Market Place
Last month, we had carried an article ‘Hydroxychloroquine: Hype versus reality’ that
highlighted some of the limitations of the study undertaken in France at
the infection hospital l'Institut Hospitalo-Universitaire (IHU) Méditerranée Infection in Marseille. On March
16, Professor Didier Raoult
had published a video explaining
the trials following which the US
President Donald Trump had tweeted last month that hydroxychloroquine (HCQ) taken together with azithromycin had a real chance to be one of the biggest game changers in
the history of medicine.
The excitement over HCQ being a potentially effective treatment for Covid-19 led to a tremendous demand surge globally for the drug and countries like India, Hungary and Finland, which are major manufacturers of the active pharmaceutical ingredient (API) restricted exports. Following direct discussions between President Trump and India’s Prime Minister Narendra Modi last week, India relaxed its restrictions and cleared the export of 3.58
million tablets of HCQ to the US along with nine metric tons of API required in
the manufacturing of the drug.
While
the consignment of HCQ from India arrived in the US last week, Raoult has
since been criticized by the scientific community for his methods, especially
the lack of a control group to establish a benchmark for the success of his
experimental treatments.
The pushback
started last month, when clinical studies published in Chinese patients showed
limited clinical improvement over standard care. In a controlled clinical study on 30 patients, a report published by the Journal
of Zhejiang University in China revealed that patients who got treated by HCQ didn’t fare any better than those who did not get the medicine.
This
week, we examine some of the findings of fresh studies undertaken in France,
Brazil and China on HCQ to examine its efficacy in the treatment of Covid-19.
French
study results do not support HCQ use in hospitalized patients
A study
undertaken in France, spearheaded by doctors in Paris, collected data from routine care of adults in four French hospitals with documented
SARS-CoV-2 pneumonia and who required oxygen to emulate a target trial aimed at assessing the effectiveness of HCQ
at 600 mg/day.
This
study included 181 patients with SARS-CoV-2 pneumonia; and out of this 84
received HCQ within 48 hours of admission (HCQ group) and 97 did not (no-HCQ
group).
An
analysis of this study reveals that 20.2 percent patients in the HCQ group were
transferred to the ICU or died within seven days as opposed to 22.1 percent in
the no-HCQ group. In the HCQ group, 2.8 percent of the patients died within
seven days as against 4.6 percent in the no-HCQ group. And 27.4
percent and 24.1 percent, respectively, in both the groups developed acute respiratory
distress syndrome within seven days. Eight patients receiving HCQ (9.5 percent) experienced electrocardiogram (ECG) modifications requiring HCQ discontinuation.
The
authors concluded that the results do not support the use of HCQ in patients
hospitalized for documented SARS CoV-2-positive hypoxic pneumonia.
Chinese study shows benefits in alleviation of symptoms but not in clearing virus
In
another randomized controlled trial in China, which tracked 150 patients hospitalized with Covid-19, 75 patients were
assigned to HCQ plus standard of care (SOC) and 75 were assigned to SOC alone. The results
concluded that administration of HCQ did not result in a higher negative
conversion rate but more alleviation of clinical symptoms than SOC alone in
patients hospitalized with Covid-19. Adverse events were significantly
increased in HCQ recipients.
While
the primary endpoint for this trial was the negative conversion of SARS-CoV-2
within 28-days, the study does mention that more rapid alleviation of clinical
symptoms with SOC plus HCQ than with SOC alone was observed during the second
week.
Minimum
requirements for the SOC included the provision of intravenous fluids,
supplemental oxygen, regular laboratory testing, and SARS-CoV-2 test,
hemodynamic monitoring and intensive care and the ability to deliver
concomitant medications.
HCQ was administrated with a loading dose of 1,200 mg daily for three
days followed by a maintained dose of 800 mg daily for the remaining days
(total treatment duration: two weeks for mild/moderate patients, three weeks
for severe patients).
Brazilian study reports hazards on its analog chloroquine
A small
study undertaken in Brazil on the effects of the anti-malaria drug chloroquine (CQ), which is structurally similar to HCQ, was abruptly halted because some patients taking high doses developed irregular heart rates generating “safety hazards.” The findings were revealed in a study funded by the Brazilian state of Amazonas.
The
Brazilian study included 81 hospitalized patients, with about half being
given a 450 milligram dose of chloroquine twice on the first day of the study followed by one daily
450 milligram dose for four more days. The other participants
were prescribed a dose of 600 milligrams twice daily for 10 days.
Patients
taking higher doses experienced heart arrhythmias within three days.
Eleven patients died by the sixth day of treatment and the research on the
high-dosages, therefore, had to be ended.
“Preliminary findings suggest that the higher CQ dosage (10-day regimen) should not be recommended for Covid-19 treatment because of its potential safety hazards,” the study's abstract said. “Such results forced us to prematurely halt patient recruitment to this arm.”
The lower-dosage portion of the study did not include enough patients to gauge whether it is effective in treating severely ill patients. The researchers said that more studies assessing the efficacy of chloroquine are “urgently needed.”
Heart incidents linked to HCQ in France
France
has reported 43 cases of heart incidents linked to treating Covid-19 patients with HCQ. According to a
statement issued by the French drug safety agency ANSM, the country has recorded about 100 health incidents and four deaths linked to experimental drugs for Covid-19 patients since March 27. Three other patients had to be revived.
Some 82
incidents were deemed “serious.” Most of those were split between HCQ and HIV antivirals lopinavir-ritonavir.
Last
month, Nigeria reported cases of chloroquine poisoning. “These drugs should only be used in hospitals, under close medical supervision,” ANSM said.
Our view
A large multinational collaboration presenting data obtained from
health care systems (claims data or electronic medical records) in Germany,
Japan, Netherlands, Spain, UK and the USA concludes that short-term HCQ
monotherapy does appear to be safe. However, it notes that long-term HCQ dosing
is indeed tied to increased cardiovascular mortality.
