2/13/2018
`
`As combination drugs flood India, a U.S. pharma giant profits
`
`SIDE ROAD: A billboard for Abbott in Mumbai. The American pharmaceutical company and hundreds of other firms in India are selling drugs that
`have been approved by a state but not by the central government. REUTERS/Danish Siddiqui
`
`Broken Health
`
`As combination drugs engulf India, an
`American pharmaceutical giant profits
`
`By Krista Mahr and Zeba Siddiqui
`
` Filed Dec. 15, 2015, 1:07 p.m. GMT
`
`Part 3: A unit of Abbott Laboratories is marketing a drug in
`India that doesn’t have New Delhi’s approval – or that of the
`U.S. drug authorities. Experts say the misuse of combination
`
`https://www.reuters.com/investigates/special-report/india-medicine-abbott/
`
`Exhibit 1117
`IPR2017-00807
`1/17
`ARGENTUM
`
`000001
`
`

`

`2/13/2018
`
`As combination drugs flood India, a U.S. pharma giant profits
`
`drugs risks boosting antibiotic resistance, turning India into
`an incubator of “superbugs.”
`
`MUMBAI – Prabhu Dayal arrived at a clinic on the
`outskirts of Mumbai on a muggy afternoon in July
`to see the doctor about a cold and cough. The 75-
`year-old had been feeling unwell for a few days and
`hoped to get something to treat his symptoms.
`
`He did. But the prescription Dayal left with that day
`wasn’t for any regular cold medicine.
`
`It was for a powerful antibiotic cocktail marketed in
`India by a unit of U.S. pharmaceutical giant Abbott
`Laboratories. It is not approved for sale in
`major markets such as the United States, United Kingdom, Germany, France, Japan and
`Australia. Medical experts say it doesn’t make sense to prescribe the cocktail for cold symptoms.
`And a government-appointed panel in India recommended to the Health Ministry last year that
`it not be approved for sale here, citing lack of safety and efficacy data and a high potential for
`“misuse.”
`
`In fact, the drug has not been approved by the central government, as required by the Drugs
`Controller General of India (DCGI), the regulator responsible for approving new drugs.
`
`Under India’s complex drug-approval regime, many pharmaceutical manufacturers have
`obtained permission from a single state to make new fixed-dose combination drugs, or FDCs,
`like the Abbott one - and are selling them in other parts of the country without the approval of
`the central government. FDCs combine two or more drugs in a single pill.
`
`India’s top drug regulator is trying to shut down this avenue. “The first clearance of new drugs
`which anyone wants to market in India, that has to be given by the national regulatory
`authority,” G.N. Singh, the Drugs Controller General of India, told Reuters.
`
`But inconsistent enforcement of the drug laws means that hundreds of FDC drugs are being
`sold in India without the approval of the central government. Policymakers have also now given
`pharmaceutical companies a chance to retroactively prove the safety and efficacy of these drugs,
`including the Abbott one. They are currently under review in New Delhi.
`
`Doctors and public health experts both in India and abroad say the proliferation and misuse of
`antibiotic combinations here may be contributing to antibiotic resistance, making India a
`potent incubator of so-called superbugs. Some of these superbugs have been found in patients
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`As combination drugs flood India, a U.S. pharma giant profits
`2/13/2018
`who travelled from India to the United States, Britain and other countries.
`
`The drug prescribed to Dayal was Zimnic AZ, which combines two antibiotics in a single pill.
`Last year, the Illinois-based Abbott’s India units had sales of more than $1 billion. Its revenue
`in India from combination drugs in 2014 was 24.62 billion rupees ($367 million), according to
`IMS Health, a Connecticut-based firm that provides data on the healthcare industry.
`
`In interviews, former and current medical representatives for Abbott said Zimnic AZ has been
`promoted and administered as a treatment for a wide variety of illnesses, including colds,
`fevers, urinary tract infections, drug-resistant typhoid and sexually transmitted diseases.
`Reuters visited chemists who were also selling the drug for respiratory ailments and to prevent
`post-operative infection. The doctor who prescribed Zimnic AZ for Dayal said the elderly
`patient seemed to be suffering from a respiratory tract infection.
