Market Place
The coronavirus pandemic changed the way we lived our lives, and
regulatory agencies were no exception to that rule. In early March 2020, the US
Food and Drug Administration (FDA) announced that it was postponing most inspections outside the United States. And the agency said only foreign inspections “deemed mission-critical” will be considered on a case-by-case basis.
As an interim measure, the FDA ensured the safety of products imported into the US through physical examinations and/or product sampling at borders, by reviewing a firm’s compliance history and by requesting records “in advance of or in lieu of” on-site drug inspections.
By the end
of 2020, FDA and the European Directorate for the Quality of Medicines &
HealthCare (EDQM) had managed to complete over 2,200 inspections across the
world. According
to a report published on the Regulatory Affairs Professionals Society (RAPS)
website, across all approval types, the number of cases where pre-approval
inspections by the FDA were skipped in favor of alternative approaches rose
from 48 percent in July-September 2020 to 60 percent by October-December 2020.
Although inspections were down in 2020, the FDA’s Center for Drug Evaluation and Research (CDER) met its user fee commitments.
The FDA was the most active locally and issued almost 40 warning letters to drug manufacturers based in the US. Consistent with the previous years’ trend, warning letters in the US were followed by those issued to manufacturers in India (13) and China (7).
View cGMP Non-Compliance Recap 2020 Dashboard (Free Excel Available)
Celgene
investors lose out on deal sweetener due to FDA inspection delays
The
suspension of inspections impacted Bristol Myers Squibb
the most. It was hopeful of getting an FDA approval for its CAR-T therapy — lisocabtagene maraleucel (liso-cel) — for the treatment of adults with relapsed or refractory large B-cell lymphoma after at least two prior therapies. However, the FDA extended the action data by three months due to the pandemic, with no decision taken even after its November 2020 deadline.
The FDA
approval of liso-cel by December 31, 2020 was one of the milestones of the
contingent value rights (CVRs) issued upon the close of the Celgene acquisition by Bristol Myers
to its investors. Since the approval never came through by December-end, Celgene investors lost out on
the deal sweetener.
One of the
reasons for the delayed approval was the inspection of a Lonza
facility (which is under contract to make viral vectors for liso-cel) which was
finally inspected in December 2020. The Form 483 issued
last month revealed problems such as lack of storage
area controls and inadequate measures to prevent microbial contamination.
Liso-cel finally bagged the FDA nod this month.
View cGMP Non-Compliance Recap 2020 Dashboard (Free Excel Available)
Manufacturing problems, data-integrity issues drive Akorn to bankruptcy
Akorn, which has seen a series of
problems over the last few years, filed its Chapter 11 petition
in the Delaware bankruptcy court last year. The Illinois-based company listed
as much as US$ 10 billion in debt and US$ 10 billion in assets in its Chapter
11 petition.
The
drugmaker said it had given up on finding itself a
buyer amidst the uncertainties brought about by the pandemic.
In April 2018, Fresenius had walked away from a
US$ 4 billion takeover of Akorn, citing a breach of FDA’s data integrity requirements by Akorn. Its shareholders then sued Akorn for concealing data integrity problems. In August 2019, Akorn settled the matter with its shareholders.
Akorn has
received several FDA warning letters over the last few years, including
those issued to its Somerset (New Jersey) facility in June 2019, to its Decatur
(Illinois) facility in January 2019 and to its Amityville (New York) facility
in February 2019.
View cGMP Non-Compliance Recap 2020 Dashboard (Free Excel Available)
Ipca placed back on FDA import alert after US overcomes chloroquine shortage
In March 2020, when chloroquine (CQ) and hydroxychloroquine (HCQ) were considered
possible treatments for Covid-19, the FDA had partially lifted an import alert on Ipca’s two plants to ensure the supply of chloroquine tablets. The exemption had
allowed Ipca to export APls chloroquine phosphate and hydroxychloroquine sulfate from the company’s API manufacturing facility situated in Ratlam (Madhya Pradesh, India).
In June, once questions were raised around the efficacy of chloroquine in treating Covid, FDA said no shipment of API
chloroquine phosphate will be excluded from the import alert.