Moreover, significant risks are identified for combination users of HCQ
and azithromycin, even in the short-term. There is a 15-20 percent increased
risk of angina/chest pain and heart failure, and a two-fold risk of
cardiovascular mortality in the first month of treatment.
At the same time,
French Professor
Didier Raoult published expanded study results highlighting that 1,061 patients treated for at least three days with the HCQ and azithromycin combination had a cure rate of 98 percent and “no cardiac toxicity was observed”.
As of
today, controlled studies undertaken on HCQ
indicate that the drug does little to eliminate the presence of the virus but
it does help in the short-term to make patients feel better, especially those
who have a milder Covid-19 infection.
For now, there is likelihood that HCQ may turnout of be another TamiFlu.
The drug was widely prescribed during the swine flu outbreak in 2009. A recent
study concluded that the drug reduced the persistence of flu symptoms from seven days to 6.3 days in adults and to 5.8 days in children. But the report’s authors said drugs such as paracetamol could have had a similar impact. If that indeed is the case with HCQ, millions of dollars may get wasted on the drug, just as they were wasted in 2009 during the swine flu outbreak.
Impressions: 3528
https://www.pharmacompass.com/radio-compass-blog/covid-19-hcq-update-studies-in-france-brazil-china-raise-more-questions-on-its-efficacy-safety
#PharmaFlow by PHARMACOMPASS
16 Apr 2020
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While the world feels the heat of the Covid-19 pandemic with the global pharmaceutical supply chain getting impacted, normalcy is returning
to China. According to new reports, the production of drugs and APIs in China is also returning to normal.
In a press conference held by top Chinese officials this week, the country’s ministers highlighted that as of March 28, the average operating rate of industrial enterprises across China had reached 98.6 percent and the production of some key vitamin, antibiotic and analgesic raw material drug companies had returned to normal with yields of major products reaching above 80 percent.
Officials had paid heed to resumption of production
The officials
highlighted that during the critical period of epidemic prevention and control,
the Chinese government had paid close attention to the resumption of production
of API companies. After receiving reports that some companies in Hubei had not
resumed work, which would impact the supply chains of products like metronidazole, ibuprofen, and taurine, the
authorities urgently coordinated with the relevant departments of Hubei, other
provinces, cities and counties to carry out key scheduling for some API
manufacturers and actively organized employees to return to work.
However, despite
these initiatives, due to the impact of the epidemic, wherein some enterprises
had stopped production and subsequently faced challenges with logistics and
transportation difficulties, there was a shortfall in supply.
The export
volume of APIs did decrease this year compared with the same period last year
and the officials estimated that most products witnessed a drop of about 10 to
20 percent, and in some cases the decline of individual varieties had reached
30 percent. Repeated communications between the officials and these
companies revealed that the main contributor to the decline in exports was sea
freight, as international shipping had greatly reduced, and transportation
costs have also increased.
Although
international transportation has become a bottleneck for the supply of some
APIs, the press conference highlighted that the output of other APIs had
exceeded the level of the same period last year.
China to meet global demand for chloroquine
The officials
made a special mention of medications like chloroquine phosphate which have
received significant attention as a potential treatment of the novel
coronavirus. After chloroquine phosphate was identified as a potentially
effective treatment, the government worked with the two major API manufacturers
in China to organize the companies to meet international demand. For example, Chongqing Kangle Pharmaceuticals exported 4.9
tons of chloroquine APIs within five days.
This news from
China is encouraging to the global supply chain as following the rising interest in a chloroquine analog — Hydroxychloroquine (HCQ) — the
Indian government issued a directive which
prohibits the export of HCQ API and formulations made from HCQ. The directive
did, however, offer exemptions to exports from special economic
zones/export-oriented units and in cases where export is made to fulfill an
export obligation under any advance license issued on or before the date of the
notification.
Last week, Hungary, which is also one of the world’s largest exporters of HCQ, also banned the commercial export of the ingredient and the
United Kingdom (UK) banned the export of finished formulations of HCQ as part
of a list of 135 medicines posted that cannot be exported from the UK
because they were needed for the UK patients.
In early
March, the Indian government had also restricted the exports of
13 APIs along with some of their finished formulations. The list included paracetamol tinidazole metronidazole acyclovir vitamin B1 vitamin B6 vitamin B12 progesterone chloramphenicol and neomycin.
However, a recent report published in The Economic Times highlighted that out of 13 drugs whose exports were restricted, the government is likely to lift the ban on the following five APIs — paracetamol, tinidazole, metronidazole, ornidazole and azithromycin. There were
also reports of significant pressure from the US on the Indian government for products
like paracetamol and the officials expect the ban to be lifted in the coming
days.
The Chinese
officials further went on to provide assurances that the supply of chloroquine phosphate can be increased in accordance with international market demand and that China’s Ministry of Industry and Information Technology will also organize the implementation of monitoring and production scheduling of key products, coordinate and solve the export transportation difficulties encountered by enterprises and strengthen communication.
Our view
The press
conference highlighted that China attaches great importance to the safety of
the global pharmaceutical industry supply chain and President Xi Jinping had
promised at the G20 summit of member states on March 26 that China will
increase its efforts to supply APIs to the international community.
The Chinese
government is working earnestly to implement the commitment to maintain the
production of API manufacturers and ensure the safety and stability of global
industrial chain supply, the statement emerging out of the press conference
said.
Given the global pharmaceutical supply chain’s overwhelming dependence on China, the nation’s return to normalcy is a positive sign for countries across the world. For the time being, the pandemic has only increased the world’s dependence on China. All countries that want to reduce their reliance on China will take time not just to build capacities, but also to emerge out of the Covid-19 crisis.
Impressions: 1591
https://www.pharmacompass.com/radio-compass-blog/chinese-industrial-activity-revival-at-98-6-percent-officials-assure-of-api-supplies
#PharmaFlow by PHARMACOMPASS
02 Apr 2020
The
President of United States Donald Trump’s
tweet
late last week has swung the pharmaceutical industry’s
focus on hydroxychloroquine, an anti-malarial drug which has been in use since
the 1950s and is now used to treat a variety of autoimmune disorders.
