Market Place
Acquisitions and spin-offs dominated headlines in 2019 and the tone was set very early with Bristol-Myers Squibb acquiring
New Jersey-based cancer drug company Celgene in a US$ 74 billion deal announced on
January 3, 2019. After factoring
in debt, the deal value ballooned to about US$ 95 billion, which according
to data compiled by Refinitiv, made it the largest healthcare deal on
record.
In the summer, AbbVie Inc,
which sells the world’s best-selling drug Humira, announced its acquisition of Allergan Plc, known for Botox and other cosmetic
treatments, for US$ 63 billion. While the companies are still awaiting
regulatory approval for their deal, with US$ 49 billion in combined 2019
revenues, the merged entity would rank amongst the biggest in the industry.
View Our Interactive Dashboard on Top drugs by sales in 2019 (Free Excel Available)
The big five by pharmaceutical sales — Pfizer,
Roche, J&J, Novartis and Merck
Pfizer
continued
to lead companies by pharmaceutical sales by reporting annual 2019 revenues of
US$ 51.8 billion, a decrease of US$ 1.9 billion, or 4 percent, compared to
2018. The decline was primarily attributed to the loss of exclusivity of Lyrica in 2019,
which witnessed its sales drop from US$ 5 billion in 2018 to US$ 3.3 billion in
2019.
In 2018, Pfizer’s then incoming CEO Albert Bourla had mentioned that the company did not see the need for any large-scale M&A activity as Pfizer had “the best pipeline” in its history, which needed the company to focus on deploying its capital to keep its pipeline flowing and execute on its drug launches.
Bourla stayed true to his word and barring the acquisition of Array Biopharma for US$ 11.4 billion and a spin-off to merge Upjohn, Pfizer’s off-patent branded and generic established medicines business with
Mylan, there weren’t any other big ticket deals which were announced.
The
Upjohn-Mylan merged entity will be called Viatris and is expected to have 2020
revenues between US$ 19 and US$ 20 billion
and could outpace Teva to
become the largest generic company in the world, in term of revenues.
Novartis, which had
followed Pfizer with the second largest revenues in the pharmaceutical industry
in 2018, reported its first full year earnings after spinning off its Alcon eye
care devices business division that
had US$ 7.15 billion in 2018 sales.
In 2019,
Novartis slipped two spots in the ranking after reporting total sales of US$
47.4 billion and its CEO Vas Narasimhan continued his deal-making spree by buying New
Jersey-headquartered The Medicines Company (MedCo) for US$ 9.7
billion to acquire a late-stage cholesterol-lowering
therapy named inclisiran.
As Takeda Pharmaceutical Co was
busy in 2019 on working to reduce its debt burden incurred due to its US$ 62
billion purchase of Shire Plc, which was announced in 2018, Novartis also purchased
the eye-disease medicine, Xiidra, from the Japanese drugmaker for US$ 5.3 billion.
Novartis’ management also spent a considerable part of 2019 dealing with data-integrity concerns which emerged from its 2018 buyout of AveXis, the
gene-therapy maker Novartis had acquired for US$ 8.7 billion.
The deal gave Novartis rights to Zolgensma,
a novel treatment intended for children less than two years of age with the
most severe form of spinal muscular atrophy (SMA). Priced at US$ 2.1 million,
Zolgensma is currently the world’s most expensive drug.
However,
in a shocking announcement, a month after approving the drug, the US Food and
Drug Administration (FDA) issued a press release on
data accuracy issues as the agency was informed by AveXis that
its personnel had manipulated data which
the FDA used to evaluate product comparability and nonclinical (animal)
pharmacology as part of the biologics license application (BLA), which was
submitted and reviewed by the FDA.
With US$
50.0 billion (CHF 48.5 billion) in annual pharmaceutical sales, Swiss drugmaker
Roche came in at number two position in 2019
as its sales grew 11 percent driven by
its multiple sclerosis medicine Ocrevus, haemophilia drug Hemlibra and cancer medicines Tecentriq and Perjeta.
Roche’s newly introduced medicines generated US$ 5.53 billion (CHF 5.4 billion) in growth, helping offset the impact of the competition from biosimilars for its three best-selling drugs MabThera/Rituxan, Herceptin and Avastin.
In late 2019, after months of increased
antitrust scrutiny, Roche completed
its US$ 5.1 billion acquisition of Spark Therapeutics to strengthen its presence in
gene therapy.
Last year, J&J reported almost flat worldwide sales of US$ 82.1 billion. J&J’s pharmaceutical division generated US$ 42.20 billion and its medical devices and consumer health divisions brought in US$ 25.96 billion and US$ 13.89 billion respectively.
Since J&J’s consumer health division sells analgesics, digestive health along with beauty and oral care products, the US$ 5.43 billion in consumer health sales from over-the-counter drugs and women’s health products was only used in our assessment of J&J’s total pharmaceutical revenues. With combined pharmaceutical sales of US$ 47.63 billion, J&J made it to number three on our list.
While the sales of products like Stelara, Darzalex, Imbruvica, Invega Sustenna drove J&J’s pharmaceutical business to grow by 4 percent over 2018, the firm had to contend with generic competition against key revenue contributors Remicade and Zytiga.
