Market Place
Data integrity – currently the hottest topic in quality
management – should be a straight forward subject to understand. Yet, for those
who have doubts about how to get it right, the FDA published “Data
Integrity and Compliance with cGMP” guidance last week. It follows similar
publications by the UK’s Medicines and Healthcare Regulatory Agency (MHRA)
and the World Health Organization (WHO). Sri Krishna’s flagrant data integrity violationsWhile regulatory authorities are publishing guidance
documents for good data and document management practices, major Indian paracetamol
manufacturer, Sri
Krishna Pharmaceuticals’ warning
letter was published by the FDA earlier this month. The findings didn’t come as a surprise, as European regulators had highlighted
similar concerns in early 2015 and the FDA had placed Sri Krishna’s Unit II facility on an import alert
since August 2015. However, the FDA finding that the “firm was destroying original batch records and backdating revised replacement pages” indicates a malaise that runs far deeper than what any guidance document can help resolve. FDA uncovers serious data
integrity problems at an Indian clinical research organization (CRO) It was just last week when PharmaCompass
raised the issue of
data-integrity concerns at clinical research organizations (CROs) in India. This week, FDA issued an ‘untitled
letter’ to Semler Research Center Private Limited located in Bangalore, India. The FDA also notified “sponsors of New Drug Applications (NDAs) and Abbreviated New Drug Applications (ANDAs) that clinical and bioanalytical studies conducted by Semler Research Private Limited (Semler) located in Bangalore, India, are not acceptable as a result of data integrity concerns, and need to be repeated.”A summary of the observations at Semler are available at Barbara Unger’s blog post, “Data Integrity Issues at a CRO and Consequences for
Sponsors”. Four Chinese firms on FDA’s import alertCompanies placed on FDA’s import alert list before their warning letters are made public are invariably organizations the FDA believes have severe compliance problems. Four companies in China were placed on the FDA’s import
alert list this month – Beijing Lunarsun
Pharmaceutical, two facilities of Chongqing
Lummy Pharmaceutical, Xinxiang
Pharmaceutical and Xinxiang Tuoxin Biochemical. In addition, Jiangxi Yuneng Pharmaceutical was also placed on the import alert list for refusing to accept an FDA
inspection. Back home, FDA
confronts a defiant Pharmakon While India and China have been making headlines for
manufacturers failing to comply with regulations, none of the problems compare
with what the FDA is encountering with the US-based compounder, Pharmakon
Pharmaceuticals. On February 16, 2016, the FDA received reports of serious
adverse events experienced by three infants associated with the use of the
recalled super-potent morphine
sulfate, products produced by Pharmakon. FDA test results
showed the product was nearly
2,500 percent the labeled potency. A subsequent FDA inspection found “insanitary conditions, including poor sterile production practices, and other deficiencies”. On April 11, 2016 the FDA recommended that Pharmakon cease sterile operations until appropriate corrective actions were implemented by the facility. It also recommended a recall of all non-expired drug products that are intended to be sterile. However, Pharmakon informed FDA that it
would neither initiate a recall nor cease sterile production leaving the FDA with little choice but to immediately inform healthcare professionals not to use the products marketed as ‘sterile’ from Pharmakon. A voluntary nationwide recall was announced by Pharmakon
only after the FDA had sent out their alert. The FDA had
previously inspected Pharmakon in March
and April
2014, and issued a warning
letter in May 2015. The April 2014 inspection was a “follow up on adverse event
reports related to super-potent midazolam products administered to neonatal
infants.” 2015 saw the highest
generic drug approvals everWhile some manufacturers of generic drugs struggle with their quality systems, the FDA’s Office of Generic Drugs (OGD) completed
its first full year of operations. In its 2015
annual report published recently, the office highlighted that last year “marked the highest number of generic drug approvals and tentative approvals ever awarded by the FDA – more than 700 in all.”The office
had a pending list of 2,866 abbreviated new drug
applications (ANDAs) and 1,873 prior approval supplements (PASs), as of October
1, 2012. However, by the end of 2015, the FDA completed first actions on 84
percent of ANDAs and 88 percent of PASs. Therefore, the regulatory body is
already close to 90 percent of its goals set for 2017. Our viewAlthough companies in India continue to make headlines for
failure to comply with manufacturing standards, others won
key approvals in 2015 indicating that the compliant ones have enormous opportunities they can capitalize on in the United States – the largest pharmaceutical market in the world. For companies interested in looking for opportunities in the
US market, PharmaCompass’ compilation
“Drugs with no patents and no competition – here’s our list of new ‘price-gouging’ targets” is a good place to get started.
Impressions: 4507
https://www.pharmacompass.com/radio-compass-blog/data-integrity-roundup-fda-s-guidance-note-problems-in-china-and-record-approvals-in-2015
#PharmaFlow by PHARMACOMPASS
21 Apr 2016
Share
Each year,
the US Food and Drug Administration (FDA) approve hundreds
of new medications. A small subset of approvals, classified as novel drugs, are considered to
be truly innovative products that often help advance clinical care.