Trump had
tweeted: “HYDROXYCHLOROQUINE & AZITHROMYCIN, taken together, have a real chance to be one of the biggest game changers in the history of medicine. The FDA has moved mountains — Thank You! Hopefully they will BOTH (H works better with A, International Journal of Antimicrobial Agents) be put in use IMMEDIATELY. PEOPLE ARE DYING, MOVE FAST, and GOD BLESS EVERYONE!”
We look at the study quoted by Trump to know the efficacy of these drugs, and whether the world is any closer to finding a cure for the novel coronavirus which has impacted people across the world over the last two months. Our findings suggest it maybe too early to term the combo as a game-changer. Here’s our detailed analysis:
The
study in France that wasn’t
done by Sanofi
The US
President’s tweet referenced the results
of a study conducted in France, which was published in the International
Journal of Antimicrobial Agents last week title “Hydroxychloroquine and azithromycin as a treatment of COVID‐19: results of an open‐label non‐randomized clinical trial”.
The study
was performed at the infection hospital l'Institut Hospitalo-Universitaire
(IHU) Méditerranée Infection in Marseille and Professor Didier Raoult published a video explaining the trials on
Monday, March 16. All patients at the Marseille center were given oral
hydroxychloroquine sulfate 200 mg, three times per day during 10 days.
Social
media posts incorrectly promoted the French study as a trial conducted by the
country’s largest drugmaker Sanofi and went on to recommend Sanofi’s hydroxychloroquine
brand Plaquenil as ‘anti-corona’.
There is
no mention of Sanofi or Plaquenil in the research publication which attributes
its funding support to the French government.
Effectiveness of hydroxychloroquine, azithromycin against Covid-19
An analysis of the results of the study shows that on
day 6 the effectiveness of the treatments on 36 patients was:
— 100 percent (6/6 patients tested negative) for hydroxychloroquine + azithromycin
— 57 percent (8/14 patients tested
negative) for hydroxychloroquine as a stand-alone therapy
— 13 percent (2/16 patients tested negative) for the control therapy (which is not described in the paper)
The lesser known details — 1 patient died, 3 patients transferred to ICU
However,
the original study had enrolled 42, and not 36 patients. The publication shares the details of the six
hydroxychloroquine-treated patients who failed to complete the trial and could
not be tested on day 6 for the presence of Covid-19. The reasons to not be
tested were:
- Three
patients, who were still testing positive, were transferred to the intensive
care unit (ICU)
- One
patient, who tested negative on day 2, died on day 3
- One
patient, although testing positive on days 1 to 3, stopped treatment because of
nausea
- One
patient left the hospital after testing negative on days 1, 2
The
results also highlight that one patient who was still testing positive on day 6
under hydroxychloroquine only treatment, received azithromycin in addition to
hydroxychloroquine and was cured off her infection on day 9.
However,
one of the patients under hydroxychloroquine and azithromycin combination who
tested negative at Day 6, tested positive on Day 8.
Negative results were reported at a lower limit
The trial
in France used the RT-PCR testing methodology to determine if a person had
Covid-19 and reported the Cycle Threshold (CT) reading.
The RT-PCR
technology builds on a Nobel Prize winning technique of PCR, or polymerase
chain reaction, which is a DNA amplification technique that is routinely used
in laboratories to turn tiny amounts of DNA into large enough quantities that
can be analyzed. For scientists to
detect a virus like Covid-19, they also need to turn its genome, which is made
of a single-strand RNA, into DNA. In order to do this, an enzyme called
reverse-transcriptase is utilized.
Combining
the two techniques created RT-PCR and when the DNA is combined with a
fluorescent dye, that glows in the presence of DNA, PCR can actually tell
scientists how much DNA there is.
The cycle
threshold (CT) is the number of cycles which are required for the fluorescent
signal to cross an established threshold. CT levels are also inversely
proportional to the amount of target nucleic acid in the sample (i.e. the lower
the CT level the greater is the amount of the viral load).
As per the
method guidelines published on the United States Food and
Drug Administration (FDA) website “when all controls exhibit the expected performance, a specimen is considered negative if all 2019- nCoV marker (N1, N2) cycle threshold growth curves DO NOT cross the threshold line within 40.00 cycles (< 40.00 Ct)”.
The French
study reported negative results at a CT value of 35 as against the FDA guidance
of 40 cycles, which indicates reporting negative results earlier than what
would have been acceptable to the FDA.
In
addition, as a lower CT number indicates a higher amount of the nucleic acid
load, in all cases where the patients had a CT of less than 22 at the start of
the study, they failed to test negative on the hydroxychloroquine-only
treatment.
The
hydroxychloroquine-azithromycin combination was only administered and effective
on patients with a CT of more than 23.
The
expected surge in demand for hydroxychloroquine
Following
Trump’s tweet, Novartis pledged to donate up to 130
million hydroxychloroquine tablets, pending regulatory approvals for
Covid-19, Mylan announced it was ramping up production to
make 50 million tablets and Teva said it was donating 16 million
tablets to hospitals around the US.
PharmaCompass’ MarketPlace has been flooded with
requests for hydroxychloroquine sulphate, chloroquine phosphate (although hydroxychloroquine
clinical safety profile is better than that of chloroquine, in long-term use,
and allows higher daily dose) and azithromycin and API suppliers have informed
us that their capacities are sold out.
With pharmacies running out of the drugs, in a surprise move the FDA made an exception to the four-year old ban
placed on India’s
Ipca Labs, one of the major
manufacturers of chloroquine and hydroxychloroquine, to sell their drugs in the United
States.
The
company informed the bourses that due to the shortage implications and/or
medical necessity of certain drugs and finished products, the import alert for
the company's hydroxychloroquine sulphate and chloroquine phosphate APIs and
hydroxychloroquine sulphate tablets had been partially lifted.
In a
recent August 2019 inspection, the FDA had observed “a cascade of failure” in Ipca’s quality unit.
