Market Place
In June 2015, PharmaCompass
reported on antibiotic contamination in rivers in China, which wasn’t a result of the factories that produce antibiotics. The issue had opened another battlefront for the global war on superbugs, or bacteria that grow resistant to drugs.
China,
the largest producer and user of antibiotics in the world, has also been in
news for using colistin — a last resort antibiotic — in agriculture, to speed growth of animals raised for meat.
But the problem has spread much beyond
China.
India has one of the highest rates of antibiotic
consumption and antimicrobial resistance. In 2016, India consumed more than 2.6 billion packs or US$ 2.3 billion (INR 150 billion) worth of antibiotics, a statistic that puts it among the world’s largest consumers of antibiotics.
Last week, three news reports — based on actual studies conducted in India — highlight the fact that the problem is grave. They point to the fact that multinational drug companies are continuing to produce and sell unregulated antibiotics in India; that chickens reared in India are being given colistin, the strongest antibiotic, to promote growth; and that pharma companies are irresponsibly disposing off heavy metals and industrial solvents, posing serious threat to health.
These reports reveal that both drug companies and their consumers in India are behaving irresponsibly, and aren’t giving much thought to the growing
menace of antimicrobial resistance.
Strongest
antibiotics administered on chickens
A
study by the Bureau of Investigative Journalism revealed that chickens raised in India for food have been dosed with colistin, an ‘antibiotic of last resort’.
Hundreds
of tonnes of colistin are shipped to India
each year. The drug is being given to chickens and other farm animals to make
them gain weight faster and as pre-emptive protection against diseases. But the
antibiotic is also used as a last line of defense in humans whose infections
are not responding to other drugs.
The
report found 2,800 tonnes of colistin were shipped to developing countries including India,
Vietnam, Russia, Mexico, Colombia and Bolivia for use on
animals in 2016. The bureau said the total was likely to be higher as the
product could be delivered under a different name, and to countries which do
not make their customs data public.
The consequences of the use of colistin on animals will be “felt throughout the world because resistance to strong antibiotics is spread among organisms,” a report published in The Guardian said. With increasing resistance to drugs, diseases that
were commonly treatable in the last century will become deadly once again.
Studies in China
have revealed that a wide variety of E. coli bacteria have developed resistance to colistin, The gene known as mcr-1—which has the capacity to move from one bacterium to another— was found in about 1 percent of E. coli bacteria and 1 percent of a bacteria, known as Klebsiella pneumoniae, that can cause pneumonia, bloodstream infections, and wound infections.
There is nothing to prevent Indian farmers, which include some of the world’s biggest food producers, from exporting their chickens and other related products to countries across the world.
Production and
sale of unregulated antibiotics
The second
indicator to the worsening menace of antibiotic resistance in India came from a
study undertaken in the UK. It said
multinational companies continue to produce and sell unregulated antibiotics in
India.
The
report released this week by researchers at Queen Mary University of London and Newcastle University, said millions of antibiotic pills being
sold in the Indian market have not been regulated in India, the UK or US. The
research was published in the British Journal of Clinical Pharmacology.
Out
of 118 different formulations of fixed dose combination (FDC) antibiotics sold
in India between 2007 and 2012, 64 percent were not approved by the Central Drugs Standard Control Organization (or CDSCO,
the regulatory body for Indian pharmaceuticals and medical devices), even
though sale or supply of unapproved new medicines in India is illegal. FDCs are
formulations composed of two or more drugs in a single pill.
In
fact, many of the unapproved FDCs combine poorly chosen antimicrobials that can
worsen resistance problems. The FDC
antibiotics were sold under more than 3,300 brand names made by almost 500 drug
makers, of which 12 were MNCs. The report said Abbott, Astra Zeneca, Baxter, Bayer, Eli Lilly, GlaxoSmith-Kline, Merck/MSD, Novartis, Pfizer,
Sanofi-Aventis, and Wyeth, manufactured 45 percent (53) of the 188 FDCs under 148 brand names.
Only
4 percent of the FDCs were approved in the US or UK.
Drug
companies polluting environment
A Swedish financial services group — Nordea — released a report that raised doubts whether even the well-known pharmaceutical companies operating in Hyderabad were following pollution control measures. The Nordea report comes at a time when India’s environment ministry is sitting on a proposal to clear the Hyderabad Pharma City project, proposed over 19,633 acres of land.
