This week’s Phispers takes you through pharmaceutical news from across the globe – from Joe Biden’s computer aided cancer moonshot to AbbVie’s second largest venture capital buyout in history and a lot more. After GMP troubles,
migraine patch gives Teva a fresh headacheLast week, Phispers carried news on Teva’s facility
in Hungary, which was placed on the US Food and Drug Administration’s import alert list. The FDA inspection had found the plant not conforming to the current good manufacturing practices (GMPs). This week, there is more bad news for Teva Pharmaceuticals. The company had bought NuPathe in early 2014 for about US $ 114 million. Through this acquisition, Teva had got its hands on the only migraine patch approved in the US – known as Zecuity. The patch first hit the market in September 2015. However, in less than a year of its launch, Teva's Zecuity
is under
the FDA radar for concerns over “serious” adverse events including burning and scarring. Moreover, a large number of users have also reported other problems, such as severe redness, pain, skin discoloration, blistering and cracked skin, the FDA said. Britain’s Patel brothers do a Martin Shkreli on drugs needed by NHSWhile America’s Martin Shkreli faced additional
criminal charges this week of conspiracy to commit securities fraud during
his tenure as the CEO of Retrophine (2012 to 2014), Britain saw its own avatars of Shkreli. Millionaire brothers Vijay and Bhikhu Patel, also known as ‘Bollygarchs’ – have been accused of being part of a group of businesses that hike up prices of common drugs needed by the National Health Service (NHS), the publically-funded healthcare system for England. The Patel brothers have allegedly exploited a loophole in NHS’ pricing system. Today the four businesses, including two with past and present links to the Patel siblings, have allegedly hiked the price of common drugs by up to 12,500 per cent. The unreasonably high prices have cost the NHS an additional £ 262 million (US $ 381 million) a year. This sum has conveniently gone into the pockets of the Patel siblings and their associates. Cancer treatment
least affordable in India and ChinaWhile we all know that Americans pay the highest prices in
the world for cancer drugs, a new study highlights how cancer treatments are
least affordable in lower income countries. The study – presented at the annual meeting of the American Society of Clinical Oncology in Chicago – looked at the prices of cancer drugs in seven countries, while not taking into account discounts or rebates. The lowest drug prices were found in India and South Africa.
But then, when adjusted for the cost of living, cancer drugs appeared to be
least affordable in India and China. The study only strengthens the case for politicians,
healthcare providers, doctors, insurers and patients, who have been opposing
the high prices commanded by modern cancer drugs. Drug companies justify the
high prices, citing the high cost of drug research and the need to make profits
to continue spending on research and drug development. Sun Pharma sells two
US facilities to Frontida BioPharmaSun
Pharmaceuticals – India’s largest drug maker – is
selling off two oral solid dosage manufacturing plants in the US to
Frontida BioPharm Inc. (a part of Frontage
Pharma). The sell-off is part of Sun Pharma’s plans to consolidate its manufacturing facilities in the US. The plants are situated in Philadelphia and Illinois. Sun Pharma earns about half of its total revenues from the
US. And this is the drug maker’s second divestment in the US in the last six months. In December, it had divested
its manufacturing plant in Ohio to Nostrum
Laboratories. The company is also looking to sell facilities and business
units from the Ranbaxy
portfolio. In September 2015, it put
a plant in Ireland on the block to optimize its overall manufacturing base and
also sold
the central nervous system business (of erstwhile Ranbaxy) to Strides
Shasun for INR 1.65 billion (US $ 24.8 million). China’s Fosun leads the race for India’s Gland Pharma with US $ 1.27 billion bidLast week, Hong Kong-listed Shanghai
Fosun (Fosun Pharma) revised its offer to buy KKR-backed Gland
Pharma to US
$ 1.27 billion, the highest so far.
