Medicines Made in India Set Off Safety Worries

 

NEW DELHI — India, the second-largest exporter of over-the-counter and prescription drugs to the United States, is coming under increased scrutiny by American regulators for safety lapses, falsified drug test results and selling fake medicines.

Dr. Margaret A. Hamburg, the commissioner of the United States Food and Drug Administration, arrived in India this week to express her growing unease with the safety of Indian medicines because of “recent lapses in quality at a handful of pharmaceutical firms.”

India’s pharmaceutical industry supplies 40 percent of over-the-counter and generic prescription drugs consumed in the United States, so the increased scrutiny could have profound implications for American 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.

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Dr. Hamburg was met by Indian officials and executives who, shocked by recent F.D.A. export bans of generic versions of popular medicines — like the acne drug Accutane, the pain drug Neurontin and the antibiotic Cipro — that the F.D.A. determined were adulterated, suspect that she is just protecting a domestic industry from cheaper imports.

“There are some people who take a very sinister view of the F.D.A. inspections,” Keshav Desiraju, India’s health secretary until this week, said in a recent interview.

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.

“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.”

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. She 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 New Delhi pharmacies found that 12 percent 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 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.

“Some of the fake tablets were used by pregnant women in the post-surgical prevention of infections,” said Dr. M. Ishaq Geer, senior assistant professor of pharmacology at the University of Kashmir. “That’s very serious.”

Investigations of the deaths are continuing, but convictions of drug counterfeiters in India are extremely rare.

Satish Reddy, president of the Indian Pharmaceutical Alliance, said Indian drug manufacturers were better than the F.D.A. now contends. “More rigorous enforcement is needed, for sure, but this impression that India is overrun with counterfeits is unjustified,” Mr. Reddy said.

But Heather Bresch, chief executive of Mylan, which has plants in the United States and India, said regulatory scrutiny outside 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.”

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For Dr. Hamburg, the trip 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 percent of the seafood consumed in the United States, 50 percent of the fresh fruit, 20 percent 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.

He became suspicious when doctors began seeing chemotherapy patients whose cancer showed none of the expected responses to the drugs — and who also had none of the usual side effects. The drugs that had been prescribed were among the mainstays of cancer treatment — methotrexate, docetaxel and vincristine. Laboratory tests confirmed that the drugs were bogus, and Mr. Mwesige estimated that in 2011 20 percent 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. Last month, the United States Federal Aviation Administration downgraded India’s aviation safety ranking because the country’s air safety regulator was understaffed, and a global safety group found that many of India’s best-selling small cars were unsafe.

India’s Central Drugs Standard Control Organization, the country’s drug regulator, has a staff of 323, about 2 percent 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 25 percent 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.

Some top manufacturers are already warning that they may leave, tough medicine for an already slowing economy.

“I’m a great nationalist, an Indian first and last,” Dr. Hamied said. “But companies like Cipla are looking to expand their businesses abroad and not in India.”

American businesses and F.D.A. officials are just as concerned about the quality of drugs coming out of China, but the F.D.A.’s efforts to increase inspections there have so far been frustrated by the Chinese government.

“China is the source of some of the largest counterfeit manufacturing operations that we find globally,” said John P. Clark, Pfizer’s chief security officer, who added that Chinese authorities were cooperative.

Using its new revenues, the F.D.A. tried to bolster its staff in China in February 2012. But the Chinese government has so far failed to provide the necessary visas despite an announced agreement in December 2013 during a visit by Vice President Joseph R. Biden Jr., said Erica Jefferson, an F.D.A. spokeswoman.

The United States has become so dependent on Chinese imports, however, that the F.D.A. may not be able to do much about the Chinese refusal. The crucial ingredients for nearly all antibiotics, steroids and many other lifesaving drugs are now made exclusively in China.

 

 

Phys Ed February 5, 2014, 12:01 am

Shivering as a Form of Exercise

By GRETCHEN REYNOLDS

Kicking The Habit: CVS To Stop Selling Tobacco, Sacrificing $2 Billion In Sales For Public Health And Future Growth

 

 

CVS, the largest pharmacy chain in the United States, will stop selling cigarettes and other tobacco products in all of its 7,600 stores by October 1, its parent company CVS Caremark CVS -1.66% announced this morning. It is the first time any retailer has ever dropped this deadly cash cow, and it is part of a major shift in direction for the drugstore giant.

 

“We’ve got 26,000 pharmacists and nurse practitioners who are helping millions of patients each and every day,” said Larry Merlo, the chief executive of CVS Caremark. “They manage conditions like high blood pressure, high cholesterol, and diabetes — all conditions that are worsened by smoking. We’ve come to the decision that cigarettes have no place in an environment where healthcare is being delivered.”