`
`Combining cefixime and azithromycin - the two antibiotics that make up Zimnic AZ - is risky,
`said Ramanan Laxminarayan, director of the Center for Disease Dynamics, Economics & Policy,
`a think tank with offices in Washington and New Delhi. By administering these two drugs in a
`single dose, “you’d be creating strains (of bacteria) resistant to both these antibiotics,” said
`Laxminarayan, who lectures on public health at Princeton University.
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`As combination drugs flood India, a U.S. pharma giant profits
`
`OVERKILL: Patients like Prabhu Dayal, a 75-year-old watchman in Mumbai, are being prescribed powerful antibiotic combinations for common
`cold symptoms. REUTERS/Danish Siddiqui
`
`“Drug resistant strains spread globally,” he
`said. “They already have. It’s very hard to
`regulate the movement of people.”
`
`“Drug resistant strains
`spread globally. They
`already have. It’s very
`hard to regulate the
`movement of people.”
`
`The fact that Abbott and hundreds of other
`companies in India are able to sell drugs like
`Zimnic AZ without the central government’s
`approval is evidence of a health system in
`disarray. This year, Reuters has documented
`how the training of doctors in India – the
`world’s largest exporter of physicians – was
`riddled with fraud and unprofessional teaching
`practices. A second article revealed how an
`Indian doctor facing corruption charges is next
`in line to head the World Medical Association, the leading international medical ethics body.
`
`Ramanan Laxminarayan, director of
`the Center for Disease Dynamics,
`Economics & Policy
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`Nearly half the drugs on the market in India last year were combinations. These include
`medications consisting of three different drugs apiece, doctors said. In the United States,
`combinations made up 13.9 percent of drugs on the market, while in China the number was 14.4
`percent, according to IMS Health. Last year, about 78 percent of combination drugs in India
`were sold by local firms, with multinationals making up the rest, the health data provider said.
`
`Abbott declined to answer questions from Reuters about why it was selling a drug in India
`without the approval of the central government.
`
`The manufacture and marketing of Zimnic AZ in India “is aligned with local regulations,” said
`Varsha Chainani, director of public affairs for Abbott in India. Chainani noted that more than
`15 other companies in India are also manufacturing and marketing the same combination
`under different brand names.
`
`Abbott didn’t respond to questions about whether it was appropriate to prescribe Zimnic AZ for
`patients like Dayal with cold symptoms. The company wouldn’t say for which specific
`indications the drug had been approved in India and what marketing instructions have been
`given to its medical representatives. Abbott declined to say what it was doing to address
`concerns that combinations like Zimnic AZ may be contributing to antibiotic resistance.
`
`“It would be inappropriate to comment in view of the pending evaluation,” said Chainani,
`referring to the drug review currently being conducted by the Drugs Controller General of India.
`“Abbott will abide by the final outcome of the proceedings in this regard.”
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`https://www.reuters.com/investigates/special-report/india-medicine-abbott/
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`As combination drugs flood India, a U.S. pharma giant profits
`
`UNDER THE MICROSCOPE: Abbott says its combination drug Zimnic AZ is in line with local regulations. But an official in New Delhi says the
`combination is currently “under the scanner” for safety and efficacy. REUTERS/Adnan Abidi
`
`COMBINATION FEVER
`
`Fixed-dose combination drugs like Zimnic AZ aren’t unique to India. They are used worldwide
`to improve patients’ compliance in complicated courses of treatment for such conditions as
`HIV, tuberculosis and malaria. It’s easier to get patients to take one drug than a number of
`different pills.
`
`Combination drugs are also useful in increasing compliance among the many Indian patients
`who can’t read, said Sanjay Sikaria, director of drugmaker Suncare Formulations Private Ltd in
`Uttarakhand state. “FDCs are not bad,” he said. “Rampant misuse of these drugs is bad.”
`
`That’s the problem in India, where there has been an explosion of combination drugs. They
`have become a way to boost sales and increase market share: More and more companies have
`tacked on ingredients to existing drugs so they can peddle a new product to doctors and
`chemists, say people in the country’s highly competitive pharmaceutical sector.
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`Combination drugs are profitable because of high demand from doctors, who see them as a way
`to ensure patient compliance, say people in the pharmaceutical industry. Many doctors also see
`them as providing “quick-fix solutions” that cover multiple possible symptoms with a single pill,
`said a physician employed by a pharmaceutical company. “The market needs it and demands
`it,” he said.
`
`Between 2011 and 2014, India’s fixed-dose combination market grew more than 40 percent in
`rupee terms, according to IMS Health.