American healthcare company Baxter
International and private equity fund Advent made their offers in May. The frontrunner for Gland Pharma, until recently, was Baxter
with its bid at US $1.1 billion, a news report said. Fosun Pharma is part of Chinese billionaire Guo Guangchang’s extensive business empire. Fosun is believed to have completed its due diligence on Gland Pharma sometime last week. Final negotiations are planned for next week, and we hope to hear a formal announcement on Gland Pharma sometime in the third week of June. Joe Biden launches
open-access cancer database as part of the Cancer Moonshot InitiativeOn Monday, American Vice President Joe Biden announced the
launch of an open-access
cancer database that will allow researchers to better understand cancer and
develop more effective treatments. This first of its kind database, a part of the National
Cancer Moonshot initiative, known as the Genomic Data Commons (GDC), contains
the raw genomic and clinical data of 12,000 patients. The database has detailed
analyses of the molecular makeup of cancers and information on which treatments
were used and how patients responded. The database will encourage the much-needed collaboration
among scientists in different disciplines to research important aspects of
cancer and find new ways to help patients, Biden told doctors. Medicines containing
aspirin can cause stomach bleeding, warns FDAAspirin-containing
medicines to treat heartburn, sour stomach, acid indigestion, or upset stomach
can cause stomach or
intestinal bleeding, warns the USFDA. Since aspirin thins the blood, FDA believes the aspirin in
these combination medicines is contributing to major bleeding events. The
instances of bleeding, however, are rare. In 2009, FDA had issued a warning about serious stomach bleeding risk with aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs). When FDA reviewed its Adverse Event Reporting System database, it found eight new cases of serious bleeding caused by aspirin-containing antacid products since the 2009 warning. Some of those patients required blood transfusion. “Take a close look at the Drug Facts label, and if the product has aspirin, consider choosing something else for your stomach symptoms,” an FDA official said. AbbVie blockbuster
buyout disappoints investorsOn Sunday, AbbVie began
explaining why it paid a whopping US $ 5.8 billion upfront – with US $ 4 billion reserved for milestones – for biotechnology company Stemcentrx and its cancer drug Rova-T (rovalpituzumab tesirine). AbbVie’s acquisition of Stemcentrx is the second largest venture-capital backed startup acquisition in history, after Facebook paid
$19 billion to buyout WhatsApp. However, the first set of data provided by AbbVie disappointed investors. Although the drug’s performance against small cell lung cancer, a disease which has not seen a change in survival rates since the 1970s, showed that 68 percent of the patients achieved a clinical benefit, the expectations from the investor community were much higher.Rova-T targets a protein called “DLL3 that is normally found only deep inside cells. But DLL3 winds up all over the outside of some types of cancer cells. Rova T pairs an antibody, which detects DLL3, with a powerful chemotherapy that kills the cells the antibody detects.” Major fire at Nectar
Lifesciences plant in Punjab, IndiaOn June 3, a fire
broke out in Unit-II of Nectar
Lifesciences Limited, a leading pharmaceutical company, in India. Huge
stocks of pharmaceutical products, chemicals and goods were destroyed in the
fire. However, no loss of human life was reported. The fire broke out around 9.15 pm at the solvent recovery
plant and spread to the other sections of the unit and caused damage. Fire tenders
had to be arranged from neighboring cities to douse the flames.Nectar Lifesciences is a manufacturer of both active
pharmaceutical ingredients and finished formulations with a focus on
antibiotics like Cefixime, Cefpodoxime
Proxetil, Ceftazidime
etc.
Impressions: 2103
Recently announced regulatory
action against Indian and Chinese companies is creating a significant
imbalance in the global supply chains of APIs. This imbalance is likely to open
opportunities for other companies in Asia, and may also drive manufacturing back
to Europe and the US.Last week, three companies – one in India and two in China – ran into problems with European regulatory agencies due to inspections conducted at their facilities. Data falsification, a problem recurring in Asia for the past few years, raised its ugly head yet again. The three companies that received non-compliance reports were
plagued with problems similar to those seen in the past at the Asian operations
of Ranbaxy,
Wockhardt,
Zhejiang
Hisun, Novacyl
etc. The European
regulatory actionTake the case of Jinan Jinda Pharmaceutical Chemistry, China, where an inspection was conducted on
June 26, 2015, by the Italian Ministry of Health. An unofficial and
non-controlled storage area containing mainly raw materials and finished
products was made inaccessible to the inspectors. Since the door of the area had
been removed and replaced with a panel fixed with screws to the wall, the inspection
team concluded that there was a serious risk of data falsification. At Parabolic Drugs, India, where an inspection was conducted by the Italian Ministry of Health on June 17, 2015, the inspectors found the quality management system to be seriously uncontrolled and deficient in almost all “principles” mentioned in the EU’s Good Manufacturing Practices (EU-GMP) guidelines. Falsification of data and documents along with integrity and security of data in the quality control laboratory were among the observations listed in the non-compliance report.Similarly, at Wuxi Jida Pharmaceuticals, China, inconsistent and conflicting answers were received from the personnel and the management. The fact that answers were modified according to the inspectors’ requests and that documentation was shown in an ambiguous way led the Italian inspection team to conclude that the company did not comply with the requirements of EU-GMP.The Certificates of Suitability (CEP/COS), given to certify