US-headquartered Merck, which is known as
MSD (short for Merck Sharp & Dohme) outside the United States and
Canada, is set to significantly move up the rankings next year fueled by its
cancer drug Keytruda, which witnessed a 55
percent increase in sales to US$ 11.1 billion.
Merck reported total revenues of US$ 41.75 billion and also
announced it will spin off its women’s health drugs,
biosimilar drugs and older products to create a new pharmaceutical
company with US$ 6.5 billion in annual revenues.
The firm had anticipated 2020 sales between US$ 48.8 billion and US$ 50.3 billion however this week it announced that the coronavirus pandemic will reduce 2020 sales by more than $2 billion.
View Our Interactive Dashboard on Top drugs by sales in 2019 (Free Excel Available)
Humira holds on to remain world’s best-selling drug
AbbVie’s acquisition of Allergan comes as the firm faces the expiration of patent protection for Humira, which brought in a staggering US$ 19.2 billion in sales last year for
the company. AbbVie has failed to successfully acquire or develop a major new
product to replace the sales generated by its flagship drug.
In 2019, Humira’s US revenues increased 8.6 percent to US$ 14.86 billion while internationally, due
to biosimilar competition, the sales dropped 31.1 percent to US$ 4.30 billion.
Bristol Myers Squibb’s Eliquis, which is also marketed by Pfizer, maintained its number two position
and posted total sales of US$ 12.1 billion, a 23 percent increase over 2018.
While Bristol Myers Squibb’s immunotherapy treatment Opdivo, sold in partnership with Ono in Japan, saw sales increase from US$ 7.57 billion to US$ 8.0 billion, the growth paled in comparison to the US$ 3.9
billion revenue increase of Opdivo’s key immunotherapy competitor Merck’s Keytruda.
Keytruda took the number three spot in drug sales that
previously belonged to Celgene’s Revlimid, which witnessed a sales decline from US$ 9.69 billion to US$ 9.4 billion.
Cancer treatment Imbruvica, which is marketed
by J&J and AbbVie, witnessed a 30 percent increase in sales. With US$ 8.1
billion in 2019 revenues, it took the number five position.
View Our Interactive Dashboard on Top drugs by sales in 2019 (Free Excel Available)
Vaccines – Covid-19 turns competitors into partners
This year has been dominated by the single biggest health emergency in years — the novel coronavirus (Covid-19) pandemic. As drugs continue to fail to meet expectations, vaccine development has received a lot of attention.
GSK reported the highest vaccine sales of all drugmakers with
total sales of US$ 8.4 billion (GBP 7.16 billion), a significant portion of its
total sales of US$ 41.8 billion (GBP 33.754 billion).
US-based Merck’s vaccine division also reported a significant increase in sales to US$ 8.0 billion and in 2019 received FDA and EU approval to market its Ebola vaccine Ervebo.
This is the first FDA-authorized vaccine against the deadly virus which causes
hemorrhagic fever and spreads from person to person through direct contact with
body fluids.
Pfizer and Sanofi also reported an increase in their vaccine sales to US$ 6.4
billion and US$ 6.2 billion respectively and the Covid-19 pandemic has recently
pushed drugmakers to move faster than ever before and has also converted
competitors into partners.
In a rare move, drug behemoths — Sanofi and GlaxoSmithKline (GSK) —joined hands to develop a vaccine for the novel coronavirus.
The two companies plan to start human trials
in the second half of this year, and if things go right, they will file
for potential approvals by the second half of 2021.
View Our Interactive Dashboard on Top drugs by sales in 2019 (Free Excel Available)
Our view
Covid-19 has brought the world economy to a grinding halt and shifted the global attention to the pharmaceutical industry’s capability to deliver solutions to address this pandemic.
Our compilation shows that vaccines and drugs
for infectious diseases currently form a tiny fraction of the total sales of
pharmaceutical companies and few drugs against infectious diseases rank high on
the sales list.
This could well explain the limited range of
options currently available to fight Covid-19. With the pandemic currently infecting
over 3 million people spread across more than 200 countries, we can safely
conclude that the scenario in 2020 will change substantially. And so should our
compilation of top drugs for the year.
View Our Interactive Dashboard on Top drugs by sales in 2019 (Free Excel Available)
Impressions: 54752
https://www.pharmacompass.com/radio-compass-blog/top-drugs-and-pharmaceutical-companies-of-2019-by-revenues
#PharmaFlow by PHARMACOMPASS
29 Apr 2020
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Data
integrity continued to be a hot topic in the pharmaceutical industry through
2017. According to a recent analysis by GMP (good
manufacturing practices) intelligence expert, Barbara Unger, approximately 65
percent of all US Food and
Drug Administration (USFDA) warning letters
issued in FY2017 (October 1, 2016 until September 30, 2017) included a data integrity component.
However, in the previous year, this number was even higher — at 79 percent — implying there has been a decline in non-compliance incidents pertaining to data integrity in 2017.
Click here for our compilation of all non-compliances in 2017 (Excel version available) for FREE!