An NGO — Changing Markets Foundation — was commissioned by Nordea to study the polluted water accumulated adjacent to manufacturing units and seeping from them. The units were of the pharmaceutical companies Mylan, Dr Reddy’s Laboratories and three
others. Samples were also collected from the back side of hazardous waste
disposal facility at Gaddapotharam, run by Ramky Enviro Engineers.
The NGO found the “occurrence of a range of heavy metals and industrial solvents commonly used in pharmaceutical manufacturing. In some cases, these were found to be present at extremely high concentrations, orders of magnitude higher than maximum regulatory limits or safe exposure…posing serious threat to health.”
“The mere presence of some of these substances is cause for alarm given their extreme toxicity. In addition, the occurrence of mixtures of chemicals shows a lack of adequate treatment prior to discharge,” the report said.
Hexavalent
chromium denoted as Cr(VI), a known carcinogen, was found in most of the
collected samples. In groundwater sample from Gaddapotharam, Cr(VI)
concentration was an alarming 10,900 micrograms/liter against the maximum
permissible limit by BIS of 50 microgram/litre.
Spokespersons of Dr Reddy’s Laboratories and Mylan, however, rejected the report as false.
An earlier report by Changing Markets – titled ‘Superbugs in the Supply Chain - How pollution from antibiotics factories in India and China is fueling the global rise of drug-resistant infections’ had revealed
the presence of drug-resistant bacteria at pharmaceutical manufacturing sites
in India.
On-the-ground research and analysis of water samples had
found high levels of drug-resistant bacteria at sites in three Indian cities:
Hyderabad, New Delhi and Chennai. Out of 34 sites tested, 16 had been found to
be harboring bacteria resistant to antibiotics.
At four of the sites, resistance to three major classes of antibiotics was detected, including antibiotics of ‘last resort’, those used to treat infections that fail to respond to all other medicines.
The report had cited
Hyderabad-based Aurobindo Pharma as one of the worst offenders. However, Pharmaceuticals Export Promotion Council of India (Pharmexcil), which is part of India’s ministry of commerce, had termed the report as “fabricated” and “backed by vested interests” to malign the Indian pharma industry—the world’s largest producer of antibiotics.
Our view
Antibiotics first
came into use after the somewhat
serendipitous event on September 3, 1928 that led to the discovery of penicillin by Alexander Fleming. Since then, many of the bacteria these
drugs are designed to target have developed antibiotic resistance. The Centers
for Disease Control and Prevention (CDC) notes that there are 2 million antibiotic-resistant
infections resulting in 23,000 deaths in the United States each year due to
these superbugs.
Antibiotic
resistance is a global healthcare challenge. It is said to overtake cancer in
number of deaths by 2050 and cost the world economy almost US$ 100
trillion.
Ninety percent of
the 10 million deaths caused by antibiotic resistance are expected to occur in
Asia and Africa. In comparison, deaths due to cancer are estimated to be 8.3
million, diabetes 1.5 million, diarrhea 1.4 million and road accidents 1.2
million.
China has pledged
to step up R&D into new antimicrobials and to curb overuse of existing
medicines to counter growing global antimicrobial resistance through a national action plan unveiled in
August 2016. India needs to vigorously follow suit.
According to a
report published in The Economist, the cost of banning antibiotics
as growth enhancers in farm animals is not great. A study undertaken by the US
government suggests it might reduce the bottom line of those who currently use
them by less than 1 percent. The European Union has already enacted such a ban.
India has taken
strong action against smoking in public places to reduce passive smoking. In a
similar way, it needs to come up with strict laws to fight the menace of
antibiotic resistance.
Impressions: 2947
https://www.pharmacompass.com/radio-compass-blog/india-s-antibiotic-crisis-pollution-unapproved-drugs-overdosed-poultry
#PharmaFlow by PHARMACOMPASS
08 Feb 2018
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This week in Phispers, we bring you news on J&J’s Invokana, a drug that reduces heart risk while increasing the risk of amputation of toes. There is news from Google, which is tying up with India’s Aravind Eye Care System for its artificial intelligence eye doctor initiative. And WHO takes a step towards reducing antibiotic resistance by grouping antibiotics into ‘Access’, ‘Watch’ and ‘Reserve’.
Manufacturing errors trigger drug recalls by Lupin and Dr. Reddy’s in the US
Earlier this month,
we carried an article on the end of India’s pharma honeymoon.
News this week from Lupin and Cipla added another dimension to the problem as manufacturing
errors triggered drug recalls in the United States.