In 2015, the
FDA approved 45 novel drugs, an all-time record high. PharmaCompass has compiled a list of novel drugs approved by the FDA in 2015.The FDA also approved new dosage forms of existing products in the market (email us if you would like a copy), like the 3D printed version of anti-epilepsy drug, Spritam (Levetiracetam).
This week, PharmaCompass focuses on the new dosage
forms of existing drugs that got approved last year.
Modified blockbusters
Improving the delivery form of a blockbuster drug is something that not only helps patients but often successfully extends the patent life of the cash-generating drugs for Big Pharma. Here are some blockbuster drugs that saw their modified versions being launched in 2015:
Jadenu (deferasirox): With
almost a billion dollars in revenues in 2015, Exjade (deferasirox) was approved in 2005 as a
tablet for use in a suspension. Novartis, the innovator,
got approval in March 2015
for Jadenu, a once-daily oral tablet. Jadenu (deferasirox), a new formulation
of Exjade, is the only once-daily oral tablet for iron chelation. Jadenu has
simplified daily treatment administration for patients with chronic iron
overload.
Nexium
24HR (esomeprazole magnesium): Also
known as the Purple Pill, Nexium – Astra
Zeneca’s blockbuster drug for acid reflux that generated annual sales in America of more than US $ 3 billion – went generic in 2015. In order to extend Nexium’s market, Pfizer and AstraZeneca came together to promote an over-the-counter (OTC) version of Nexium. A capsule version of OTC Nexium was approved in 2014 and is known as
Nexium 24HR. Last year, the FDA granted approval to the tablet form of the
drug.
Iressa
(gefitinib): AstraZeneca re-introduced Iressa in
the US market in 2015. The
FDA had approved Gefitinib in May 2003 for non-small cell lung cancer. Approved
as a third-line therapy, in 2010 the FDA requested AstraZeneca to voluntarily withdraw Iressa tablets
from the market, as post-marketing studies had failed
to verify and confirm clinical benefit. Iressa (gefitinib) is now back in the US as a first-line therapy for a type of lung cancer. However, the patent protection is limited – only one listed patent in the Orange Book which expires next year, and five US Drug Master Files already submitted.
Onivyde (irinotecan): Liposomal formulation of anti-cancer
drugs have been in vogue for some time. Merrimack Pharmaceuticals got its novel encapsulation of Irinotecan in a liposomal formulation approved for the
treatment of patients with metastatic pancreatic cancer, sold under the brand
name Onivyde.
Vivlodex (meloxicam): In October 2015, the FDA approved 5 mg and 10 mg (administered once daily) doses of Vivlodex™ (meloxicam) capsules, a nonsteroidal anti-inflammatory drug (NSAID) used for the management of osteoarthritis pain. The previously approved doses for meloxicam capsules were 7.5mg and 15mg. Vivlodex uses a proprietary SoluMatrix Fine Particle Technology™, which contains meloxicam as submicron particles that are approximately 10 times smaller than their original size. The reduction in particle size provides an increased surface area, leading to faster dissolution.
Kalydeco (ivacaftor): A cystic fibrosis drug from Vertex Pharmaceuticals – Kalydeco – has been making headlines
because of its high price (more than US $ 300,000 a year). Price concerns
aside, 2015 saw the launch of a pediatric version of the drug as a ‘weight-based oral granule formulation of Kalydeco that can be mixed in soft foods or liquids’.
Extended release versions
Many of
the approvals granted by the FDA last year were to extended release
formulations (a pill formulated so that the drug is released slowly) of
existing drugs.
Kremers Urban’s
extended release version of Methylphenidate
capsules made headlines last year because of a reclassification of the drug by
the FDA. Under the new classification rating, methylphenidate hydrochloride extended-release tablets can be prescribed but may
not be automatically substituted for J&J’s reference drug Concerta (methylphenidate hydrochloride). Kremers Urban was almost sold last year. But due to this reclassification, investors aborted their US $ 1.53 billion buyout. Kremers Urban was later acquired by Lannett Company Inc.
In
addition, extended-release versions of Aspirin, Carbidopa/Levodopa, Paliperidone Palmitate, Tacrolimus
and Morphine Sulphate also received green signals for a market launch.
First generic opportunities
Last year, PharmaCompass
shared the names of some drugs which had no generic competition and were also
not protected by patents. (Read: “Litigation Free, first generic opportunities list”).
Deferiprone (a drug that chelates iron and is
used to treat iron overload in thalassemia major) met the criteria. But it still
has no generic competitor and is now available as a new dosage form.
Amedra Pharmaceuticals, now owned by Impax Laboratories, has enjoyed the rights to sell Albendazole tablets for almost two decades
without generic competition in the US. Albendazole is a medication used for the
treatment of a variety of parasitic worm infestations. In 2015, patients were
provided access to chewable tablets of Albendazole.
New combinations at work
The FDA also approved
multiple combination drugs where the individual active ingredients had been brought
to market previously.
Most of the combination drugs
approved belong to major pharma players like Novartis, Novo Nordisk, Bristol Myers etc.