2017’s recurring concern – a failure
to thoroughly investigate problems
In PharmaCompass’ 2016 compilation, serious charges of blatant data manipulation surfaced at organizations around the world.
In 2017, we witnessed a reduction in data-integrity violations
uncovered at pharmaceutical manufacturers due to the absence of audit trail
software in quality control testing equipment.
However, the implementation of audit trails has resulted in the emergence of a new failing – the improper handling of out-of-specification (OOS) results.
Failure “to thoroughly investigate any unexplained discrepancy or failure of a batch” became a recurring theme in concerns highlighted at major generic players like Mylan, Fresenius, Teva, Dr Reddy’s, Hetero Labs and Lupin.
In the case of Fresenius’ oncology API plant in India, USFDA investigators found employees had halted and invalidated
HPLC (high-performance liquid chromatography) analyses nearly 250 times when they
believed the tests were going to end with OOS results.
The
USFDA warned Fresenius SE after the company’s Indian plant that makes cancer-drug ingredients for the US market aborted hundreds of drug-quality tests.
Click here for our compilation of all non-compliances in 2017 (Excel version available) for FREE!
The situation at Lupin wasn’t much better as the warning letter issued to its formulation manufacturing facilities in Goa and Indore (Pithampur Unit II) said the company failed to “thoroughly review any unexplained discrepancy” as Lupin invalidated approximately 96 percent of all OOS results obtained at Pithampur and over 75 percent of them in Goa.
Failure to resolve
recurring problems also led the USFDA to tell Meridian Medical
Technologies, a division of Pfizer that
makes the EpiPen injector
device (sold by Mylan NV), that serious component and product failures had
been associated with patient deaths.
In its warning
letter, the USFDA said the Pfizer unit failed to adequately investigate
problems at its manufacturing facility in Brentwood, Missouri. It also did not
take appropriate corrective actions before a USFDA inspection earlier this
year.
Meridian had received hundreds of complaints that
the EpiPen device, which is used to combat serious allergic reactions,
failed to operate during life-threatening emergencies.
Click here for our compilation of all non-compliances in 2017 (Excel version available) for FREE!
Non-compliances at
finished drug producers
outnumbered those at API facilities
During 2017, the
number of finished pharmaceutical companies cited for compliance concerns
significantly outnumbered the number of active pharmaceutical ingredient (API)
producers.
While the FDA issued 48 warning letters to drug product manufacturers, API producers received only 18 warning letters. The actions by the European regulators was similar — 15 non-compliance certificates were issued to finished drug producers, as compared to only two API manufactures who were found lagging behind in compliance standards.
China, India and the
United States continued to lead the countries where regulators found most
shortcomings.
As compared to the
previous year, in 2017 regulators issued fewer non-compliance certifications as
the FDA had
been hampered by staffing shortages. As a result, the FDA’s inspections in India “dropped 27 percent in fiscal 2017 from a year earlier, to 185 from 252.”
Click here for our compilation of all non-compliances in 2017 (Excel version available) for FREE!
In 2017, EU and
FDA started their mutual recognition program. But will it work?
2017 was also a
landmark year for the US and European regulators as the USFDA and the European Medicines Agency (EMA) announced their program
for mutual recognition of inspections of drug manufacturers, which
became operational on November 1, 2017.
The FDA will now recognize eight EU drug regulators – from Austria, Croatia, France, Italy, Malta, Spain, Sweden and the UK – as capable of conducting inspections of manufacturing facilities that meet the USFDA requirements.
This is an unprecedented move — prior to this, the USFDA had never recognized another country’s inspectorate.
As
part of the agreement, the European Commission (EC), the US FDA and the EMA signed a confidentiality commitment that allows the USFDA to share non-public
and commercially confidential information, including trade secret
information relating to inspections with European regulators.
As the mutual
recognition of inspections program goes live, there were examples of many
companies that were found to be consistently out of compliance by both the FDA
and regulators from the EU. Yet, there were cases where the regulators came to
different conclusions about the state of a particular facility they had
inspected.
While
European regulators had raised compliance concerns at Biocon, the company went ahead and got an FDA nod
for its biosimilar of Roche’s blockbuster cancer drug — Herceptin.
Click here for our compilation of all non-compliances in 2017 (Excel version available) for FREE!
The case of Qinhuangdao Zizhu — when WHO and FDA differed
In
another case, an inspection conducted by the USFDA at Qinhuangdao Zizhu Pharmaceutical from November 28 to December 1, 2016 uncovered
significant data integrity concerns and failures in the level of adherence to
current good manufacturing practices (cGMPs) for APIs.
In
the warning letter issued to the firm, the laboratory analysts admitted to the FDA inspectors that they had been “setting the clock back and repeating analyses for undocumented reasons.”
At
Qinhuangdao Zizhu, “initial sample results were overwritten or deleted” and the company “reported only the passing results from repeat analyses”.
In addition to not having effective measures to control data within their computerized systems, the FDA investigators found that the firm “relied on incomplete information” to determine whether Qinhuangdao Zizhu’s drugs met established specifications.
The investigators found “a recurring practice of re-testing samples until acceptable results were obtained” and that batch production records “contained blank or partially completed manufacturing data”.
