medanta, said the hospital’s quality-control lab routinely tested the drugs instead of relying on the Indian drug regulator’s or Ranbaxy’s statements alone. Apollo Hospitals’ joint managing director Suneeta Reddy turned down a request for an interview.
Such concerns reflect the dilemma that the medical community in India faces when prescribing drugs from tainted Indian pharmaceutical firms. These firms were found guilty of manipulating drug quality control documents, which means the safety and efficacy of their drugs is suspect. When Sun Pharmaceuticals acquired Ranbaxy in a $4 billion deal in April this year, investors were hopeful that Sun would be able to fix Ranbaxy’s quality issues.
But in May, Sun Pharmaceuticals’ own regulatory problems got worse, with the US FDA saying the drug maker had not adequately addressed previously listed shortcomings at its Karkhadi plant.
The FDA said it would strengthen its scrutiny of Sun’s operations. A spokesperson from Sun told Forbes India that the firm would be responding in detail to the FDA and would strengthen its quality controls.
But even as the FDA increases the spotlight on Indian firms, CDSCO has maintained that the drugs from these companies are above board. In mid-2013, CDSCO carried out its own tests on Ranbaxy’s medicines, but found no quality issues. It is this glaring contradiction between the FDA’s stance and the Indian drug regulator’s stance that has doctors and patients flummoxed.
When asked if he was dissatisfied with the Indian regulator’s lack of action against Ranbaxy, Medanta’s Trehan said, “What choice do I have? We can’t start importing expensive drugs from the US.”
Lack of manpower and lax rules
The main reason for this contradiction on drug safety is that CDSCO’s net is much smaller. Its ambitious plans to recruit new personnel and create new positions have mostly remained on paper, and CDSCO continues to be dramatically short-staffed with a mere 1,500 inspectors for over 10,000 manufacturing plants. State regulators are no less crippled. Karnataka, for instance, has only 49 drug inspectors overseeing 28,000 medical stores and 248 drug manufacturing units.
The Indian regulator could be missing many quality control issues simply because it doesn’t have the staff to conduct a thorough investigation. With 1,500 inspectors, it’s impossible to monitor a large enough sample of drugs on sale.
Even if each of these inspectors visited one plant every day of the year, a manufacturing facility wouldn’t receive a visit more than once in over six years. And this isn’t counting retail outlets and blood banks, which fall under CDSCO’s jurisdiction. The Drug Controller General of India, GN Singh, who is responsible for the pharmaceutical regulation under CDSCO, didn’t respond to Forbes India’s request for an interview.
Even drug inspectors who visit plants and do their job by the book can miss problems. This is because the Indian regulator’s rulebook—the Current Good Manufacturing Practices (CGMP) listed in the Indian Drugs and Cosmetics Act—is not as extensive as the FDA’s CGMP.
“Regulations governing the manufacture of these drugs are not as detailed in India, and Indian-based companies take advantage of this lack of detail,” Dinesh Thakur, a former executive of Ranbaxy Labs who blew the whistle on its fraudulent manufacturing practices, wrote in an email to Forbes India. On his blog, Thakur compared the sections on quality control in the Indian Drugs and Cosmetics Act to its equivalent in the US Code of Federal Regulations. The role of the quality control unit in the American code is more clearly spelt out, giving drug regulators the authority to reject products or review production records. “Such detailed expectations are missing in the Indian regulations,” writes Thakur, who received $48 million under the US’ False Claims Act for alerting the FDA of Ranbaxy’s malpractices.
It’s no secret that the FDA’s scrutiny of Indian plants is much more fine-toothed than CDSCO’s. “For example, the clocks on all computers in a facility should show the same time,” says an analyst of the pharmaceutical industry, who declined to be named. “If one clock is a few minutes faster during an FDA inspection, you are asked why the times are not consistent.” While this seems like a trivial issue, according to the analyst, these time stamps would track a product accurately through the production line, highlighting anomalies. During the FDA’s inspection of Ranbaxy’s Toansa plant, inspectors, by observing the time stamps, were able to tell that test results for the same batch were being rewritten.
“The kind of effort FDA investigators put in is not something Indian investigators can do. The Indian investigator is probably a good friend of the plant employee; so, he starts chatting and objectivity goes out of the window,” says the analyst, “In the FDA’s case, the inspector is often some Caucasian who doesn’t know you from Adam. You can’t just say ‘chai pee lo [have some tea]’.”
Even when inspectors strive to be conscientious and objective, there is the problem of outside interference. Anil Gupta, a CGMP compliance expert who works for the pharmaceutical consulting firm Apothecaries, says political collusion is common. He cites the example of a drug inspector who knew a Delhi manufacturing facility was not up to standard. But each time the inspector would go to the facility, he would get a call from a local MLA to go easy on the inspection. “I will say [that] 90 percent of Indian facilities do not comply with CGMP standards. They don’t even comply with WHO standards, which are much lower,” says Gupta.