 

The decision gained immediate praise from the American Medical Association, the Robert Wood Johnson Foundation, and the American Cancer Society . “Over time, we think lives will be saved by this,” says Cancer Society President John Seffrin. But the public-health-mindedness will cost CVS billions – literally. The company sales $2 billion in sales will be shaved off its $125 billion top line. That will pressure earnings, too, though Merlo swears incremental cost cuts will keep those pressures from showing up in its profit statements.

 

Merlo says that continuing to sell cigarettes, which the Surgeon General blames for 480,000 deaths every year from heart disease, lung cancer, and stroke, was anathema to CVS’ long-term plan to become a central player in the U.S. health care system that interacts ever more closely with patients, giving flu shots, reminding them when they are not filling prescriptions, and, through its 800 Minute Clinic in-store nurse practitioner stations, prescribing medicines. “I see my role as insuring that the company is positioned for growth,” says Merlo. “And that is what this decision is about.”

 

CVS, like rivals Walgreen WAG +1% and Rite-Aid Corporation, is seeing a dramatic change to its business as it focuses less on taking marginal revenue out of drug sales and more on larger agreements with hospitals and insurance companies. In fact, CVS is in the midst of an even bigger shift than its competitors. Because of its 2007 merger with Caremark, the company is not only a drug store chain but also a pharmacy benefit manager, meaning it works with insurance companies and employers to control drug costs. The assumption is that by being a rival to both Rite-Aid and benefits manager Express Scripts ESRX -0.42%, CVS can extract better savings and offer better care to patients, saving employers money both by cutting costs and by making people healthier.

 

Among CVS’ newer offerings: a deal with insurers through which patients who have not filled a needed prescription, like a hypertension drug, are given counseling from a pharmacist if they show up wanting something else, like an antibiotic. This is possible because CVS has records of both in-store and mail-order prescriptions; unfilled prescriptions cost the medical system $300 billion annually, CVS says. Another new product will help patients sign up for expensive drugs for cancer, rheumatoid arthritis, and other “specialty” conditions, help them figure out how to pay for them, and allow them to either get them in the mail or pick them up at a CVS story.

 

These new efforts have led CVS to work more closely with hospitals, doctors’ networks, and what are called Accountable Care Organizations, new types of organizations encouraged by Obamacare in which doctors agree to be paid not for every stitch, prescription, or procedure but based on how well patients do after treatment. If CVS can help save money or keep patients healthier, it might get a piece of the action. But these efforts were leading to cognitive dissonance, says Troyen Brennan, a former professor of medicine at Harvard Medical School who is now CVS’ chief medical officer.

 

“We would always get the question: why do you continue to sell cigarettes?” says Brennan. “Because from the physicians’ and nurses’ point of view, you’re either all in for healthcare or you’re not.” He says he thinks that having been the first pharmacy to drop cigarettes will be a “competitive advantage” against other retail pharmacies because of the credibility it will give CVS when talking to physicians.

 

It’s certainly getting good buzz from organizations pre-briefed on the announcement. Risa Lavizzo-Mourey, MD, the CEO of the Robert Wood Johnson Foundation, called CVS’ cig ban “a huge and important step forward for moving us as a nation to a place where we can be healthier.” And Robin Koval, the chief executive of Legacy, the foundation formed to stop teen smoking formed when 46 states’ attorneys general settled with tobacco makers, literally said “Wow.”

 

“For the number one retail pharmacy chain to take a very bold step like this and put people and their health in front of profits sends a signal that if you want to talk the talk about being there to serve your customers and their healthcare needs, then you have to walk the walk,” says Koval.

 

In the shorter term, the cigarette ban may help with one new business: CVS is offering patients’ smoking cessation therapy, which will usually be paid for by insurance but which some patients will need to pay for out of pocket. Patients will be offered several counseling sessions with a nurse practitioner and perhaps, if they need them, nicotine replacement gums, lozenges, or patches or medicines like Chantix and Zyban that can help patients quit. CVS does not sell so-called e-cigarettes, which vaporize nicotine so it can be inhaled.

 

Will the halo from the public health praise be enough to make up for the hit to earnings? Maybe. The $2 billion in annual sales lost is only 1.6% of total revenue. In turn, CVS says that this will pressure earnings by 17 cents per share, or 40%, on an annual basis. But because the removal won’t have fully happened until October, that will only hit this year’s earnings by 6 to 9 cents per share. And CVS says it can make up those costs, maintaining its guidance, although that earnings coverage has to come from somewhere. The company is making a bold bet on rebranding itself as being not just a store, but a healthcare company. Arguably, it’s not there yet. But Merlo has established a clear sense of direction, and when it comes to a big, often slow-moving company, that is a good thing.