Our
view
We support
the authors of the study who themselves acknowledge that “our study has some limitations including a small sample size, limited long-term outcome follow-up, and dropout of six patients from the study, however in the current context, we believe that our results should be shared with the scientific community.”
While the world is desperately looking for solutions, a balanced view of the results is necessary. And it’s important to reiterate that we are far away from finding a quick fix to the single biggest health emergency in years.
Impressions: 7568
https://www.pharmacompass.com/radio-compass-blog/hydroxychloroquine-hype-versus-reality
#PharmaFlow by PHARMACOMPASS
23 Mar 2020
Now that it has been
established that the novel coronavirus is going to globally impact the drug
supply chain, it becomes imperative to analyze the extent of the impact.
Since the outbreak of
the novel coronavirus — COVID-19 — in December, PharmaCompass has been constantly reaching out to
manufacturers around the world to assess the current state of the drug supply
chain. This week, we share our preliminary analysis based on the feedback we
have received from drug manufacturers around the world.
Drug shortages are
for real
Last week, the US
Food and Drug Administration (FDA) announced the first human drug shortage
as a result of the coronavirus outbreak. In addition, the FDA announced it was
tracking 20 drugs that could face shortages. Some generic drugmakers are predicting shortages
as early as in June or July, due to the novel coronavirus.
The FDA did not disclose the name of the drug in shortage or the 20 drugs it is tracking, as this is considered ‘confidential commercial information’.
In India, a committee constituted by the country’s Department of Pharmaceuticals started monitoring the availability of 58 active pharmaceutical ingredients (APIs) to take preventive measures
against illegal hoarding and black-marketing in the country.
According to a report published in The Economic Times, after
reviewing the list of drugs, 34 were found to have no alternatives which
include critical and essential drugs like potassium clavulanate, ceftriaxone sodium sterile, piperacillin tazobactam, meropenem, vancomycin, gentamycin and ciprofloxacin.
This was immediately
followed by the Indian government restricting the exports of 13
APIs along with some of their finished formulations. The list includes paracetamol, tinidazole, metronidazole, acyclovir, vitamin B1, vitamin B6, vitamin B12, progesterone, chloramphenicol and neomycin. For most
of the products on this list, India is a net importer, as there is little
domestic manufacturing of these APIs.
COVID-19 is also
likely to impact bottomlines. Leading generic drugmaker Mylan said it expects the coronavirus outbreak to impact its financial results
while some of the largest drugmakers — including AstraZeneca, Merck and Pfizer — have said that the coronavirus outbreak could affect their supplies or sales.
Paracetamol
affected; prices double in less regulated markets
The decline in industrial activity in China is certainly taking its toll, as drugs which are on the World Health Organization’s Model list of Essential Medicines are beginning to face significant price increases in the wake of disruption of key starting raw materials for bulk drugs.
The export
restriction out of India on commonly used analgesic, Paracetamol — sold under the brand names such as Tylenol (in the US), Panadol (in the UK), Dafalgan (France) and Crocin
(India) — is not surprising as the API has witnessed almost doubling of prices in less regulated markets because exports of its key building block para-amino phenol (PAP) have dramatically reduced from China.
While there are only
a few manufacturers who produce paracetamol without being dependent on Chinese
PAP, a few major manufacturers in India depend almost completely on Chinese PAP
for their paracetamol production and usually only keep three to four months of
inventory.
By the end of
February, their inventory stockpiles had halved and in the event of a continued
supply disruption, their entire inventory pipeline is likely to dry out. In
addition, Chinese paracetamol manufacturers, who export a significant amount of
their bulk ingredient production globally, including to India, are also
currently unable to export. This is beginning to create the potential of panic
among sourcing executives across the world.
Several
antibiotics also in danger of acute shortages
While paracetamol was listed on the API watch list circulated by India’s Department of Pharmaceuticals, our survey has revealed that other products on the list like ciprofloxacin, amoxicillin and azithromycin are also facing severe raw material
shortages. As a result, the prices of these bulk drugs have also increased
sharply.
In a statement to The Economic Times, leading Indian generic manufacturer Mankind Pharma’s chairman and managing director said
amoxicillin is the most commonly used API to manufacture antibiotics and the
company has invested Rs 1 billion (US$ 14 million) in placing irregular orders
with vendors to try and address the potential shortage that is expected. He
went on to say that if the situation continues until April, there will be an
acute shortage.
In a statement to the US House of Representatives last October, Janet Woodcock, the FDA’s Director of Center of Drug Evaluation and Research, said the FDA has determined that there are three WHO Essential Medicines whose API manufacturers are based only in China. The three medicines are: capreomycin, streptomycin (both indicated to treat Mycobacterium
tuberculosis) and sulfadiazine (used to treat chancroid and trachoma).
Streptomycin is also on the watch list published by India’s Department of Pharmaceuticals along with commonly used anti-hypertensives like losartan, valsartan, telmisartan and olmesartan and diabetes treatment metformin.
Intermediates
becoming a problem for generic drugmakers
PharmaCompass’ discussions have also revealed that in many cases while API manufacturing factories in China have returned to work, there are disruptions in the availability of raw materials and/or logistics at sea ports and airports which have led to unavailability of supplies.
While the FDA has a
list of the number of API facilities in China which are in a position to supply
to the United States, Woodcock said in her statement that the FDA “cannot determine with any precision the volume of API that China is actually producing, or the volume of APIs manufactured in China that is entering the US market.”
This visibility
reduces drastically when one has to assess the dependence of each API
manufacturer around the world on China for intermediates. Our discussions have
revealed that it is these intermediates which are becoming a problem for most
API manufacturers, even those based in India.
It was worth
highlighting that a manufacturing process change at an intermediate stage of
commonly used blood pressure medicine valsartan resulted in the recall of
millions of pills as it was found to contain a cancer causing impurity above
acceptable levels. Similarly, in 2008, the adulteration of heparin in China,
which killed 81 people and left 785 severely injured, was an outcome of the
subcontracting of precursor chemicals of Heparin.