On
March 8, 2017, Qinhuangdao Zizhu Pharmaceutical was placed on import alert
by the USFDA.
Click here for our compilation of all non-compliances in 2017 (Excel version available) for FREE!
Almost
a year prior to the USFDA inspection, in October 2015, the company had been
inspected by a WHO Prequalification Team (PQT) for levonorgestrel, mifepristone and ethinylestradiol APIs. The inspection found “five major deficiencies including data integrity issues and several minor deficiencies”.
The
WHO, however, went ahead and closed its inspection as compliant, based on
corrective and preventive actions (CAPAs) provided by the manufacturer.
In
view of the USFDA actions, and the fact that Qinhuangdao Zizhu Pharmaceutical
is the only WHO-PQT prequalified source of levonorgestrel API (as was seen in a similar case at Mylan), the WHO approach towards the compliance position was to
focus extensively on product quality.
READ: FDA and EU differ on cGMP standards at the same facilities: How will they mutually recognize inspections?
Our view
As the US regulators push hundreds of new generic drugs to market
in an effort to drive down prices of generic drugs in the United States, the
industry should get ready for an increasing number of inspections in the coming
years.
Our compilation indicates that in 2017, while most companies had installed the infrastructure necessary to combat issues related to data-integrity, there were problems that were systemic in nature. These ‘systemic problems’ remain, and the industry must get ready as the FDA and European inspectors join hands to crack down on them.
PharmaCompass’ 2017 Recap of FDA Warning Letters, Import Alerts & EU Non-Compliances is an easy way to evaluate companies that have run into compliance challenges so that appropriate risk mitigation strategies can be adopted.
Impressions: 9112
https://www.pharmacompass.com/radio-compass-blog/2017-recap-of-warning-letters-import-alerts-and-non-compliances
#PharmaFlow by PHARMACOMPASS
11 Jan 2018
Last year, data
integrity was a hot topic of discussion in the pharmaceutical industry.
According to a recent analysis by GMP (good manufacturing practices)
intelligence expert, Barbara Unger, approximately 80 percent of all FDA warning
letters in 2015 and 2016 included a data integrity component, and approximately
70 percent of the published European GMP non-compliance reports cited similar
shortcomings.
With a little over
half the year gone, PharmaCompass analyzed the regulatory action for
current GMP (cGMP)
non-compliance to evaluate how things are looking so far in 2017.
Click here to access the compilation of all 2017 non-compliances (Excel version available) for FREE!
As
per our analysis, of all the non-compliance actions taken by the US and
European regulators, India and China continue to see the highest level of
activity, followed by the United States.
While most of the companies in the list are less known
pharmaceutical players, inspections uncovered deficiencies at leading companies
like Pfizer,
Teva,
Mylan
and B Braun.
Data integrity violations continue to remain high
The US Food
and Drug Administration (US FDA) and EU inspections continued to uncover data
integrity issues across countries such as India, China, Italy and Japan.
In a warning letter posted earlier this year, for a January 2016 inspection, FDA investigators uncovered data-integrity violations at ACS Dobfar’s Italian drug manufacturing facility — FACTA Farmaceutici SpA. At FACTA, for multiple lots of sterile drug product, the
original data showed failing results. However, the final data reportedly showed
passing results.
The company was found storing original data in an “unofficial” and uncontrolled electronic spreadsheet on a shared computer network drive. The analyst told investigators that original data was first recorded in the “unofficial” spreadsheet and later transcribed to an “official” form.
Investigators
also documented that employees at FACTA used paper shredders to destroy
critical laboratory and production records.
During an
inspection performed exactly at the same time, FACTA’s EU GMP certification was renewed by the Italian regulators!
Click here to access the compilation of all 2017 non-compliances (Excel version available) for FREE!
Discrepancies
in conclusions drawn by regulators
This year,
while the United States and the European Union (EU) finally announced that they will be able to utilize each other’s good manufacturing practice (GMP) inspections of pharmaceutical manufacturing facilities, the road ahead looks uncertain as, in addition to incidents like FACTA, there have been multiple instances of discrepancies in the conclusions arrived at by regulators.
This year saw
the WHO grant an all clear for a Mylan facility
where the FDA had data-integrity concerns and a
similar situation arose at an active pharmaceutical ingredient (API) facility
in China.
An
inspection conducted by the USFDA at Qinhuangdao Zizhu Pharmaceutical from November 28 to December 1, 2016
uncovered significant data integrity concerns and failures in the level of
adherence to cGMP for APIs.
Click here to access the compilation of all 2017 non-compliances (Excel version available) for FREE!
In
the warning letter issued to the firm, the laboratory analysts admitted to FDA inspectors that they had been “setting the clock back and repeating analyses for undocumented reasons.”
At Qinhuangdao Zizhu, “initial sample results were overwritten or deleted” and the company “reported only the passing results from repeat analyses”.
On
March 8, 2017, Qinhuangdao Zizhu Pharmaceutical was placed on import alert
by the USFDA.