 

By GRETCHEN REYNOLDS

By KRISTIN WARTMAN Published: December 1, 2013

“What’s really interesting about children is, the preferences they form during the first years of life actually predict what they’ll eat later,” said Julie Mennella, a biopsychologist and researcher at the Monell Center. “Dietary patterns track from early to later childhood but once they are formed, once they get older, it’s really difficult to change — witness how hard it is to change the adult. You can, but it’s just harder. Where you start, is where you end up.”

This may have profound implications for the future health of Americans. With some 70 percent of the United States population now overweight or obese and chronic diseases skyrocketing, many parents who are eating a diet high in processed, refined foods are feeding their babies as they feed themselves, and could be setting their children up for a lifetime of preferences for a narrow range of flavors.

The Monell researchers have identified several sensitive periods for taste preference development. One is before three and a half months of age, which makes what the mother eats while pregnant and breast-feeding so important. “It’s our fundamental belief that during evolution, we as humans are exposed to flavors both in utero and via mother’s milk that are signals of things that will be in our diets as we grow up and learn about what flavors are acceptable based on those experiences,” said Gary Beauchamp, the director of the Monell Center. “Infants exposed to a variety of flavors in infancy are more willing to accept a variety of flavors, including flavors that are associated with various vegetables and so forth and that might lead to a more healthy eating style later on.”

There is another reason these exposures have a lifelong impact, he said: “This early exposure leads to an imprinting-like phenomenon such that those flavors are not only preferred but they take on an emotional attachment.”

This puts babies fed formula at a disadvantage because the flavors in packaged formula never change. But according to Ms. Mennella, the opportunity to expose those babies to a range of flavors is not lost. “Just because you’re formula-fed, it’s not hopeless,” she said. “Babies learn through repeated exposure, so the more varied the diet, the more likely they’ll be to accept a novel food.”

Another recent study conducted at the FoodPlus research center at the University of Adelaide in South Australia found that exposure to a maternal junk food diet (defined in the study as any food that was energy dense, highly palatable and had a high fat content) results in children with a preference for these same foods. In a rodent model, the study found that being exposed to too much junk food in utero and through breast milk leads offspring to develop a reward pathway in the brain that is less sensitive than normal. Mothers who were fed foods like Froot Loops, Cheetos and Nutella during pregnancy had offspring that showed increased expression of the gene for an opioid receptor, which resulted in a desensitization to sweet and fatty foods. “The best way to think about how having a desensitized reward pathway would affect you is to use the analogy of somebody who is addicted to drugs,” Jessica R. Gugusheff, a Ph.D. candidate at FoodPlus and the lead author of the study, wrote in an email. “When someone is addicted to drugs they become less sensitive to the effects of that drug, so they have to increase the dose to get the same high,” she wrote. “In a similar way, by having a desensitized reward pathway, offspring exposed to junk food before birth have to eat more junk food to get the same good feelings.”

Ms. Mennella at Monell has also done research on reward pathways for sweetness and has found that sweet flavors have an analgesic effect on babies and children such that babies will cry less and children will leave their hand in a cold water bath for longer periods with sweet flavors in their mouths. Ms. Mennella has also found that in obese children, while the level of sweet they prefer is the same as that of normal-weight children, sweet flavors are not as effective as an analgesic. “I hypothesized maybe it’s because of some disruption in the opioid system, so maybe they need more sweet to get the same effect,” she said.

These research studies call into question the ethics of marketing poor-quality foods to children as well as the marketing of infant formula.

In the United States, according to the Centers for Disease Control and Prevention, about 15 percent of mothers breast-feed exclusively for six months, with rates significantly lower for African-American mothers. The American Academy of Pediatrics recommends that women breast-feed exclusively for at least six months and then continue some breast-feeding as they introduce solid foods for the next six months. The World Health Organization recommends breast-feeding up to 2 years of age or beyond.

But infant formula is a booming billion-dollar industry with three companies controlling almost 98 percent of the market: Mead Johnson, maker of Enfamil, Abbott, manufacturer of Similac, and Nestlé (now Gerber), maker of Good Start.

Functional foods, or foods that allegedly deliver nutritional benefit beyond what is available in natural foods, are a food industry creation to convince consumers that their products are superior to, or can replace, natural, whole foods. Globally, infant formula is the fastest growing functional food; the market is on track to grow by nearly $5 billion in 2013 alone.

But formula is only part of the problem since breast-fed babies of mothers eating too many refined and processed foods are also at risk. Claims by the food industry that personal responsibility, exercising more, and eating less are the solutions to obesity and diet-related disease are turned on their head with these studies. If babies are developing food preferences in utero and before 2 or 3 years of age through no fault of their own, how can we then blame them when they become obese children and adults?

If we hope to reverse the tide on obesity and diet-related disease in America, regulating processed food products and infant formula, and creating clear warning labels to deter parents from feeding their children potentially harmful foods may be our best shot. Let’s make sure future generations have the best chance to become healthy adults.