Our view
The over-dependence
on China for key starting materials has been the subject of discussion ever
since we launched PharmaCompass. Rosemary Gibson explored this subject
in detail in her book China Rx: Exposing the Risks of America’s Dependence on
China for Medicine.
The restrictions imposed on industrial activity and transportation in China in the first two months of this year has resulted in NASA’s satellite images showing a decline in pollution levels over China.
While China works
towards getting its industrial and transportation engine up and running to 2019
levels, the outbreak has spread to other countries which will further increase
the demand for drugs to fight the virus.
This is a time when
the pharmaceutical industry needs to act responsibly and make decisions which
are in the best interests of patients globally.
Sharing information is one such step — it will allow for drug stockpiles and inventories that exist to be re-distributed to areas which need them most. For, in the event of an urgent need, drugs will become available to those who are most in need.
Impressions: 8056
https://www.pharmacompass.com/radio-compass-blog/covid-19-india-restricts-drug-exports-amid-rising-prices-of-essential-bulk-drugs-fda-announces-first-drug-shortage
#PharmaFlow by PHARMACOMPASS
04 Mar 2020
In our mid-2018 compliance review, we look at inspection challenges
faced by companies across the world. In the first half of this year,
manufacturing compliance challenges dominated headlines. But we also saw
shortcomings at major pharmaceutical companies like Pfizer, Bayer
and Akorn
generate news.
While China, India and the US continued to be the top three countries
where regulators uncovered compliance issues, this year has also seen the FDA
take action against many South Korean companies. The European authorities found
concerns in India, Taiwan, Italy and Spain. However, there were no
non-compliance reports issued to firms in China until the end of June 2018.
While data-integrity violations and a failure to thoroughly
investigate deviations continued to remain a major concern for inspectors, this
year the real concern emanated from the supply of product to market (which had
the potential to impact product quality or patient safety).
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all Mid-Year Non-Compliances in 2018 (Excel version) for FREE!
China: API with a cancerous impurity, vaccine scandal and data-integrity
woes
The most recent regulatory non-compliance issue pertains to the
European Medicines Agency (EMA) raising concern over the active pharmaceutical
ingredient (API) valsartan supplied by China’s Zhejiang Huahai Pharmaceuticals.
The concern was the impurity — nitrosodimethylamine (or NDMA) — detected by the company in their valsartan API. NDMA is
classified as a probable human carcinogen and its presence was unexpected as it was not detected by routine tests carried out by
Zhejiang Huahai.
Zhejiang Huahai sold over US$ 50 million of
the API in 2017 and supplies to most major manufacturers producing valsartan
medicines available in the EU and United States.
While a review is underway, national
authorities across the EU, US and Asia are recalling medicines containing
valsartan supplied by Zhejiang Huahai.
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in 2018 (Excel version) for FREE!
Vaccine scandal: A major vaccination scandal has sparked off a huge outcry in China as vaccine
maker Changsheng Biotechnology was found to have falsified production data for
its rabies vaccine.
Changchun
Changsheng Bio-tech Co, in Changchun, reported serious irregularities, including fabricating
production records in the manufacture of rabies vaccines for human use, during
an inspection by the State Drug Administration, China FDA said in a statement.
Although there has been no evidence of harm
from the vaccine, the firm has been ordered to halt production and recall
rabies vaccines. And Chinese Premier Li Keqiang has urged severe punishment for the people involved, saying the incident had “crossed a moral line”.
Data-integrity violations: This year, the FDA also posted
the warning letter issued to Henan Lihua Pharmaceutical in China, a company that produces steroid APIs
like hydrocortisone and prednisone.
The warning letter
highlighted data integrity concerns that landed Henan on FDA’s import alert list in March 2018.
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in 2018 (Excel version) for FREE!
During the inspection, the FDA investigator observed numerous blank batch manufacturing records in an open cabinet in the firm’s manufacturing workshop office.
Among these was multiple blank, product release forms marked with a red quality assurance release stamp stating ‘Permitted to Leave [the] Factory’.
The FDA also posted a warning letter issued to Jilin Shulan Synthetic Pharmaceutical, a manufacturer of caffeine API in China. The letter revealed
flagrant data-integrity violations.
Another warning letter was
issued by the FDA to API manufacturer Lijiang Yinghua Biochemical and Pharmaceutical, following
an October 2017 inspection.
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in 2018 (Excel version) for FREE!
United States: Drug shortages due to Pfizer’s manufacturing problems
Drug
major Pfizer’s production problems continued to make headlines this year. An article in Fortune put the blame on Pfizer’s much-touted US$ 17 billion acquisition of Hospira in 2015 for turning the United States’ chronic drug shortage into a full-blown crisis.
According to the article, as of May 11 this year, Pfizer — which is the world’s largest maker of sterile injectable drugs — had 370 products that are depleted or in limited supply, 102 of which the company has indicated will not be available until 2019.
“The simple answer to why America currently has so many shortages of generic sterile injectable drugs: America’s leading manufacturer of generic sterile injectable drugs hasn’t been making them,” the article said.
Mylan’s flagship product EpiPen is also likely to face shortages due to problems at Pfizer. Although Mylan owns the rights to the EpiPen, it subcontracts manufacturing of the auto-injector to Meridian Medical Technologies, a division of Pfizer.
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While Mylan is putting pressure on Pfizer
to do more to tackle shortages of this life-saving medicine, Pfizer has
struggled to meet demand for the EpiPen and the FDA had put the medicine on its
official shortages list.
In September last year, the FDA had
issued a warning letter to Meridian
Medical Technologies over serious component and product failures that had
been associated with patient deaths.
Pfizer’s
troubles are far from over as an FDA inspection of an ex-Hospira sterile
manufacturing facility in India resulted in the issuance of a 32 page Form 483. The
same facility was issued a warning letter by the FDA in 2013.
Germany: FDA highlights contamination, data-integrity concerns at Bayer facility
In a shocking warning letter issued
by the FDA to Bayer Pharma’s finished pharmaceuticals manufacturing facility
located in Leverkusen, Germany, investigators found compliance shortcomings
ranging from concerns over data-integrity to serious product contamination
problems.