`
`A study published in the journal of Public
`Library of Science (PLOS) in May found that
`over 70 percent of non-steroidal anti-
`inflammatory drug (NSAID) combinations,
`which are used as painkillers, were being
`marketed in India without central government
`approval. The authors recommended that
`unapproved drug combinations be banned
`immediately.
`
`“We have fixed-dose combinations in every
`category of drug,” said Anurag Bhargava,
`professor of medicine at Yenepoya Medical
`College in the southern state of Karnataka. “The
`single ingredient versions are harder to find.”
`
`DELHI TAKES ‘LONGER’
`
`“We have fixed-dose
`combinations in every
`category of drug... The
`single ingredient
`versions are harder to
`find.”
`
`Anurag Bhargava, professor of
`medicine at Yenepoya Medical
`College
`
`FDCs have grown rapidly in India, in part because over the years pharmaceutical companies
`have procured licenses from a state to manufacture new drugs, without obtaining central
`government approval.
`
`The Abbott combination won approval this way, according to Akums Drugs & Pharmaceuticals
`Ltd, which manufactures Zimnic AZ in Uttarakhand, a state known for its Himalayan peaks and
`thriving drug manufacturing industry. In 2010, Uttarakhand’s state drug licensing authority
`granted approval to Akums to manufacture the combination of cefixime and azithromycin, the
`components of Zimnic AZ, according to the company. Each of those drugs is individually
`approved by the government. Akums said it also makes the combination for an Indian drug
`company.
`
`Asked why Akums was manufacturing a drug without the approval of the central government,
`former company chairman D.C. Jain said state authorities were as qualified as the central
`government to assess a drug, and that the process of applying for approval from a state and the
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`2/13/2018
`central government was similar.
`
`As combination drugs flood India, a U.S. pharma giant profits
`
`Since getting a state license, Akums said it has filed an application to New Delhi for the
`combination.
`
`Getting a green light from New Delhi takes “a little longer,” said Jain, who is now a consultant
`at Akums.
`
`Akums did not respond to a request from Reuters for a copy of the document showing that the
`combination of cefixime and azithromycin had been approved by the state. When Reuters
`visited the state drug controller’s office in Uttarakhand, staff could not find a record of the
`license.
`
`One of several committees convened by the drug
`controller to review drug cocktails in 2014
`recommended that the combination of these two
`antibiotics should not be approved. The panel found
`that the drug was “not a standard antibiotic
`combination” and that “the misuse potential is very
`high,” according to the committee’s recommendation,
`a copy of which was obtained by Reuters through a
`freedom of information request.
`
`After years of intermittent efforts to limit the sale of
`state-licensed FDC drugs, the government is making
`another attempt to weed out those it considers
`“irrational.” More than 3,000 different brands of
`combination drugs are currently under review in New Delhi, a drug regulatory official said.
`
`ANOTHER CHANCE: India’s drugs chief, whose office is
`located at the food and drug administration building in
`New Delhi, says he has to give manufacturers a chance
`to prove that drugs currently being sold without the
`approval of his office are safe. REUTERS/Anindito
`Mukherjee
`
`Asked about the status of the cefixime-azithromycin combination, G.N. Singh, the drugs
`controller general, said he could not comment on a specific case. But the drug regulatory
`official said the combination was “under the scanner” because pairing the two drugs that make
`up Zimnic AZ “is not appropriate.”
`
`‘IT DOESN’T MAKE SENSE’
`
`Pharmaceutical companies in India employ armies of medical representatives to pitch a drug to
`doctors.
`
`“We promoted it for typhoid and urinary tract infection mainly,” Jessy Prashanth, a former rep
`for Abbott in the state of Andhra Pradesh, said of Zimnic AZ. “But we also asked doctors to use
`it in cases of persistent cough, cold and fever.” Prashanth now works for Alkem Laboratories
`Ltd, an Indian company that sells the same combination under a different brand name.
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`2/13/2018
`A medical representative working for Abbott in Maharashtra state, who spoke on condition of
`anonymity, said he only promoted the drug for respiratory tract infections and typhoid. But
`from visits to chemists and doctors, he was aware it was being prescribed for “everything from
`soft skin tissue infections, pneumonia, respiratory tract infection, to (urinary tract infection),
`severe fever, typhoid fever and sexually transmitted diseases,” he said. “It covers most things
`people go to a general practitioner for.”