Lupin voluntarily recalled a lot of its birth control pills — Mibelas 24 Fe — in the US. A market complaint indicated a packaging error, making the lot number and expiration
date no longer visible. This product is an oral contraceptive for women.
As a result of the
packaging error, the FDA says the first four days of the birth control packet have four
non-hormonal placebo tablets as opposed to the active tablets. This may place
the user at risk for contraceptive failure and unintended pregnancy.
Similarly, Dr. Reddy’s had to recall hundreds of thousands of cartons of a popular acne medicine — Zenatane — manufactured by Cipla’s plant in Pune.
According to FDA enforcement reports, Dr. Reddy’s is recalling 190 lots, consisting of 778,279 cartons of its Zenatane brand isotretinoin capsules, in four dose sizes. The voluntary Class II recall was initiated in late May after the products failed dissolution testing.
During this period of
turmoil, the Indian company which is generating a lot of positive press is Cadila Healthcare.
Cadila’s US
division Zydus Pharmaceuticals’ subsidiary Nesher Pharmaceuticals has received final FDA approval to
market Nystatin Topical Powder, an anti-fungal
antibiotic used to treat skin infections caused by yeast.
There is more good
news from Zydus Cadila. After years of patent battles, the FDA has approved Zydus Cadila’s generic version
of Shire’s ulcerative colitis drug Lialda.
This came as a rude
shock to Shire investors who had believed the US$ 800 million drug was safe for
a few more years. However, there is a chance that instead of a flood of
generics, the Zydus' generic may be the only competition for Lialda for sometime.
Zydus Cadilla has indicated that its version will have a six-month exclusivity.
J&J’s diabetes
drug saves heart at the cost of toes; Sanofi’s insulin slashes hypoglycemia risks for seniors
Would you like to
sacrifice your toes to save yourself from a heart attack? Well, a diabetes drug
made by Johnson & Johnson (J&J), does just that. The drug — Invokana — decreases the risk of heart attacks and strokes, while increasing the risk of amputation,
particularly of toes.
According to the
results of the 10,142-patient study, funded by J&J, for every three heart
attacks, strokes, or cardiovascular deaths prevented by Invokana, there were
two amputations, 71 percent of them of toes or the lower foot.
While this is a setback to J&J, its rivals — Eli Lilly and Boehringer Ingelheim — who make a similar drug called Jardiance, may be cheering the findings of this
study, performed on sodium-glucose co-transporter 2 (SGLT2) inhibitors. These
drugs prevent the kidney from absorbing sugar from the blood.
But scientists are not sure why the drugs would prevent cardiovascular disease, and it’s unclear why one of them would lead to amputations. “It justifies the need to test each medicine,” Harlan Krumholz of Yale University said.
Another study
examining an at-risk population of seniors who
had switched to basal insulin found Sanofi’s Toujeo to outdo its peers at cutting the risk of
hypoglycemia in older patients.
During a six-month follow-up, the study found that amongst the ‘at-risk’ seniors, those taking Toujeo were 57 percent less likely to experience hypoglycemia than those who switched to competing insulins—such as Novo Nordisk’s Tresiba and Levemir, and Toujeo’s predecessor, Lantus.
Google ties up
with Indian hospital chain for artificial intelligence eye doctor initiative
Google will soon begin
work on a grand experiment that would use machines to widen access of
healthcare. If successful, this initiative will protect millions of diabetes patients
from an eye disease that leads to blindness.
Last year, researchers at Google had said they had trained image recognition algorithms to detect signs of diabetic retinopathy roughly as accurately as human experts. Left untreated, diabetic retinopathy causes blindness. The software examines photos of a patient’s retina to spot tiny aneurisms that would help detect early stages of the disease.
Google is working
with the Aravind Eye Care System in India, a network of eye hospitals, in order
to integrate this technology.
“This kind of blindness is completely preventable, but because people can’t get screened, half suffer vision loss before they’re detected,” Lily Peng, a product manager with the Google Brain AI research group, said. “One of the promises of this technology is being able to make healthcare more accessible.” There are more than 400 million people worldwide with diabetes, including 70 million in India.
FDA tells Endo to
pull out its opioid pain medication, as Gottlieb attacks addiction
Last week, the US FDA
asked drugmaker Endo Pharmaceuticals to remove its powerful opioid pain medication — Opana ER — from the market, due to “the public health consequences of abuse”.
