Market Place
This week, PharmaCompass brings you a compilation of the Drug Master Files (DMFs) updates at the US Food and Drug Administration (FDA) over the past two quarters. These applications provide an overview of the products active pharmaceutical ingredient (API) manufacturers are investing in. And, they also give a sneak preview into the next possible first-to-file (FTF) generic challenges to patented drugs.
Here are some key findings from our compilation of the FDA’s DMF updates over the second and third quarter of 2016, details of which were provided in July and October:
India leads
the pack, as the number of filings remain the same
Over the period, there were a total of 379 updates of DMFs at the FDA. This number
indicates a pace in filings that is nearly the same as the previous quarters.
We had seen 180 DMFs updates in the last quarter (Q4) of 2015 and 190 in the first quarter (Q1) of 2016.
During the last
two quarters, the DMF updates were led by Indian companies, such as Macleods Pharmaceuticals (14 DMFs), MSN Labs (13 DMFs), Hetero
(12 DMFs), Lupin (9 DMFs), Cipla and Biophore. The other prominent companies were Mylan and Teva.
Companies
with compliance issues stay away
Unlike previous
quarters, where
companies with compliance problems continued to submit DMFs, the last two
quarters were slightly different, since companies like Zhejiang Hisun and Ipca
Laboratories did not submit DMFs.
However,
Emcure Pharmaceuticals — whose Pune facility was inspected by
the FDA last year and a warning letter was issued to the company for violations of current good manufacturing practices (cGMPs) in March this year — submitted one DMF (for Phytonadione)
While
China shut down antibiotic manufacturing in the Shijiazhuang
city, raising concerns about the global supply chain’s dependence on China, Sinopharm Weiqida Datong
Pharmaceutical, located about 300 kilometers away from Shijiazhuang, filed DMFs for the key building blocks of antibiotic manufacturing — 6-APA and 7-ACA.
Once
again, this filing reinforces the dependence of global
antibiotic manufacturing on China.
Click here to view all the updates of the second and third quarter of 2016 (Excel version available) for FREE!
Imminent FTF challenges
The
FTF challenges to Alvimopan Dihydrate (Merck’s Entereg), Apremilast (Celgene’s Otezla), Bosutinib (Pfizer’s Bosulib), Daclatasvir
Dihydrochloride (Bristol-Myer
Squibb’s Daklinza), Elvitegravir (an ingredient in Gilead’s Vitekta,
Stribild, Genvoya), Ibrutinib (AbbVie’s
Imbruvica), Ospemifene (Shionogi’s Osphena), Perampanel (Eisai’s Fycompa), Pomalidomide (Celgene’s Pomalyst), Regorafenib (Bayer’s Stivarga), Tofacitinib (Pfizer’s Xeljanz) and
Vortioxetine
Hydrobromide (Takeda’s Trintellix) seem to be imminent in
view of the recent filings of DMFs.
Roche’s 2014 acquisition of
InterMune for US $ 8.3 billion to gain rights to Esbriet (pirfenidone)
is likely to come under attack as three more DMFs were submitted during the
period under review.
The ink wasn’t dry on the deal papers of Pfizer’s US $1 4 billion acquisition of Medivation in August this year, when two more companies — Watson Pharma (now Allergan) and Scinopharm — submitted filings for Enzalutamide, the product for
which Pfizer paid all that money. This takes the total number of US submissions
for this product to seven.
Apixaban and Canagliflozin are most actively filed products
The most actively updated DMFs in the past six months were for the APIs of Bristol-Myer Squibb’s new-age anticoagulant Eliquis (Apixaban)
and Johnson & Johnson’s diabetes treatment Invokana (Canagliflozin). Sixteen DMFs were submitted for Apixaban along with nine for
Canagliflozin.
Products
like Dimethyl Fumarate and Teriflunomide — which were the
most frequently filed DMFs in our previous reports — continued to see vigorous filing activity.
Synbias Pharma made a submission
for Nelarabine, the only
submission for a Novartis product that was approved in 2005
and for which the only listed patent is expiring in June 2017. Similarly DSM’s submission of Dexpanthenol is the only DMF
listed for a product used in a variety of injectable and intravenous solution
products.
Established
pharmaceutical companies like Quimica Sintetica and Piramal Healthcare made submissions for products — Benznidazole and Norprostol — which are currently not approved in the United States, indicating the possibility of development projects being underway.
Our view
With drug filings ranging from multiple FTFs to cannabis derivatives,
updates over the two quarters have shown that regardless of the compliance
news, activity in the API industry is extremely robust.