While reviewing a drug product manufacturing
operation, FDA investigators found residue on equipment which seemed most
likely from a drug product that had been previously processed in the same room.
When Bayer tested the samples of the tablets being produced to “assess the potential of cross-contamination”, the testing confirmed contamination of the previously processed product inside the tablets which resulted in a recall of several lots of drug products.
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Before the FDA inspection, Bayer had started its own data-remediation program to discontinue the practice of using “test” injections during testing. However, when the FDA investigators performed their own inspection, they found unreported data from in-process tablet weight checks. Bayer’s staff had programmed their in-process weight checker not to report values that varied more than a specified amount from the tablet target weight.
The inspection was held between January 12 and
20, 2017, and responses submitted to the FDA in May and August 2017
failed to address the concerns of the agency.
Fresenius aborted US$ 4.3
billion takeover of Akorn: ‘Blatant fraud’ or buyer’s remorse?
This year also saw German healthcare group
Fresenius abandon its US$ 4.3 billion takeover of US generic drugmaker Akorn over
data-integrity concerns.
Illinois-based Akorn filed a lawsuit in the
Delaware Chancery Court asking that Fresenius be required to “fulfill its obligations” under the buyout agreement.
In a court filing made public, Fresenius alleged that its investigation uncovered “blatant fraud at the very top level of Akorn’s executive team, stunning evidence of blatant and pervasive data integrity violations.”
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Akorn’s lawsuit acknowledged it investigated the possible submission of falsified data and
fired an executive who was involved.
Fresenius claims the executive involved in the fraud wasn’t fired. Instead, he was suspended and given a consulting position with a US$ 250,000 salary. The executive, whose name is redacted from the court filings, stands to receive a payout if the merger is consummated.
The most significant instance
of a data integrity issue involves an ANDA for the drug product azithromycin that was pending with the FDA, which Akorn had submitted
on December 21, 2012.
The court will decide if the data-integrity concerns are truly legitimate or being blown out of proportion by Fresenius, who may be suffering from buyer’s remorse and wants to exit the deal.
The court agreed to put Akorn’s case on fast track and the trial is currently underway.
South Korea: Teva’s potential blockbuster gets delayed due to problems at Celltrion
As Korea emerges as a force
to reckon with in the emerging world of biosimilars, the USFDA's issuance of a warning letter to Celltrion (a major manufacturer of biosimilars that has also partnered
with Pfizer for commercialization in the United States) came as a major
setback.
In an inspection conducted by
the FDA from May 22 to June 2, 2017, the investigators raised concerns over
multiple poor aseptic practices during the set-up and filling operations.
The warning letter highlights
an example where during the aseptic filling of vials, an operator used
restricted access barrier system (RABS) to remove a jammed stopper by reaching
over exposed sterile stoppers
in the stopper bowl. The RABS disrupted the unidirectional airflow over the
stopper bowl, creating a risk for microbial contamination.
After the operator removed
the jammed stopper, the filling line was restarted, but the affected stoppers
were not cleared.
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At Celltrion, the FDA
raised concern over 140 complaints received between October 2015 to May 2017,
which were identified to have occurred because of vial stoppers.
The deficiencies at Celltrion impacted Teva as the Korean company is the main API supplier for Teva’s migraine drug fremanezumab.
Teva confirmed that the USFDA had extended the goal date of the
Biologics License Application (BLA) for fremanezumab. The Prescription Drug
User Fee Act (PDUFA) action date for fremanezumab is currently set
for September 16, 2018.
The Celltrion warning letter
was followed by an announcement by the US-based Evolus that a USFDA pre-approval inspection of Daewoong Pharmaceutical’s plant in South Korea, where a botox biosimilar is being produced, resulted in 10 observations.
Back in 2013, Daewoong had inked a
contract with Evolus to export DWP-450 (a botulinum neurotoxin candidate),
which was expected to be released in the US market around 2017-18.
While Daewoong said it expects “no significant further actions”, Evolus’ SEC filing highlights that “any failure to adequately resolve the FDA’s observations at the Daewoong facility would likely cause FDA approval of DWP-450 to be delayed or denied”.
In May, the FDA declined to approve Evolus’ Botox rival citing deficiencies related to the chemistry and manufacturing of its potential treatment for frown lines.
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India: Data-integrity
violations, invalidation of OOS results continue
Alkem has ‘no quality control unit’: After eight days of inspecting Alkem Laboratories’ finished formulation facility in India in March 2018, the FDA investigators concluded — “there is no quality control unit”.
Alkem’s head of quality control (QC) and quality assurance (QA) confirmed out-of-specification (OOS) results for the assay for a batch of tablets. However, the company did not recall the product, which was distributed in the US market.
Less than three weeks before the inspection, the “firm’s QC department deleted two-thousand one hundred one (2,101) files” on its computer network.
Alembic invalidated OOS results: In the seven days that the FDA investigator — Jessica L Pressley — spent at
Alembic Pharmaceuticals’ oral solid dosage manufacturing facility in Tajpura, Gujarat, she uncovered that the firm invalidated 131 of the 140 OOS results (an invalidation rate of 94 percent) for products marketed in the US.
The firm attributed the invalidation to
analyst errors. In 2017, the invalidation rate was 91 percent.
The Form 483 shares a concern that the “OOS results that were invalidated by the firm’s QC unit were without rationale and supporting documentation.”
Alchymars falsified lab data: A September 2017 inspection by the USFDA at Alchymars ICM SM Private Limited in India uncovered that the firm “was falsifying laboratory data”. During the inspection, the FDA investigator found that an analyst reported far fewer colony-forming units (CFU) in a water sample than those observed on the plate by the investigator.
The FDA raised serious concerns as Alchymars uses the water to manufacture
APIs intended for use in sterile injectable dosage form drug products.
Alchymars is part of a group of companies and the factory is controlled by Trifarma in Italy, a
company which was cited
by the FDA for data-integrity violations in 2014.
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Our view
This year, concerns over pharmaceutical
manufacturing spread beyond China, India and the United States as data
integrity issues also emerged in Japan and Australia.