Boehringer’s diabetes treatments – Jardiance (empagliflozin) – approved in 2014 and
Tradjenta (linagliptin) approved in 2011, were
combined and the combination drug product Glyxambi was approved in 2015. Another
combination of empagliflozin, with metformin – Synjardy – was also approved in August last
year.
Lesser known companies also
got combination drugs approved. UK-based
development company Vernalis got approval for its cold-cough treatment, Tuzistra XR – an extended release suspension of codeine polistirex and chlorpheniramine
polistirex.
Similarly, US-based biopharmaceutical startup, Spriaso LLC, also
working in the cold and cough therapeutic area, got an extended release tablet
containing codeine phosphate and chlorpheniramine maleate approved.
Symplmed, a company which is
developing various forms of Perindopril, got approval for Prestalia (a
combination of perindopril arginine and amlodipine besylate) for the
treatment of hypertension.
Our view
Each year, the FDA approves several
pharmaceutical drugs in order to improve patient care; and often versions of
these drugs are marketed and distributed across the globe.
PharmaCompass’ list of drugs approved in 2015 is now available – just email us for your copy.
Accelerate your drug development
PharmaCompass has also launched
the Drug Development Assistance tool on its platform.
Simply search for the drug or the active ingredient of your interest, click on the Drug Development icon on the left menu bar and you can see the inactive ingredients used to formulate
the various drug products approved in the United States.
Impressions: 5421
https://www.pharmacompass.com/radio-compass-blog/fda-s-drug-approvals-in-2015-novel-drugs-new-versions-of-existing-drugs
#PharmaFlow by PHARMACOMPASS
14 Jan 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: 7495
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
Legally
cultivated cannabis, in some parts of the United States, resulted in a boom,
which could never have been previously imagined. Just last year, there were so
many growers that, in the state of Washington alone, more
than 20,000 kg of marijuana (cannabis) was available, which didn’t have any takers!Last year also saw the stock
market recognize the value of little known, GW
Pharmaceuticals, a UK based company, focused on developing medicines from
marijuana. Their product, Sativex, already
approved in 27 countries is currently awaiting USFDA approval. With Wall Street valuing GW Pharmaceuticals at almost $2
billion, is there a future for marijuana based medicines? Increasing production
of legal marijuanaMarijuana or cannabis, is ‘still’ classified as schedule 1 drug, which means that the Drug Enforcement Agency (DEA), believes there is no currently accepted medical use and the drug isn’t safe to use even under medical supervision. However, with all the research interest, the DEA has proposed a
massive increase in the amount of marijuana production. It will hopefully
allow, that the demands of the researchers will finally be met. Highly
curative?There
are two key active ingredients inside Marijuana, Cannabidiol (CBD) and Tetrahydrocannabinol (THC). While the potency of marijuana is linked to the amount of Tetrahydrocannabinol (THC) inside it, Cannabidiol (CBD) which isn’t responsible for the high, is the one considered to have the wider scope for medical applications. Epidiolex// treatment of epilepsy in
children?An orally-administered liquid
containing CBD has received orphan drug status in the US, under the brand name Epidiolex. GW Pharmaceuticals, the
developer of Epidiolex is also performing their second
Phase III clinical trial to demonstrate its effectiveness in the treatment
of epilepsy in children. Sativex// treatment
of spasticitySativex, a mixture of THC and CBD, is approved for sales in
countries for the treatment of spasticity (muscle spasms and stiffness) related
to multiple sclerosis; a disease that affects 1.3 million people worldwide, of
which up to 80% suffer from spasticity.In addition to THC and CBD, GW
Pharmaceuticals, has also developed a portfolio of products based on the other
cannabinoids found in the plant. Marinol// approved in
1985GW Pharmaceuticals isn’t alone since synthetic derivatives of THC have also been on the market for years. Dronabinol
(brand name: Marinol), approved in 1985 for prevention of nausea and vomiting
during chemotherapy, is estimated to have current sales
of almost $450 million. After the initial launch, the
product also got approval for appetite and weight loss in patients with HIV/AIDS.
The product got reclassified, in
1998 by the DEA, from a Schedule II drug to a Schedule III one which allowed
access to a wider patient base. An open ‘high-way’ for businessInsys
Therapetuics, another player in this space, who had their novel,
more bio-available formulation of Dronabinol rejected by the FDA, still commands a market valuation of almost $3
billion. Plant based medicines, like Paclitaxel,
Docetaxel,
Morphine,
Codeine
have made billions for the pharmaceutical industry in the past and the market
valuations of GW Pharmaceuticals and Insys Therapeutics indicates similar
expectations for developing medicines from marijuana. With many other cannabinoids in the plant, raw material
availability no longer as restricted as in the past, licensing
opportunities on new indications available from the National Institute of Health (NIH)– it is just a matter of who hits the marijuana ‘high-way’ first?
Impressions: 2269
https://www.pharmacompass.com/radio-compass-blog/marijuana-based-medicines-highway-to-pots-of-gold
#PharmaFlow by PHARMACOMPASS
16 Jul 2015