You can view the PharmaCompass compilation of
the new DMF filings by clicking here or simply by sending us an email to get
your own Excel version of the new submissions.
Click here to view all the updates of the second and third quarter of 2016 (Excel version available) for FREE!
Impressions: 4464
https://www.pharmacompass.com/radio-compass-blog/us-dmf-filings-indicate-a-robust-api-industry-with-multiple-first-to-file-challenges
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08 Dec 2016
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Pharmaceutical Whispers (Phispers) this week cover another major heparin scandal emanating from China, GSK may have a new CEO in 2017, the pharma
world reducing dependence on China for antibiotics, regulatory moves to
accelerate drug approvals in the US and China and a lot more. Chinese heparin producer fails European inspection Last week, heparin producer Dongying Tianyong in China failed a European Directorate for the Quality of Medicines (EDQM) inspection. Heparin is a substance widely used as an injectable anticoagulant and as an intermediate. Results obtained from suppliers of crude heparin appeared to be manipulated and the quality system was identified as very weak and deficient, and not in compliance with the EU GMPs. The inspection was conducted in December while the summary report was posted February 25, 2016. Back in
2008, major recalls of heparin were announced by the US Food and Drug
Administration (FDA) due to contamination of the raw heparin stock imported
from China, causing 81 deaths. The FDA had also indicated the contamination may
have been deliberate
and had identified Changzhou
SPL, a Chinese subsidiary of Scientific
Protein Laboratories, as the source of the contaminated heparin. The contaminant – oversulfated chondroitin
sulfate – cost US $ 9 a pound compared with US $ 900 a pound for heparin, creating one of the biggest pharmaceutical quality scandals in history. Dongying Tianyong also manufactures Enoxaparin
Sodium, an active pharmaceutical ingredient (API) produced from heparin, for which a ‘recall of product’ has been considered and the company’s regulatory filing has been suspended. Is there going to be a repeat of the scrutiny on heparin manufacturers
in China once again? World’s antibiotic supply chain will not rely completely on ChinaIn July 2015, Novartis
announced it is shutting down three of its plants, one of which produced the
antibiotic intermediate 7-ACA (7-aminocephalosporanic acid) – the core chemical structure (building block) for producing a whole host
of cephalosporin antibiotics. At the time, PharmaCompass had expressed concern that
the Novartis’ plant shut down has created an urgency to find alternatives to Chinese APIs, since the global supply of
7-ACA would be dependent on China in view of the announced closure. However, the
global imbalance will not occur any time soon as International Chemical Investors Group (ICIG) announced the acquisition of Novartis’, Frankfurt-Höchst-based site which produces 7-ACA. With this acquisition, CordenPharma
Group (the pharma platform of ICIG)
will become one of the major suppliers of 7-ACA to customers worldwide. Expect accelerated drug approvals in China and
the USThe
China Food and Drug Administration (CFDA) said in a statement it would accelerate the approval of drugs. For pharmaceutical firms, the
approval of drugs has been a headache for long and they complain it takes too
long to get drugs to market.The newly appointed FDA commissioner, Dr. Robert Califf, mentioned
that accelerated generic drug approvals will be high on his list of priorities.
In addition, policy leaders in the United States have suggested speedy reviews
of generic drugs that lack competition. This is one of the two specific
actions aimed at reducing generic drug shortages more rapidly and price
gouging. The other action suggested by the policy leaders is to give the FDA
permission to clear a generic product based on an equivalent approval from a
foreign country. Mylan breathes a sigh of relief, Teva’s Epipen launch “significantly delayed”While on the topic of accelerated approvals, Mylan breathed
a sigh of relief as their billion-dollar allergy-reaction injector, Epipen will
not see Teva as a competitor until at least 2017. Teva’s launch has been “significantly
delayed” as the FDA found “major deficiencies” in its application. Epipen contributed 13% to Mylan’s global revenues last year. Libido pill problems
greet Valeant CEO on return from leaveOne of the pharmaceutical industry’s poster boys for high