`
`The two antibiotics that make up Zimnic AZ attack similar bugs in the body and have the same
`potential side effects, said Jonathan Zenilman, chief of the infectious diseases division at Johns
`Hopkins Bayview Medical Center in Baltimore. By coupling cefixime and azithromycin in one
`dose, he said, patients face a heightened risk of gastrointestinal side effects, like nausea,
`vomiting and diarrhea.
`
`“It doesn’t make sense,” he said. “The toxicity is
`duplicative.”
`
`Akums, the manufacturer of Zimnic AZ, said no
`adverse drug reactions have been reported
`since the combination has been on the
`market. For four years after a new medication is
`approved by the central government in India,
`drugmakers are required to submit a Periodic
`Safety Update Report to New Delhi, which
`should include adverse reactions.
`
`Akums said Abbott regularly submitted update
`reports for Zimnic AZ. Neither Akums nor
`Abbott responded to a Reuters request to see
`the findings.
`
`Earlier this year, the
`government reviewed
`some 6,200
`combination drugs, of
`which some 15 to 20
`percent were
`considered “irrational.”
`
`Government official in New Delhi
`
`India’s system for collecting data on problematic drug reactions is weak. The country reported
`about 37,800 suspected cases of adverse drug reactions to the World Health Organization’s
`global database last year. China, with a comparable population, submitted close to 214,000
`reports for the same period, while the United States reported some 785,000 cases.
`
`DRUG-RESISTANT TYPHOID
`
`Standing in his chemist shop in the Uttarakhand capital of Dehradun, pharmacist Varat Negi
`said he usually fills Zimnic AZ prescriptions for throat infections and tonsillitis.
`
`“Many doctors prescribe it,” Negi said, pointing reassuringly to the Abbott logo on the back of
`the blister pack. “It’s a big company.”
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`Cefixime and azithromycin have been administered together before - but usually as two
`separate drugs, and to treat very specific problems. The U.S. Centers for Disease Control and
`Prevention (CDC) says the two drugs may be used together as an alternative treatment for
`gonorrhea, a sexually transmitted disease.
`
`Results from a study sponsored by the Center of Geographic Medicine and Tropical Disease at
`the Sheba Medical Center in Israel also suggest a combined therapy of the two drugs was
`effective in treating drug-resistant typhoid, said Eli Schwartz, the doctor who conducted the
`research. Israeli doctors started to look into the treatment because travelers were bringing
`drug-resistant typhoid back to Israel from India and Nepal, he said.
`
`Still, growing drug resistance is a key risk of the
`widespread misuse of antibiotic fixed-dose
`combinations, especially in a country like India where
`prescription drugs are frequently sold over the
`counter. Bacteria develop resistance to antibiotics
`when repeatedly exposed to the same drugs over time.
`
`The Central Drugs Standard Control Organization
`(CDSCO), the regulatory office headed by the drug
`controller, has tried several times to tame the fixed-
`dose combination market in the past decade. In 2007,
`the government ordered states to withdraw 294
`combinations that were on the market without the
`approval of the central government.
`
`It didn’t go well. In southern India, drug companies and industry associations took the
`government to court over the order. The court stayed the withdrawal order, and eight years on,
`the cases are still pending in the Madras High Court.
`
`Now the drug controller is trying again. In a review of some 6,200 drugs completed earlier this
`year, only about 40 percent were considered ready for approval by a government-appointed
`committee. Some 15 to 20 percent were deemed “irrational,” according to the drug regulatory
`official who spoke on condition of anonymity.
`
`The government has yet to demand that the irrational drugs be removed from the market.
`Instead, it has issued the equivalent of a show-cause notice to drugmakers, giving them another
`opportunity to justify these products.
`
`Drugs Controller General Singh told Reuters his office is committed to ensuring patient safety
`and that he was confident states were no longer granting manufacturing licenses for new drugs.
`But he said the government was giving drugmakers another chance to make a case for their
`
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`products.
`
`As combination drugs flood India, a U.S. pharma giant profits
`
`Akums, the drugmaker that manufactures Zimnic AZ for Abbott, received a government notice
`in September saying Akums needed to provide regulators with more information, said
`former company chairman Jain. Otherwise, the combination of cefixime and azithromycin
`would be considered irrational. Akums provided additional data to the government, and in late
`November the combination was still under review, Jain said.