“We are facing an opioid epidemic — a public health crisis — and we must take all necessary steps to reduce the scope of opioid misuse and abuse,” FDA Commissioner Dr. Scott Gottlieb said. “We will continue to take regulatory steps when we see situations where an opioid product’s risks outweigh its benefits, not only for its intended patient population but also in regard to its potential for misuse and abuse,” he added.
Opioid overdoses killed 33,000
Americans in 2015, with half of those involving a prescription opioid.
Opana ER, which is oxymorphone hydrochloride, is used to manage severe pain. The FDA
approved it for this use in 2006. The drug is about twice as powerful as OxyContin, another often abused opioid.
In 2012, Endo
reformulated the drug to make it more resistant to physical and chemical
tampering. While the drug met the standards for approval, FDA says Endo never
showed that the reformulation would reduce abuse.
Amgen loses bid to delay Novartis’ biosimilar; FDA rejects Coherus’ biosimilar for Neulasta
Amgen lost a case in the Supreme Court of the United States that
sought to delay biosimilars of its rivals. Amgen had argued that its biosimilar rivals
should be forced to delay their 180-day marketing notices until the FDA had
made up its mind on the marketing application.
However, on Monday, the Supreme Court took a decision by determining that the law never imposed a two-tier timing system for these notices. Therefore “the applicant may provide notice either before or after receiving FDA approval.”
This has proven to be
a clear win for Sandoz — the generic unit of Novartis that is fielding an array of copycat biologics. The group is launching a copy of Amgen’s Neupogen. And in the process, Sandoz has
unleashed a fresh wave of biosimilars hitting the US market.
However, Amgen won somewhere else — the FDA rejected Coherus Biosciences’ application for a biosimilar of Amgen’s blockbuster Neulasta (a drug that fights infections in cancer
patients). This action effectively delays any rival until 2018, at the
earliest.
The FDA's response
comes as Amgen gears up for biosimilar competition for Neulasta, which
generated about US$ 4.6 billion in sales last year. The FDA requested Coherus
for a re-analysis of certain data and asked the drug developer for more
manufacturing information.
WHO updates list
of essential medicines; groups antibiotics into three categories
Last week, the World
Health Organization (WHO) released its Essential Medicines List (EML), with a
new advice on which antibiotics to use for common infections and which to
preserve for serious circumstances. Amongst the additions to the WHO Model list of essential medicines
for 2017 are medicines for HIV, hepatitis C, tuberculosis and leukaemia.
The EML is used by
many countries to increase access to medicines. The updated list has added 30
drugs for adults and 25 for children, and specifies new uses for 9
already-listed products. In all, it contains 433 drugs deemed essential to
address the most important public health needs.
This time, WHO has grouped antibiotics into three categories – ACCESS, WATCH and RESERVE – with recommendations on when each category should be used.
Initially, the new
categories apply only to antibiotics used to treat 21 of the most common
general infections. If found useful, it could be broadened in future versions
of the EML to apply to drugs to treat other infections.
Antibiotics in the
ACCESS group must be available at all times as treatments for a wide range of
common infections. It includes drugs like amoxicillin, an antibiotic used to treat infections such as
pneumonia.
The WATCH group
includes antibiotics that are recommended as first- or second-choice treatments
for a small number of infections. For example, the use of ciprofloxacin, used to treat cystitis (a type of
urinary tract infection) and upper respiratory tract infections (such as
bacterial sinusitis and bacterial bronchitis), should be dramatically reduced
to avoid further development of resistance.
The third group, RESERVE, includes antibiotics that should be considered as last resorts, such as colistin and some cephalosporins. These must be used
only in the most severe circumstances when all other alternatives have failed.