that the material complies with the requirements laid down in the relevant
monograph of the European Pharmacopoeia, of these three companies were
suspended. A sense of urgency in
EuropeThe time between the Italian inspections and issuance of the
non-compliance report was less than six weeks. This turnaround is quite
remarkable, considering this is peak holiday season in Europe.Last week also witnessed the US FDA, which has historically
been more active compared to the Europeans, issue a warning
letter to Mahendra
Chemicals in India. During a May 2014 inspection, the US FDA inspectors found employees had completed batch
production record entries days after operations had ended. Moreover, they
released lots before proper approvals, and failed to maintain original
manufacturing data for critical steps. Investigators found backdated batch
production records, signed by the Technical Director, who stated he was not in
the facility on the dates when the records were signed. Even though such
glaring concerns related to data integrity were observed, it still took the US
FDA over a year to issue the warning letter; substantially longer than the six
weeks taken by the European regulatory agencies.However, the speed of the issuance by the Italian Ministry
of Health is not drastically different to the Romanian Health Authority, which
issued a non-compliance
report (NCR) to Zhuhai United, China, in June 2015, for an inspection held
in April. Similarly, the Slovenian Health Authority issued an NCR
to Polydrug Laboratories, India, within three months (the inspection was held
in March this year). In the case of Huzhou
Sunflower, China, the French health agency issued an NCR in March, while
the inspection was held in January this year.The recent EU ban on 700 generic medicines due to
manipulation of clinical trials at Indian GVK Biosciences, is yet another case
which highlights the recent action taken by the European regulatory agencies
(read our previous analysis: Will
data integrity concerns on clinical trials done at GVK Biosciences go beyond
Europe?). New market opportunities
in an imbalanced supply chainThe outcome of these inspections create market opportunities for other competing firms. Jinan Jinda’s inspection was focused on an antibiotic used to treat urinary tract infections – known as Nitrofurantoin.
Post the inspection, Jinan is prohibited from supplying Nitrofurantoin
to the European market.As per the PharmaCompass database, Jinan Jinda is one of the three holders of a COS/CEP for Nitrofurantoin and the recommended suspension of their COS/CEP is an opportunity for the other two COS/CEP holders – global generic major Mylan Laboratories
and Indian company, Unimark
Remedies. In addition to these companies, FIS
Fabbrica Italaina Sintetici and Cambrex
Profarmaco, both based in Italy, are also active in the business of
supplying this API. Unlike Jinan Jinda, which only had one CEP filing, India’s Parabolic Drugs
produces multiple antibiotics, although not at the scale of global majors Sandoz, Fresenius
Kabi and DSM.
A suspension of 11 active CEPs, which had been granted to Parabolic, does seem
to indicate an apparent shift in the supply chain of APIs. However, the suspension of Parabolic’s CEPs means that for antibiotics like Pivampicillin, there are no suppliers left who have a valid CEP. Parabolic’s inability to supply the market with products like Dicloxacillin
Sodium, for which the inspection was conducted, is an opportunity for Sandoz, Aurobindo
Pharma and the Italian operations of Fresenius
Kabi – all of whom are integrated manufacturers and are not specialized API suppliers. For another antibiotic Bacampicillin, following the suspension of Parabolic Drugs, Fresenius Kabi’s Italian operations will be the only supplier left with a valid CEP.With Sandoz’s recent announcement of their plant shut down in India and the fate of Ranbaxy’s manufacturing operations being uncertain, under the new management of Sun
Pharma, the supply options for CEP grade Cefopodoxime
Proxetil get reduced substantially and are now dependent on just two plants
-- Hanmi
Fine Chemical in Korea and Sandoz’s Austrian operations. The situation thus created is not drastically different to
the one resulting from the inspection
failure of North China Pharmaceutical Group Semisyntech, which left Sandoz
as the only manufacturer of Benzylpenicillin
Procaine (this was before Novartis announced the shutdown of their
Frankfurt facility).PharmaCompass has summarized a list of all CEPs for the 12
products (11 of Parabolic and 1 of Jinan Jinda), in case our readers want to assess
the status of their overall supply chain in view of the recent inspection
outcomes (please click here to send
us a request). Our viewWhile the US FDA inspectors have historically been more active,
the recent months have shown a sense of urgency on the European side as well. The era where companies were securing their supply of APIs
by looking for low-cost players in Asia appears to be waning away.In our view, inspection outcomes like these may well drive
manufacturing back to Europe and other countries where the cost of
manufacturing has historically been high. The devaluation of the Euro, coupled
with the speed with which regulatory action has been taken on these Indian and
Chinese firms, seem to suggest that trade protection conversations may well get
started in the not-so-distant future.