Almost
a year prior to the USFDA inspection, in October 2015, the company had been
inspected by a WHO Prequalification Team (PQT) for levonorgestrel, mifepristone and ethinylestradiol APIs. The inspection concluded with “five major deficiencies, including data integrity issues and several minor deficiencies”.
The WHO went ahead and closed their inspection as ‘compliant’, based on corrective and preventive actions (CAPAs) provided by the manufacturer.
In view of the US FDA actions, and the fact that Qinhuangdao Zizhu
Pharmaceutical was the only WHO-PQT prequalified source of levonorgestrel API, as in the case of Mylan, the WHO approach towards the compliance position was focused extensively on product quality.
In Japan, at Sato Yakuhin Kogyo, FDA investigators found analysts
performed testing in duplicate without scientific justification, while in
China, the French Ministry of Health found manipulation, backdating and falsification
of GMP documents such as batch manufacturing records, GC (gas chromatography)
and HPLC (high performance liquid chromatographs) chromatograms at Chongqing
Succeway Pharmaceutical.
Click here to access the compilation of all 2017 non-compliances (Excel version available) for FREE!
Heparin makes
headlines again in China; Indian firm fakes strike
This year, concerns
over the testing of Heparin in China re-emerged when FDA issued a warning letter to a contract testing laboratory — Shandong Analysis and Test Center. However, the activities at these companies to deceive inspectors paled in comparison to Vikshara Trading in India where the company faked a strike to prevent an FDA inspection.
When the FDA
inspection finally occurred, the FDA obtained evidence that the firm actively
manufactured numerous products at the time of the supposed strike.
Concerns over
product quality in the United States
In a warning letter
issued to ChemRite CoPac in the US, the FDA found that the company was manufacturing oral drug
solutions using the same equipment that was being used to manufacture numerous
non-pharmaceutical materials including an industrial car care product. The car
care product being made was paraffin-based and carried labels such as “harmful or fatal if swallowed” and “keep out of reach of children.”
The ingredients of
these non-pharmaceutical products were extremely difficult to remove from the
manufacturing equipment, and could contaminate the drug products, the FDA said.
At Raritan Pharmaceuticals, a company that makes teething tablets, the FDA found the drug contained ingredients, such as belladonna, which could pose potential toxic effects for its consumers — infants and children under two years of age.
Click here to access the compilation of all 2017 non-compliances (Excel version available) for FREE!
Sterile drug
manufacturing continues to be a global challenge
Non-compliant
operations uncovered at Sato Pharmaceutical (Japan), Euro Far Allergi (Spain), Tubilux (Italy), Biocon (India), Nova DFL Industrie (Brazil), Pfizer’s US operations (ex-Hospira) show that aseptic sterile drug manufacturing continues to
be a global challenge as companies struggle to get into compliance.
In February
2015, Pfizer acquired a site in McPherson, Kansas, through its US$ 17 billion acquisition of Hospira. Pfizer was aware of Hospira's manufacturing record
when it struck the deal, as the company was issued FDA warning letters in four of the seven continents — Europe, North America, Asia and Australia.
Approval of two drugs have been held up this
year due to compliance concerns at McPherson.
Click here to access the compilation of all 2017 non-compliances (Excel version available) for FREE!
The USFDA also warned manufacturers of non-sterile, water-based drug products of Burkholderia cepacia
complex (BCC or B cepacia) contamination, as there were product recalls due to
this and other water-borne opportunistic pathogens found in pharmaceutical
water systems.
The regulator’s warning stemmed from a multi-state outbreak of infections. In March this year, Phispers had carried a news item on Badrivishal Chemicals & Pharmaceuticals,
a manufacturer of docusate sodium. It had been placed on FDA’s import alert list in December last year.
Concerns over
water systems were also mentioned in the warning letters issued to Humco
Holding Group in the United States and Resonance Laboratories in India.
Click here to access the compilation of all 2017 non-compliances (Excel version available) for FREE!
Omitting names of
original suppliers; shipping drugs from banned API makers
The USFDA
investigators found companies in India (Sal Pharma) and China (Suzhou Pharmaceutical Technology and Lumis Global Pharmaceuticals)
omitting the name and address of the original API
manufacturers on certificate of analysis and declared themselves to be the
manufacturers. In the case of Suzhou, one of its suppliers
was placed on FDA’s import alert list.
However, the company shipped API
manufactured from the banned supplier by providing misleading declarations.
Last year, PharmaCompass
had reported on Teva’s newly built sterile manufacturing facility in Godollo, Hungary, and the issues
highlighted by the FDA in its warning letter and the product recalls from this unit. As part of its global restructuring, while Teva is now winding up its sterile injectables plant in Godollo, it remains to be seen what decision
will be taken on its API manufacturing facility in Hangzhou (China), where the FDA had
highlighted concerns over process capability and the resulting impact on
product quality.
Wockhardt’s global compliance problems also continued with its manufacturing facility in the United States — Morton Grove Pharmaceuticals — receiving a warning letter.
Click here to access the compilation of all 2017 non-compliances (Excel version available) for FREE!