Impressions: 3377
https://www.pharmacompass.com/radio-compass-blog/j-j-s-diabetes-drug-reduces-heart-risk-at-the-cost-of-toes-google-s-ai-eye-doctor-initiative
#PharmaFlow by PHARMACOMPASS
15 Jun 2017
This week, Phispers covers news about David Cameron urging the G7 to fight superbugs, FDA regulatory action against Corden Pharma’s Italian facility and a new implant that fights opioid addiction.Teva’s largest sterile medicines plant in Hungary placed on FDA import alert listTeva Pharmaceutical’s facility in Hungary was placed on the US Food and Drug Administration’s import alert list. The action was taken after an FDA inspection found that the plant was not conforming to the current good manufacturing practices (GMPs). All drugs produced by the finished dosage forms facility – barring antibiotics Amikacin and Bleomycin – have been placed on the import alert list. Teva had commissioned the US $ 110 million plant in Gödöllő, Hungary, in 2012. At the time, Teva had announced that the facility was one of the largest sterile medicines plants in the world. The plant has an annual production capacity of 160 to 200 million units of injectables and the six production lines can produce six different products simultaneously. It supplies medicines to patients in over 70 countries in Europe, North America, and the Far East. The FDA import
alert is bad news for Teva and comes at a time when investors believe the US $ 41 billion
it paid for Allergan’s generic business was too high a price. FDA inspection in Corden Pharma’s Italy plant uncovers ‘black grime and filth’ While details about Teva’s GMP shortcomings are awaited, an inspection by the FDA of Corden Pharma Latina’s active pharmaceutical ingredients (API) facility in Italy revealed that “black grime and filth were visible” on tiles and stagnant water was found collecting under aseptic filling machines. Meanwhile, Corden Pharma said it will respond to FDA’s warning letter and stressed that the supplies of APIs and finished dosage forms manufactured at its Italy plant will not be impacted. The FDA also
posted on its website the long-awaited warning letter for Megafine Pharma in India, which had been placed on FDA’s import alert list in October 2015. The warning letter revealed the usual data-integrity concerns. On a positive
note, Granules India shared it has successfully addressed FDA’s observations during a recent inspection. It would be worthwhile to have more companies share such positive news so that the ‘noise’ about non-compliances gets balanced. This comes at
a time when the Indian drug regulator is introducing a risk-based inspection model to address concerns at manufacturing
plants in India. Cameron urges G7
nations to step up fight against superbugsBritain has asked G7 nations to do more to fight
killer superbugs. This was after the United States reported the first case in the country of a patient with bacteria resistant to a last-resort antibiotic – colistin.
The antibiotic is reserved for nightmare bugs. The patient, a 49-year old woman
from Pennsylvania, succumbed to the truly pan-drug resistant bacteria. In Japan, David Cameron, Britain’s Prime Minister, said leading countries need to tackle resistance by reducing the use of antibiotics and rewarding drug companies for developing new medicines. “In too many cases antibiotics have stopped working. That means people are dying of simple infections or conditions like TB (tuberculosis), tetanus, sepsis, infections that should not mean a death sentence,” he said at a conference in Japan. “If we do nothing about this there will be a cumulative hit to the world economy of US $ 100 trillion and it is potentially the end of modern medicine as we know it,” he said. FDA approves implant
that dispenses opioid addiction medicationThe FDA has approved an implant that continuously dispenses
an opioid
addiction medication – buprenorphine – for six months. Branded as Probuphine, the device will cost less than US $ 1,000 per month, said the spokesperson for Braeburn Pharmaceuticals – the company that has the commercial rights to the implant in the United States. That’s a lot more expensive than other forms of buprenorphine existing in the market, such as a daily pill or a dissolvable film. But it’s cheaper than Vivitrol,
another form of opioid medication, priced at around US $1,100 a month. However, doctors have cautioned that the implant, originally
developed by Titan
Pharmaceuticals, needs to be supplemented with counseling and other forms
of support. Sun Pharma subpoenaed
for information on drugs it sells in the USIndia’s largest pharmaceutical company – Sun
Pharmaceutical Industries – was subpoenaed
by the US Department of Justice (DoJ). The DoJ sought more information about
the pricing and marketing of the generic drugs Sun Pharma sells in the US. The DoJ, through its antitrust division, has also asked Sun Pharma’s US unit for details related to communications with competitors, employee and corporate records. The subpoena is part of a wider probe by American regulators into the steep increase in prices of generic drugs in the recent past. The investigation had been prodded by US Senator Bernie
Sanders and Democratic Representative Elijah Cummings. Other generic drug
manufacturers like Dr. Reddy’s Laboratories and Allergan also received subpoenas from regulators
seeking similar information last year. Alibaba tells vendors
to stop online sales of medicines in ChinaAlibaba Group Holding has told vendors on its Tmall website
to stop selling drugs online. The Chinese e-commerce company cited an “urgent” directive issued by a local regulator that halts drug sales through third-party platforms. A Reuters news report mentioned a circular issued by the Hebei province branch of the China Food and Drug Administration (CFDA) on “urgent control measures relating to drug products”. No reasons for such a directive had been cited.
Impressions: 5960
https://www.pharmacompass.com/radio-compass-blog/gmp-problems-at-teva-s-hungary-plant-place-it-on-fda-s-import-alert-list-alibaba-halts-online-sale-of-medicines
#PharmaFlow by PHARMACOMPASS
02 Jun 2016