Impressions: 3615
Over
700 commonly used generic medicines were
recommended for suspension by the European Medicines Agency (EMA) based on data
integrity concerns, over clinical studies conducted at GVK Biosciences in
Hyderabad, India.What
will be the global fallout of the European decision? The European decision has
impacted products from companies such as:Abbott Laboratories, Accord Healthcare (Intas), Actavis, Alembic, Apotex, Betapharm (Dr. Reddy’s), Brown & Burk UK, Fair Med Healthcare AG, Glenmark, Lupin, Micro Labs, Mylan, Orion Corporation, Ranbaxy, Ratiopharm, Sandoz, Sanofi-Aventis, Stada, Teva, Torrent, Wockhardt, Zydus… and many, many more.The
original recommendation of suspending
some of the medicines
made in January 2015, was an outcome of an inspection of GVK Biosciences’ site in Hyderabad (GVK BIO is a Clinical Research Organization-
CRO) by the
French medicines agency (ANSM) through the EMA. The EMA stated in their official release: “The
inspection revealed data manipulations of electrocardiograms (ECGs) during the
conduct of some studies of generic medicines, which appeared to have taken
place over a period of at least five years. Their systematic nature, the
extended period of time during which they took place and the number of members
of staff involved cast doubt on the integrity of the conduct of trials at the
site.” 1000 drugs reviewed// 700
rejectedWhile
over 1,000 pharmaceutical forms and strengths were reviewed at the GVK site,
over 300 of them had sufficient supporting data available from other sources.
As a result, these medicines were allowed to remain on the market in the EU.However, for the over 700 other medicines, the EMA after its second review, maintained its previous recommendation of January 2015, to suspend medicines, where no additional supporting data from other studies was available. Only one exception after that second review was spared from suspension, as the company was able to address the EMA’s concerns: it was Bivolet Nebivolol (5 mg tablets/ marketing authorisation holder: Neo Balkanika EOOD).While the agency noted that “there is no evidence of harm or
lack of effectiveness linked to the conduct of studies by GVK Biosciences at
Hyderabad. Some of these medicines may remain on the market” if they are of critical importance for patients. However, the recommendation
will now be sent to the European Commission for a legally binding decision,
which will apply to Member States regardless of the decision taken in the
interim period.The updated list of medicines for which, the CHMP (Committee
for Medicinal Products for Human Use) recommends suspension, is available on the EMA website. Companies
are given 12 months to submit additional data. The potential global impact of the European
suspensions?The GVK Biosciences
scandal is almost as severe in magnitude and impact, as the data falsification
concerns, which were discovered at Ranbaxy (Katherine Eban’s stunning investigation in Fortune, “Dirty Medicine” covers this extensively). One of the main promoters of GVK Biosciences is Mr. D.S. Brar who was CEO & Managing Director of Ranbaxy from 1999-2004. The impact of GVK
Biosciences’ misdeeds is already being felt on new product launches. Mylan recently withdrew its European application for generic
Abilify (aripiprazole) (2014 sales US$6.2x billion) citing “identification of major GCP issues (Good
Clinical Practices).” What about the impact on the US market?In 2010, FDA discovered data integrity
violations, which bankrupted
clinical research organization, Cetero Research/PRACS. Based on the Cetero findings
in the United States, the EMA suspended seven drugs. Now it remains to
be seen, how the FDA will handle the data integrity concerns found in Europe
since products like repaglinide & candesartan cilexitil (Mylan), levetiracetam (Dr. Reddy’s), clonazepam (Sandoz), metformin hydrochloride (Actavis), tacrolimus (Panacea Biotech) all have U.S. FDA approvals. Leading GVK Biosciences’ defense is the Indian government, who warned last month that if the European Union does not reconsider their decision, it may go to the World Trade Organization. The Indian government’s position is based on an appeal by GVK Biosciences, which made the “Indian government set up a panel of experts last year to investigate
the matter and found no manipulation”, GVK Biosciences CEO Manni Kantipudi told Reuters.However, globally reputed GMP expert, Lachman Consultants, believes that the GVK Bioscience episode “could potentially impact data integrity, similar to the Cetero/PRACS
case”.It’s clear for us that this is not the end of the story…
Impressions: 4144