prescription drug prices – Valeant
Pharmaceuticals’ CEO Michael Pearson – returned to work after a nine-week medical leave owing to pneumonia. Valeant is known to acquire
medicines and then hike the prices.While Valeant’s business practices have been under close scrutiny and its shares are trading at the lowest level in two and a half years, now bad news is emerging about Addyi, the female libido pill Valeant acquired in 2015. A Dutch study found that, Addyi “gives
limited gain in sex” and the benefits were slightly “more
modest than those submitted to the F.D.A. during the approval process”. Not the kind of issue Pearson would have liked to deal with after returning to work post illness. GSK may have a new
CEO in 2017GlaxoSmithKline’s chairman Sir Philip Hampton is believed to have instructed recruiters Egon Zehnder to identify a replacement for GSK CEO, Sir Andrew Witty. Some of the drug giant’s biggest investors have been demanding a split of GSK since they
believe the sum of GSK’s parts is worth more than the current stock market value. It remains to be seen if Witty’s successor will be an internal or an external person. To keep him from leaving, IMS
Health pays Its CEO more than IBM IMS Health Holdings paid
its Chief Executive Officer Ari Bousbib US $ 34.8 million in 2015 to prevent him from leaving to a bigger rival of the data-services firm. In comparison, Accenture paid CEO Pierre Nanterme US $ 15.9 million for 2014. And IBM gave Ginni Rometty US $ 19.3 million. Both Accenture and IBM also provide data services to healthcare clients and have market valuations more than seven times IMS Health’s US $ 8.5 billion. Gilead’s sofosbuvir battles on patents and prices continue in IndiaGilead’s Hepatitis C treatment – Sofosbuvir – has been one of the most spectacular drug launches in pharmaceutical history. Sold as Sovaldi (sofosbuvir) and Harvoni
(combination of sofosbuvir and lepidasvir),
it generated 2015 sales of over US $ 19 billion. However, with the price
in the United States at almost US $ 1,000 per pill and as little as US $ 4.29
per pill in India, Gilead made headlines again as the Indian Patent Office began
hearings to determine whether Gilead Sciences “deserves a
patent” for sofosbuvir.For those interested in this topic, a detailed report on the “Patent Situation of Key Products for the Treatment of Hepatitis C” is available
on
the World Health Organization (WHO) website. Otsuka’s innovative TB drug under fire for high priceOne of the
first new tuberculosis (TB) drugs in decades made by Japanese drug maker Otsuka Pharmaceutical got
slammed this week for a ‘ridiculously high’ price tag. While Otsuka is charging US $ 1,700 for a six-month course of treatment,
delamanid, which is known
commercially as Deltyba, must be taken with other medicines, which make the
complete regimen cost anywhere from US $ 1,000 to US $ 4,500 in developing
countries. Unlike Gilead’s problems with Sofosbuvir, this drug won’t be available in India anytime soon as Otsuka still has not applied for
regulatory approvals. Deal-making round-up: AstraZeneca, Pfizer, Baxalta, Sanofi, AbbVie and Boehringer’s Astra Zeneca’s US $ 4 billion buy of Acerta got endorsed by the award of special “orphan” status to the key drug, acalabrutinib. However, the amount pales in comparison to the US $ 35 billion Pfizer
is expected to avoid
in taxes through its Allergan
merger.The European Medicines Agency had
recommended acalabrutinib as an orphan product for chronic lymphocytic
leukaemia or small lymphocytic lymphoma, mantle cell lymphoma and
lymphoplasmacytic lymphoma.Cancer deal-making remained in focus as Baxalta
and Precision Biosciences announced a partnership to develop allogeneic
chimeric antigen receptor T cell (CAR-T) therapies. The collaboration could
generate up to US $ 1.7 billion for Precision Bioscience. However, another multi-billion
oncology deal is being anticipated between AbbVie and Boehringer
and should be announced soon.While deals are being announced, Sanofi’s divesture of its European generic unit, planned to begin this quarter, may get delayed. France’s largest drug maker needs
more time to determine which assets should be included in the sale. However, it seems like all roads lead to China – AstraZeneca divested rights to two ageing heart drugs for US $ 500
million to China Medical System Holdings. China Medical will pay
AstraZeneca US $ 310 million for a licence to sell Plendil (a
blood pressure pill) in China. It will also pay AstraZeneca US $ 190 million
for the global rights of Imdur (a drug for angina treatment) outside of the US.