`
`Abbott declined to say whether it was informed of the notice sent to Akums.
`
`For Prabhu Dayal, the patient with a cold and cough, Zimnic AZ wasn’t a quick fix. Contacted
`two weeks after he was prescribed the drug, Dayal said he had completed the course but still
`wasn’t feeling well.
`
`So, he went to get another round of Zimnic AZ from the chemist, he said. It was sold to him
`again – this time without a new prescription.
`
`PANACEA: Former and current medical representatives for Abbott said Zimnic AZ was being promoted and administered for a wide array of
`conditions. In this 2012 photo, an Abbott rep rides his bike to a doctor’s clinic in the Indian city of Pune. REUTERS/Danish Siddiqui
`
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`
`As combination drugs flood India, a U.S. pharma giant profits
`
`Additional reporting by Steve Stecklow in Mumbai, Ayai Tomisawa in Tokyo, Sujoy Dhar in Kolkata, Sandhya Ravishankar in Chennai,
`Jatindra Dash in Bhubaneswar, and Aditya Kalra and Rahul Singh in New Delhi.
`
`How India mastered the ‘art of combinations’
`
`By Krista Mahr
`
`Since 1961, India’s drug controller has approved more than 1,200 combination drugs, according
`to a list published on the website of the Health Ministry’s Central Drugs Standard Control
`Organization (CDSCO), the national drug regulatory body. But many have also been licensed on
`the state level without the approval of the central government.
`
`It wasn’t until 1988 that the definition of a “new drug” under Indian law was amended to
`expressly include the combination of two or more already approved drugs.
`
`Peter Roderick, a lawyer and research fellow at Queen Mary University of London, said “it’s
`been clear since 1961 that if it’s a new drug, it needs central approval.” Roderick co-authored a
`Public Library of Science study on fixed-dose combination drugs in India that was published in
`May this year.
`
`A drug regulatory official said the law has been clear since 2002. That year, an amendment to
`the statute explicitly stated that to make a new drug, a company required prior written approval
`of the central government in support of a state license application. Some pharmaceutical
`makers maintain the requirement wasn’t clear until 2012.
`
`In 2007, the government tried and failed to get close to 300 state-licensed combination drugs
`withdrawn.
`
`“Indian companies mastered the art of combinations,” said D.G. Shah, secretary general of the
`Indian Pharmaceutical Alliance, a lobbying group for large pharmaceutical companies. “Certain
`excesses have taken place.”
`
`In 2012, the government undertook another attempt to exert control over the FDC market. That
`followed a parliamentary report critical of the functioning of the CDSCO. The report also
`underlined the health risks posed by unapproved combinations.
`
`“Many FDCs in the market have not been tested for efficacy and safety,” the committee
`reported.
`
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`On the threat of antibiotic resistance, the committee said that unauthorized FDCs “that pose
`risk to patients and communities...need to be withdrawn immediately due to danger of
`developing resistance that affects the entire population.”
`
`G.N. Singh, the Drugs Controller General, told Reuters that a government review of
`combination drugs currently under way would remove any irrational FDCs from the market.
`“Patient safety is of utmost importance to us,” Singh said.
`
`—————
`
`Broken Health
`
`By Krista Mahr and Zeba Siddiqui
`
`Photo editing: Thomas White
`
`Graphics: Foo Hwei Wen
`
`Design: Catherine Tai
`
`Edited by Peter Hirschberg
`
`        Follow Reuters Investigates  
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`Other Reuters investigations and long-form narratives
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`As combination drugs flood India, a U.S. pharma giant profits
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`Passport to Riches
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`DR Congo has introduced biometric passports costing $185 apiece. Much of that money goes not to the state but to an offshore
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`As combination drugs flood India, a U.S. pharma giant profits
`
`Cleaning Up
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`Industry-backed research has made chlorhexidine products popular in fighting superbugs in hospitals, raising concerns about their
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`https://www.reuters.com/investigates/special-report/india-medicine-abbott/
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`As combination drugs flood India, a U.S. pharma giant profits
`
`Cotton Crunch
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`A little-known seed company has defied Monsanto with the aid of a Hindu group in India. The dispute could upend the world's largest
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`As combination drugs flood India, a U.S. pharma giant profits
`
`Banks on notice
`
`Bankers expected special treatment from the government after Britain voted to leave the EU. They aren't getting it.
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