In Taiwan, the failure to establish an
adequate system for monitoring environmental conditions in aseptic processing
areas was a problem uncovered by both the FDA and EU inspectors.
A firm in France released an over-the-counter
(OTC) drug product without testing if the active ingredients conformed to
specifications.
PharmaCompass’ review of the observations indicates that as inspectors start adopting a more standardized approach towards inspections, the problems they uncover across countries are along similar lines.
At PharmaCompass, we believe that a
review of our Mid-Year Non-Compliances in
2018 will provide you with the
insights necessary to prepare and insulate your business from the concerns
raised during regulatory inspections.
Click here to access all Mid-Year Non-Compliances
in 2018 (Excel version) for FREE!
Impressions: 9106
https://www.pharmacompass.com/radio-compass-blog/mid-2018-recap-of-warning-letters-import-alerts-and-non-compliances
#PharmaFlow by PHARMACOMPASS
26 Jul 2018
This week, PharmaCompass
reviews the recently released data on prescription drugs paid for under the
Medicare Part D Prescription Drug Program in the United States in calendar year
2016.
But first, let’s understand what is Medicare.
Medicare is the federal health insurance program in the US. In 2017, it covered 58.4 million people — 49.5 million aged 65 and older, and 8.9 million disabled.
Prescription drug coverage under this
program was started in 2006, and is known as Medicare Part D.
As part of this
coverage, the Centers for Medicare & Medicaid Services (CMS) contracts insurance
companies and other private companies, known as plan sponsors, that offer
prescription drug plans to their beneficiaries with varying drug coverage and
cost-sharing requirements.
In
2017, the Congressional Budget Office (CBO) had estimated that spending on
Medicare Part D would reach US$ 94 billion, or about 16 percent of all Medicare
expenditures for the year.
Click here to access the compilation of Medicare Part D
Prescriber Summary Report
According
to the CBO, Medicare Part D is the most significant expansion of the Medicare
program since it was created by Congress in 1965.
With
more than 1.48 billion claims from beneficiaries enrolled under the Part D
prescription drug benefit program under its umbrella, our analysis of Medicare
Part D provides valuable insights into how elderly Americans use prescription
drugs.
Top 10 drugs by
cost: The ones that bore the highest cost burden for Medicare
As in 2015, in 2016
too Gilead’s Hepatitis C treatment — Ledipasvir/Sofosbuvir (Harvoni) — remained the single drug highest payout under the Medicare Part D Prescription Drug Program with a total cost of US$ 4.4 billion.
As Gilead continued
to face competition from AbbVie and Merck in the Hepatitis C space, the spending on Harvoni was down
37 percent from US$ 7.03 billion in 2015.
Click here to access the compilation of Medicare Part D
Prescriber Summary Report
Celgene’s cancer treatment, Lenalidomide (Revlimid), Sanofi and Merck’s diabetes treatments and AstraZeneca’s Crestor (Rosuvastatin Calcium) for
cholesterol followed Harvoni. All together, they cost the Medicare program over US$ 10 billion.
Generic Name
Number of Medicare Part D Claims
Number of Medicare Beneficiaries
Number of Prescribers
Aggregate Cost Paid for Part D
Claims (In USD)
LEDIPASVIR/ SOFOSBUVIR (HARVONI)
141,665
52,782
12,097
4,398,534,465
LENALIDOMIDE
239,049
35,368
10,382
2,661,106,127
LANTUS SOLOSTAR (INSULIN
GLARGINE, HUM.REC.ANLOG )
5,028,485
1,075,248
245,447
2,526,048,766
SITAGLIPTIN PHOSPHATE
4,742,505
864,442
206,223
2,440,013,513
ROSUVASTATIN CALCIUM
6,012,444
1,560,050
249,981
2,322,724,007
FLUTICASONE/SALMETEROL
5,194,391
1,196,007
275,442
2,319,808,482
PREGABALIN
4,940,115
852,497
267,532
2,098,953,250
RIVAROXABAN
4,403,332
807,820
252,141
1,954,748,890
APIXABAN
4,455,782
826,969
231,631
1,926,107,484
TIOTROPIUM BROMIDE
4,153,162
903,494
235,564
1,818,857,361
Click here to access the compilation of Medicare Part D
Prescriber Summary Report
Top 10 drugs by claims: The most commonly
used drugs of 2016
With 46.6 million claims, the thyroid hormone deficiency treatment — Levothyroxine Sodium — retained its position of being the most claimed product under Medicare’s Part D Prescription Drug Program in 2016.
The number of
Medicare Part D claims includes original prescriptions and refills.
Following Levothyroxine Sodium was the lipid-lowering agent — Atorvastatin Calcium — which had 44.5 million Medicare Part D claims that
were filed by almost 9.4 million beneficiaries.
Generic
Name
Number
of Prescribers
Number
of Medicare Part D Claims
Number
of Medicare Beneficiaries
LEVOTHYROXINE SODIUM
669,999
46,617,109
8,091,785
ATORVASTATIN CALCIUM
494,973
44,595,686
9,435,633
AMLODIPINE BESYLATE
497,017
39,913,468
7,802,905
LISINOPRIL
490,452
39,469,840
8,009,954
OMEPRAZOLE
492,951
32,909,236
7,001,160
METFORMIN HCL
611,700
31,007,932
6,394,014
SIMVASTATIN
380,560
29,687,947
6,201,911
HYDROCODONE/ACETAMINOPHEN
660,617
28,595,150
7,265,882
FUROSEMIDE
488,352
27,878,243
5,421,598
GABAPENTIN
555,997
27,627,466
5,363,382
Click here
to access the compilation of Medicare Part D Prescriber Summary Report
Top 10 drugs by prescribers: Medicines that were most popular with
doctors
Among the prescribers, albuterol sulfate (salbutamol) and Diltiazem had
over 900,000 unique providers (or
doctors) prescribing the drug.
Albuterol (salbutamol) is
used to provide quick relief from wheezing and shortness
of breath while Diltiazem is used to prevent chest
pain (angina).