Our view
Earlier this year, a major Indian API manufacturer — Divi’s Laboratories — was placed on FDA’s import alert list. It was issued a warning letter due to a variety of problems which were uncovered at the site. The concerns raised at Divi’s along with other companies indicate a shifting focus on part of the FDA investigators from audit trails as there
is greater depth in the nature of the observations.
To assist the
industry, the FDA has started posting frequently requested Form 483s on a
routine basis which provides insight for the industry to track the new areas of
regulatory focus.
You can find the Form
483s on PharmaCompass at https://www.pharmacompass.com/radio-compass-news/Quality-Alerts
Click here to access the compilation of all 2017 non-compliances (Excel version available) for FREE!
Impressions: 7732
https://www.pharmacompass.com/radio-compass-blog/mid-2017-recap-of-fda-warning-letters-import-alerts-eu-non-compliances
#PharmaFlow by PHARMACOMPASS
10 Aug 2017
This week in our compliance round up, we look at the continuing problems at Pfizer’s McPherson unit in the US and China FDA’s entry into the ICH as a regulatory member. Yet again, WHO sources API from a plant in China, where USFDA had raised data integrity concerns. Meanwhile, Aurobindo Pharma’s Unit VII clears FDA inspection with zero observations.
Problems continue at Pfizer’s US facility; its sure-shot biosimilar gets rejected
Earlier this year,
Pfizer’s fill/finish manufacturing facility in McPherson, Kansas, received a warning letter from the US Food and Drug Administration (USFDA). The compliance concern was initially revealed in a press release issued by Momenta Pharmaceuticals — a biotechnology company developing a generic version of Teva’s long-acting Copaxone® 40mg/mL (glatiramer acetate injection). Momenta is working in
collaboration with Sandoz, which in turn has tied up with Pfizer as its fill/finish
manufacturing partner.
This week, a month after the FDA staff found that Pfizer’s biosimilar of Amgen’s drug Epogen (epoetin alfa) was nearly identical and an FDA advisory committee followed to recommend approval with a 14-1 vote, the FDA issued a complete response letter (CRL) to Pfizer.
The letter cited
concerns which had already been raised in the warning letter issued on February 14, 2017, following a
routine inspection of the facility.
This development
continues to be positive news for Teva, as Copaxone generated US$ 4.22 billion in sales last year. Continued
compliance concerns at Pfizer indicate that Momenta will still have to wait for
its generic to get approved.
While
previous FDA inspections at the McPherson facility had raised concerns over the assurance of product sterility, no warning letter had ever been issued to this site.
In
February 2015, Pfizer acquired the McPherson site through its US$ 17 billion acquisition of Hospira. Pfizer was aware of Hospira's manufacturing record
when it struck the deal, as the company was issued FDA warning letters in four of the seven continents — Europe, North America, Asia and Australia.
Once again, WHO sources API from Chinese firm where FDA had
raised concerns
Three
weeks after PharmaCompass shared the differences in assessments of the World Health Organization (WHO) and the USFDA over
the observations at a Mylan finished formulation
site in India, a similar situation has arisen at an active pharmaceutical
ingredient (API) facility in China.
An
inspection conducted by the USFDA at Qinhuangdao Zizhu Pharmaceutical from November 28 to December 1, 2016 uncovered significant data
integrity concerns and failures in the level of adherence to cGMP (current good
manufacturing practices) for APIs.
In
the warning letter issued to the firm, the laboratory analysts admitted to FDA inspectors that they had been “setting the clock back and repeating analyses for undocumented reasons.”
At Qinhuangdao Zizhu, “initial sample results were overwritten or deleted” and the company “reported only the passing results from repeat analyses”.
In addition to not having effective measures to control data within their computerized systems, the FDA investigators found that the firm “relied on incomplete information” to determine whether Qinhuangdao Zizhu’s drugs met established specifications.
The investigators found “a recurring practice of re-testing samples until acceptable results were obtained” and that batch production records “contained blank or partially completed manufacturing data”.
On
March 8, 2017, Qinhuangdao Zizhu Pharmaceutical was placed on the import alert by the USFDA.
Almost
a year prior to the USFDA inspection, in October 2015, the company had been
inspected by a WHO Prequalification Team (PQT) for levonorgestrel, mifepristone and ethinylestradiol APIs. The inspection concluded with “five major deficiencies including data integrity issues and several minor deficiencies”.
The
WHO went ahead and closed their inspection as compliant based on corrective and
preventive actions (CAPAs) provided by the manufacturer.
In
view of the USFDA actions, and the fact that Qinhuangdao Zizhu Pharmaceutical
is the only WHO-PQT prequalified source of levonorgestrel API, as in the case of Mylan, the WHO approach towards the compliance position has been
to focus extensively on product quality.
The WHO has requested manufacturers that use levonorgestrel manufactured by Qinhuangdao Zizhu to take “additional measures such as comprehensive testing upon receipt” to help ensure that the quality of all batches of levonorgestrel is assured.
In
addition, the WHO has said that procurement agencies may continue to procure
FPPs that contain API produced at Qinhuangdao Zizhu Pharmaceutical, until
further notice.
The WHO-PQT is planning to conduct an on-site inspection of
Qinhuangdao Zizhu Pharmaceutical and also plans to work with finished
pharmaceutical products manufacturers to identify additional sources for
levonorgestrel.