Impressions: 4497
https://www.pharmacompass.com/radio-compass-blog/phispers-another-heparin-scandal-in-china-gsk-may-have-a-new-ceo-female-libido-pill-problems
#PharmaFlow by PHARMACOMPASS
03 Mar 2016
With Novartis shutting two plants in Germany and one in India by 2016-end, the global reliance on China for bulk drugs has increased even further, raising serious concerns over safety, supplies and national security. Which
plants? Last week, Novartis announced it will be shutting three plants of its generic business – Sandoz – by the end of 2016. The first plant is in India and the other two are located in Germany, in Gerlingen and Frankfurt. Frankfurt,
manufacturer of a key antibiotic intermediateThe Frankfurt plant is where Sandoz manufactures
7-ACA
(7-aminocephalosporanic acid), the core chemical structure (building block)
for producing a whole host of cephalosporin antibiotics. The reason given for closure -- prices of the cephalosporin active pharmaceutical ingredients (APIs) and intermediates have collapsed as Asian competitors have dumped excess capacity on the market. The shutdown of the Frankfurt facility
means that the global reliance on China for APIs, used to produce antibiotics
(such as cephalosporin) and especially
7-ACA, will increase only further. Chinese
APIs are already a security threat for India India produces a third of the world's
medicines, mostly in the form of generic drugs. However, according to an Oct 2014 report
by a Boston Consulting Group (BCG) and Confederation of Indian Industry (CII), more
than 90 percent of the key raw materials (intermediates and APIs) that go into
making at least 15-odd essential drugs come from China.The drugs listed include the most commonly used painkiller such as paracetamol, aspirin; antibiotics such as amoxicillin and ampicillin, cephalexin, cefaclor, ciprofloxacin, ofloxacin, levofloxacin; first line diabetes drug metformin; and antacid ranitidine. There are no domestic producers left for many drugs such as penicillin-G, and its derivative 6-aminopenicillanic acid, or 6-APA.Since India is still receiving a large quantity of 7-ACA from Germany (confirmed by the import statistics available on the PharmaCompass database), 7-ACA and its derivatives were not mentioned in this report.As per news reports, the Indian government
is now worried about over-dependence on imports from China. "Any
deterioration in relationship with China can potentially result in severe
shortages in the supply of essential drugs to the country. Additionally, China
could easily increase prices of some of these drugs where it enjoys virtual
monopoly," said Bart Janssens, partner, BCG, in a news
report published in The Economic Times. Recognizing the national healthcare
security challenge facing India, the Department of Pharmaceuticals (DoP) has
decided to declare the year 2015 as ‘Year of Active Pharmaceutical Ingredients.’ As part of this initiative, the Indian government intends
to build
cluster parks to boost India’s self-reliance on Chinese imports. Quality,
environmental concerns over Chinese AntibioticsChinese supplies of 7-ACA have been plagued
with multiple issues in the past. In 2012, for instance, several Chinese drug
companies were accused of manufacturing 7-ACA using contaminated ‘gutter oil’, instead of more
expensive soybean oil. Gutter oil is reprocessed oil manufactured from waste oil and animal fat collected from restaurants’ fryers, drains, grease traps and slaughterhouses. Chinese restaurants can get through a lot of cooking oil and this waste oil fuels a highly profitable gutter oil black market as there are few other outlets, such as biofuel production, for this by-product.Similarly, antibiotic pollution in the rivers of China is a serious cause of concern for the Chinese. Our previous analysis, “Antibiotic
resistant superbugs: deadlier than cancer and closer to you than you think” provides a detailed overview regarding the challenge being faced. However, with growing focus on antibiotic pollution in China, a shutdown of factories failing pollution norms would be a severe setback for the global antibiotic supply chain. In addition to these challenges, quality concerns have been raised during international regulatory inspections of some of the leading antibiotic producers in China, like Zhuhai
United and North
China Pharmaceutical Company. South
African stock outs of essential drugs a global concernThe outcomes of these challenges are already being felt in countries such as South Africa which are facing an acute shortage of critical drugs. According to a report
published in Groundup, drug shortages in South Africa’s health facilities have become a crisis. The story mentioned the situation in a hospital (Stanger Hospital) in Ilembe District KwaZulu Natal, where 200 products were out of stock. These included various doses of morphine, some antibiotics and antiretrovirals, especially paediatric ones, used to treat HIV. “About a hundred patients per week are going without ranitidine which prevents stomach ulcers. Several Ilembe facilities are even out of stock of paracetamol tablets,” the Groundup report said. There are multiple reasons for the drug stock
outs. However, unprofitability because old, off-patent products are being sold by
manufacturers at prices very close to the cost of production has played a major
role. Firms are abandoning such products and seeking higher return
alternatives. In addition, due to quality failures suppliers are unable to provide lifesaving medications to the South African population. Our
ViewThe problems of stock outs and quality concerns in South Africa can easily expand across the world and can’t be addressed until the global pharmaceutical industry reduces its reliance on China for bulk drugs and intermediates. It remains to be seen if the threat to the global supply chain will make Novartis reconsider its decision or drive a national government to buy the Frankfurt facility.
Impressions: 7491
https://www.pharmacompass.com/radio-compass-blog/novartis-plant-shut-down-creates-urgency-to-find-alternatives-to-chinese-apis
#PharmaFlow by PHARMACOMPASS
30 Jul 2015