Also
on the list of popular drugs with prescribers is Hydrocodone-Acetaminophen.
With more doctors prescribing Hydrocodone-Acetaminophen (an
opioid) than commonly used antibiotics, such as Cephalexin, Ciprofloxacin and Amoxicillin, the
series of new FDA initiatives to combat the epidemic of opioid misuse and abuse
should change the position of opioids in the top 10 drugs by prescribers in the
coming years.
Click here to access the compilation of Medicare Part D
Prescriber Summary Report
Generic
Name
Number of
Prescribers
Number of
Medicare Part D Claims
Number of
Medicare Beneficiaries
ALBUTEROL SULFATE
985,427
13,100,354
5,417,718
DILTIAZEM HCL
931,159
8,142,004
1,982,550
POTASSIUM CHLORIDE
879,491
18,945,969
4,278,000
PEN NEEDLE, DIABETIC
677,210
5,281,778
1,795,046
LEVOTHYROXINE SODIUM
669,999
46,617,109
8,091,785
HYDROCODONE/ACETAMINOPHEN
660,617
28,595,150
7,265,882
METFORMIN HCL
611,700
31,007,932
6,394,014
CEPHALEXIN
597,647
5,603,879
3,933,373
CIPROFLOXACIN HCL
594,129
7,000,081
4,851,657
AZITHROMYCIN
591,028
7,958,625
5,734,122
What does the
future hold?
Although the Part D Prescriber PUF (public use file) has a wealth of information on payment and utilization for Medicare Part D prescriptions, the dataset has a number of limitations. Of particular importance is the fact that the data may not be representative of a physician’s entire practice or all of Medicare as it only includes information on beneficiaries enrolled in the Medicare Part D prescription drug program (i.e., approximately two-thirds of all Medicare beneficiaries).
Click here to access the compilation of Medicare Part D
Prescriber Summary Report
Last
month, the Office of the Inspector General (OIG)
reviewed
the Part D claims data for the years 2011 to 2015 for brand-name drugs.
The OIG’s report found that the total reimbursement for all brand-name drugs in Part D increased 77 percent from 2011 to 2015, despite a 17-percent decrease in the number of prescriptions for these drugs.
With soaring drug prices being an issue for
regular debate in the Unites States and President Trump announcing that his
team will use strategies to strengthen the negotiating powers under
Medicare Part D and Part B, it remains to be seen how the data on prescription drugs paid for under
the Medicare Part D Prescription Drug Program will change in the coming years.
Click here to access the compilation of Medicare Part D
Prescriber Summary Report
Impressions: 2454
https://www.pharmacompass.com/radio-compass-blog/analyzing-over-us-90-billion-of-medicare-prescription-drug-part-d-spending-in-2016
#PharmaFlow by PHARMACOMPASS
05 Jul 2018
In less than three weeks, Donald Trump will assume office as the
President of the United States. He has mentioned that he wants Medicare (a
national social insurance program) to directly negotiate the price it pays for prescription drugs.
Medicare provides health insurance to Americans aged 65 or more, who
have worked and paid into the system through the payroll tax. It also provides
health insurance to younger people with some disabilities or end-stage renal
disease and amyotrophic lateral sclerosis.
In 2015, Medicare provided health insurance to over 55 million Americans — including 46 million people aged 65 or more, and nine million younger people.
As we flag off the New Year, PharmaCompass
provides insights into drug prices and prescription patterns in the US in order
to help professionals make informed decisions. We believe that the cost of
medicines in the US, which have been a subject of much public outcry and
discussions in the recent years, will continue to be scrutinized during 2017.
Medicare data for 2014
Medicare Part D, also known as the Medicare prescription drug benefit — the program which subsidizes the costs of prescription drugs and prescription drug insurance premiums for Medicare beneficiaries — published a data set (for calendar year 2014) which contains information from over one million healthcare providers
who collectively prescribed approximately US $121 billion worth of prescription
drugs paid for under this program.
For each prescriber and drug, the dataset
includes the total number of prescriptions that were dispensed (including
original prescriptions and any refills), and the total drug cost.
The total drug cost includes the ingredient cost of the medication, dispensing fees, sales tax, and any applicable administration fees. It’s based on the amounts paid by the Part D plan, the Medicare beneficiary, other government subsidies, and any other third-party payers (such as employers and liability insurers).
The total drug cost does not reflect any manufacturer rebates paid to Part D plan sponsors through direct and indirect remuneration or point-of sale rebates. In order to protect the beneficiary’s privacy, the Centers for Medicare & Medicaid Services (CMS) did not
include information in cases where 10 or fewer prescriptions were dispensed.
Top
Ten Drugs by Cost, 2014 [Most expensive for Medicare]
Drug Name
Total Claim Count
Beneficiary Count
Prescriber Count
Total Drug Cost
Sofosbuvir
109,543
33,028
7,323
$3,106,589,192
Esomeprazole Magnesium
7,537,736
1,405,570
286,927
$2,660,052,054
Rosuvastatin Calcium
9,072,799
1,752,423
266,499
$2,543,475,142
Aripiprazole
2,963,457
405,048
130,933
$2,526,731,476
Fluticasone/Salmeterol
6,093,354
1,420,515
281,775
$2,276,060,161
Tiotropium Bromide
5,852,258
1,211,919
253,277
$2,158,219,163
Lantus
Solostar
(Insulin Glargine)
4,441,782
972,882
224,710
$2,016,728,436
Sitagliptin Phosphate
4,495,964
789,828
190,741
$1,775,094,282
Lantus
(Insulin Glargine)
4,284,173
787,077
223,502
$1,725,391,907
Lenalidomide
178,373
27,142
9,337
$1,671,610,362
View the Medicare Part D National Prescriber Summary Report, Calendar Year 2014 (Excel version available) for FREE!
Top
Ten Drugs by Average Cost per Claim, 2014 [Most expensive drugs]
Drug Name
Total Claim Count
Beneficiary Count
Prescriber Count
Total Drug Cost