China
FDA approved as an ICH member
In a major boost to China’s pharmaceutical growth plans, the International Council for Harmonization (ICH) Assembly approved the China Food and Drug Administration
(CFDA) as a new Regulatory Member. This decision was taken during a meet in
Montreal, Canada, from May 31 to June 1, 2017.
While compliance concerns linger over some pharmaceutical factories in the country, China’s acceptance of this membership indicates that the country is prepared to bring its drug manufacturing and testing practices in line with international quality standards.
ICH was created in
1990 to bring regulatory authorities and the pharmaceutical industry together
in order to discuss scientific and technical aspects of drug registration. Over
the last 25 years, ICH has worked on achieving greater global harmonization so
that safe and effective drugs are developed and registered in the most
resource-efficient manner.
In India, Aurobindo’s Unit VII gets zero observations; Lupin founder passes away
Indian pharmaceutical industry lost a
veteran this week. Desh Bandhu Gupta, the founder chairman of Lupin and a self-made billionaire, died in Mumbai at the age of 79.
Five years back, he had handed over the reins of Lupin to his eldest daughter Vinita
Gupta and son Nilesh Gupta.
Desh Bandhu Gupta, or DBG as he was
known, was a deft businessman who founded Lupin in 1968 with just Rs 5,000
borrowed from his wife. Prior to this, he was the professor of chemistry at the
Birla Institute of Technology and Science, Pilani. He went on to become India’s 20th richest person with an estimated net worth of US$ 5.1 billion (according to the 2016 Forbes India Rich List).
While much of the industry abandoned making anti-TB drugs, given the low margins and the government's price controls, Lupin remained consistent as the world’s largest supplier of anti-TB drugs. DBG forged global alliances to develop new medicines to fight tuberculosis.
Meanwhile, another Indian company — Aurobindo Pharma — sailed through a USFDA inspection with zero observation. Aurobindo Pharma’s Unit VII is a formulations manufacturing facility and one of the
largest facilities for the company from which has filed the maximum ANDA
applications to the FDA.
According to a recent company presentation to investors, the company has filed 158 ANDAs (abbreviated new drug application) from this facility, of which 88 drugs received final approvals and 20 drugs have tentative approvals and 50 are currently under review.
Impressions: 4004
https://www.pharmacompass.com/radio-compass-blog/fda-problems-at-pfizer-s-us-facility-continue-china-fda-joins-ich
#PharmaFlow by PHARMACOMPASS
29 Jun 2017
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: 3373
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#PharmaFlow by PHARMACOMPASS
15 Jun 2017
GSK, Google form first bioelectronics firm; 11 generic companies benefit from the Teva Allergan deal
This week,
Phispers brings to you the details of the bioelectronics firm formed by GSK and
Google. There is also news on companies like Teva, Takeda, Jinan Jinda and Eli
Lilly, besides two other news snippets pertaining to the FDA -- while the first
one pertains to generic approvals, the other one relates to an additional black
box warning on a few antibiotics. GSK and Google
join hands to form first bioelectronics startupGlaxoSmithKline and Google’s parent company – Alphabet – have joined hands to create a new company that is focused on fighting diseases by targeting electrical signals in the human body. This way, GSK and Alphabet’s life sciences unit – known as Verily Life Sciences – will be jump-starting a new field of medicine known as bioelectronics.Verily Life
Sciences and GSK will together contribute US $ 715.12
million
over seven years to the startup Galvani Bioelectronics. The startup will develop
miniature electronic implants for the treatment of asthma, diabetes and other
chronic conditions. The
implantable devices developed by Galvani, which is owned 55 percent by GSK and
45 percent by Verily, can modify electrical nerve signals. The aim is to
modulate irregular or altered impulses that occur in many illnesses.The
new company
will be based at GSK’s Stevenage research center north of London, with a second research hub in South San Francisco.The announcement comes just weeks after GSK had said it was going to use Apple’s HealthKit to conduct clinical trials.Three years ago, GSK had first unveiled its ambitions in bioelectronics in the journal – Nature. Bioelectronic remedies attach battery-powered implants the size of a grain of rice (or even smaller) to individual nerves to correct faulty electrical signals between the nervous system and the body’s organs.GSK believes altering these nerve signals could open up the airways of asthma patients, reduce inflammation in the gut from Crohn’s disease and treat patients with a range of other chronic ailments such as arthritis. So far, the implants have only been tested on animals but the aim is to produce treatments that will supplement or replace drugs that often come with side-effects.GSK
has been working on bioelectronic medicines since 2012 in a push to develop new
patentable treatments, since its Advair respiratory treatment faces competition
from generic versions. It has invested US $50 million in a venture capital fund
for bioelectronics and provided funding to scientists working in the field. Teva divests 79
products to 11 generic players to close Allergan dealTeva
Pharmaceutical Industries – the world’s largest generics drug company – won a US
anti-trust approval to purchase Allergan's generics
business, after agreeing to divest 79 generic drugs to rival firms. This was arrived