Despite these shortcomings in its regulatory mechanism, CDSCO has argued that Indian drugs are, by and large, safe. Most pharmaceutical analysts Forbes India spoke to agreed that incidents of real harm to patients are rare. How is this possible?
Too minor for legislation
The simple answer to this is that poor quality drugs don’t always result in something as tragic as death or an epidemic. Ninety percent of the time, these drugs don’t cause newsworthy harm: Either they merely don’t work as expected, or they have side effects that are too minor to be noticed. When the former happens, a doctor usually can’t tell why this is the case. “A drug may not work for several reasons. Sometimes, we don’t know if the patient is complying with the regime. It is a very complex thing for a doctor to monitor,” says Anantharaman.
Even when a doctor realises that the drug is deficient, he will merely switch brands because there is no real system in India to report adverse effects. That is usually the end of the doctor’s involvement. “We don’t get into the quality standards,” says Anand Rao, general physician at Bangalore’s Malathi Manipal Hospital.
It is possible that many of the quality problems with drugs from firms such as Ranbaxy and Wockhardt were too minor to be reported. For example, the FDA’s May letter to Sun Pharma draws attention to the practice of trial injections. Employees at Sun’s Karkhadi plant were found to be manipulating the results of a drug impurity test. Each time the test showed that the drug wasn’t meeting FDA standards, they would discard the results and test another sample. At least on one occasion, they reported that a batch had met quality specifications, even though a sample in it had failed.
Unless this problem batch is separated and put through a clinical trial, it is impossible to know what effect it will have on patients. Even mild ineffectiveness means different things for different people and for different drugs. For a patient with a mild headache, an ineffective aspirin could lead to slightly prolonged discomfort. On the other hand, for a patient with a severe bacterial infection, an ineffective antibiotic could lead to drug resistance or even death. Speaking to analysts at an earnings call in March, Wockhardt Managing Director Murtaza Khorakiwala said they were working on fixing the quality problems, but it was difficult to say when they would be resolved.
Eventually, the perceived quality of a drug depends on the expectation the manufacturer sets. “Let’s say you are taking a proton pump inhibitor such as Esomeprazole Magnesium (Nexium) to help with severe heart burn,” Thakur wrote in an email. “The instruction for dosage says that the drug must be taken 30 minutes before a meal. If the formulation of the generic is such that it takes longer than the 30 minutes to dissolve in the stomach acid, is it really being therapeutically effective?” Thakur’s point is that even if the drug doesn’t hurt you, it isn’t doing what it promises.
It is this buffer zone between the outright dangerous and the mostly safe that Indian drug regulations are coursing. This is likely to continue until a major quality failure occurs. “In the case of the FDA, too, regulation has always been the response to an incident,” says C Om Prakash, a senior partner at the pharmaceutical consulting firm, Optimus Pharma, “You need to have a tragedy happening for the laws to change.”
Such mishaps continue to happen despite the FDA’s comparatively demanding standards. Two years ago, an epidemic of fungal meningitis killed over 40 people in the US when a compounding pharmacy failed to sterilise the vials in which it was selling an injectable drug. This, too, resulted in a new bill being framed, allowing the FDA to regulate compounding pharmacies.
The FDA’s legislative history is a case study in medical mishaps. The first among them was the ethylene glycol contamination case of 1937. Unaware of how toxic the compound ethylene glycol is to humans, a Tennessee-based pharmaceutical firm sold a raspberry-flavored oral antibacterial tonic prepared with diethylene glycol as a solvent. Around 100 people are thought to have died after consuming this poison. The impact of the incident was the Federal Food, Drug and Cosmetics Act, which marked the FDA’s transition from a policing body to one that oversaw pre-marketing safety of drugs.
You get what you pay for
There is another angle to the debate on Indian drug legislation. Some argue that if CDSCO were to dramatically improve its standards, it would make Indian medicines unaffordable to many. Status quo is preferable to this. “Drug manufacturing will become much costlier. You may drive many players out of the market. In a country like India, we have to work with lower standards,” says Bino Pathimparampil, a pharma sector analyst at India Infoline Capital.
According to Pathimparampil, most quality issues end up being minor. Even if there are some deviations in drug composition, it will still work fine.
“It is like the difference between a Maruti and a Mercedes,” says Devinder Pal, a Mumbai-based pharma company consultant, talking of the difference between CDSCO standards and FDA. “One has fewer standards, which it complies with, and the other has more standards. It doesn’t mean one is worse than the other.”
The only problem with the analogy is that unlike in the case of Maruti or Mercedes, buyers do not usually know that they are buying a drug of possibly lower quality when they opt for certain Indian brands. Manufacturers promise the same effectiveness, even if the price is lower. It is this information asymmetry that doctors like Anantharaman will continue to struggle with.