at to settle Federal
Trade Commission (FTC) charges that its proposed US $ 40.5 billion acquisition of Allergan’s generic pharmaceutical business would be anti-competitive. The remedy requires Teva to divest the drug portfolio to 11 firms, and marks the largest drug divestiture order in a FTC pharmaceutical merger case.The Teva-Allergan deal, which was announced in July 2015, solidifies Teva’s position as the world's largest maker of generics while freeing Allergan to focus on branded drugs.The
companies that
have acquired
the divested products are Mayne Pharma
Group, Impax
Laboratories, Dr Reddy’s Laboratories, Sagent
Pharmaceuticals, Cipla Limited, Zydus Worldwide
DMCC, Mikah Pharma, Perrigo Pharma
International, Aurobindo
Pharma USA,
Prasco and 3M Company. Eli Lilly CEO
steps down; company under probe by US Justice Department Eli Lilly CEO John
Lechleiter has stepped down after steering the pharma company through long R&D droughts. The company’s president David Ricks will move up to the top spot. And after a brief spell as executive chairman, Lechleiter will leave the company next spring.Lechleiter
has been the company's CEO since April 1, 2008, and the chairman of its board
of directors since January 1, 2009.The
announcement has come at a time when Eli Lilly has been asked by the
Justice Department to disclose information on relationships with pharmacy benefits
managers (PBMs), the companies that negotiate prices and set reimbursement
conditions.It
has not been clear what exactly the department of justice is looking for. In
the past, drug makers such as Novartis and AstraZeneca have agreed to
pay fines and penalties to settle allegations pertaining to PBMs. FDA continues
to race ahead with generic approvals The
American regulator has reduced its pile of ANDA (abbreviated new drug
applications) by about 500
applications in the first six months of 2016. The FDA has also approved 315 more ANDAs over the same time period and has sent 66 more complete response letters — or rejections — to drug makers.This
news comes after Bloomberg reported
last month that the FDA has become ‘something of a bogeyman’ for India’s stock markets by approving generic drug applications from India at a record place. Similarly, PharmaCompass
had reported last week that Indian
companies have been fixing compliance issues. China’s Jinan Jinda fails another EDQM inspection; compliance troubles in Denmark In
regulatory news from across the world, Jinan Jinda, a Chinese API
manufacturer that had failed an inspection by Italian regulators in June 2015,
had more bad news awaiting it a year on. In
a June 2016
re-inspection, this time by the Spanish Health Authority, the regulator maintained the ‘facilities non-compliance standing’ since two critical observations were made and the corrections from the previous inspection “were found as not having been implemented in a satisfactory way”. And critical deficiencies were found on raw data.In
the June 2015 inspection, the critical observation was related to an unofficial
and non-controlled storage area containing mainly raw materials and finished
products which had been made
inaccessible to inspectors as the door had been removed and replaced with a panel fixed with
screws to the wall.Meanwhile,
the FDA issued an untitled letter (dated July 15, 2016) to Danish allergy
immunotherapy company ALK-Abelló (ALK) over manufacturing and quality control issues at its Horsholm, Denmark facility. The letter comes after a 12-day inspection of the facility in March 2016. During the inspection, the FDA had cited ALK for four “significant deviations” from cGMP requirements. Another black
box warning added to antibiotics like Cipro and LevaquinThe
FDA has upgraded
warnings on
certain antibiotics, such as Johnson & Johnson’s Levaquin, Bayer’s Cipro
extended-release tablets and Merck’s Avelox. The FDA had
added a black box warning in 2008 about the increased risk of tendinitis in
which the tissue connecting muscle to bone becomes inflamed. In
May this year, the FDA had advised restricting the use of fluoroquinolone antibiotic for certain uncomplicated
infections and had warned about the disabling side-effects of the drug.The new warning talks about long-term risks to the drugs’ current black box warning. The agency also advised using the drugs only for serious infections. Manufacturers of fluoroquinolone have faced thousands of lawsuits from patients who claim that their injuries were caused by the drugs. J&J alone faced 3,400 lawsuits over Levaquin’s links to tendon problems and has also settled many of those cases. Takeda to
overhaul R&D, downsize operations in the UKTakeda Pharmaceutical of Japan has
said it plans to build a new pipeline of drugs. It plans to revamp its
research operations at the cost of around US $ 727 million.. The
company also plans to close some of its R&D operations in the UK. Takeda is
beginning the first ‘consultation stage’ of the layoff process in the UK, which hosts a pre-clinical R&D operation in Cambridge as well as a development center headquarter with facilities in the UK, Switzerland and Denmark.Under the revamp, Takeda’s R&D activities will be concentrated in Japan and the US, the 235-year old drug company said in a statement. Takeda plans to now focus on the three therapeutic areas of oncology, gastroenterology and the central nervous system.“We need to first build new capabilities and embrace new ways of working,” Andy Plump, Takeda’s chief medical and scientific officer, said in the statement.
Impressions: 2757
https://www.pharmacompass.com/radio-compass-blog/gsk-google-form-first-bioelectronics-firm-11-generic-companies-benefit-from-the-teva-allergan-deal
#PharmaFlow by PHARMACOMPASS
04 Aug 2016