View cGMP Non-Compliance Recap 2020 Dashboard (Free Excel Available)
Data-integrity concerns at Pfizer’s India unit; warning letters to Mylan
In 2019,
when the mega-merger of Mylan with Upjohn (Pfizer’s off-patent branded and generic established medicines business) was announced, PharmaCompass had highlighted how compliance would play a key role in determining the merger’s success.
Early last
year, Pfizer’s sterile
manufacturing operations in India received a warning letter from
the FDA. The site, located in Visakhapatnam (Andhra Pradesh, India), was
inspected from August 29 to September 6, 2019.
The warning letter highlighted that Pfizer’s operations failed to conduct adequate investigations, including the timely implementation of effective corrective action and preventive action (CAPA) plans.
The Visakhapatnam operation was acquired by Pfizer in February 2015 as
part of its US$ 17 billion acquisition of Hospira. When the deal was struck, Pfizer was aware of Hospira’s manufacturing record as the company was issued FDA warning letters in four out of seven continents.
Last year, the FDA also issued a warning letter to Mylan's API
manufacturing facility in India
which had issues related to enhanced cross-contamination risk and inadequate
cleaning procedures.
View cGMP Non-Compliance Recap 2020 Dashboard (Free Excel Available)
Serious
cross-contamination problems at Cipla; data-integrity issues at Windlas
Indian drugmaker Cipla’s finished pharmaceuticals manufacturing facility in Goa received a 38-page Form 483 following a September 2019 inspection, and the warning letter issued to the facility
highlighted severe cross contamination concerns.
During the inspection, FDA investigators observed residue on manufacturing equipment which when tested by Cipla confirmed the presence of multiple APIs. In its warning letter, the agency states that there is no assurance that the scope of Cipla’s evaluation into this cross-contamination problem was comprehensive.
Following
the inspection, Cipla informed
the FDA of its decision to suspend production in its sterile units where the
FDA had raised concerns over atypical High Efficiency Particulate Air (HEPA)
filter failures.
The FDA
also issued a warning letter to Indian finished
formulation manufacturer Windlas Healthcare, which was placed on an import alert by
the FDA on January 21, 2020. Indian generic drugmakers Panacea Biotech and Shilpa Medicare
were also issued FDA warning letters in 2020.
View cGMP Non-Compliance Recap 2020 Dashboard (Free Excel Available)
Apotex’s API unit in Mexico receives FDA warning letter
The
manufacturing operations of Canadian generic drug maker, Apotex, continued to run into problems with the FDA as its API manufacturing facility in Mexico — Signa SA de CV — received a warning letter following
an inspection from December 16 to 20, 2019. As in previous cases, this
warning letter too highlighted cGMP deviations.
The key
concern highlighted by the FDA was that the facility undertook inadequate
investigations into out-of-specification (OOS) test results. The agency said
Signa failed to appropriately justify potential root causes, expand
investigations to all potentially affected batches, and implement adequate
CAPA.
View cGMP Non-Compliance Recap 2020 Dashboard (Free Excel Available)
Our view
Although
the FDA had halted all physical inspections last year due to the pandemic, last
month the agency announced the resumption of inspections
in China and India in a bid to keep drug approvals on schedule.
On
January 27, 2021, Patrizia Cavazzoni, the acting director of CDER, said in a tweet: “FDA has begun conducting prioritized inspections by investigator staff in China and is planning to initiate prioritized inspections in India shortly.”
Earlier
this month, Alembic Pharmaceuticals said the FDA has made five
observations post an inspection of its new injectable facility at Karkhadi
(Gujarat, India) from January 29 to February 5.
With the restart of inspections in Asia, it’s only a matter of time before we see a significant increase in regulatory actions by the regulators.
View cGMP Non-Compliance Recap 2020 Dashboard (Free Excel Available)
Impressions: 3548
https://www.pharmacompass.com/radio-compass-blog/cgmp-non-compliance-recap-2020
#PharmaFlow by PHARMACOMPASS
18 Feb 2021
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The year
2020 was an eventful year for the pharmaceutical industry, with several
companies across the world working at a feverish pace to find a treatment or a
vaccine for the raging Covid-19, which has so far taken over 1.79 million lives
worldwide.
With
countries imposing lockdowns and regulators putting on-site inspections on
hold, we were expecting far lower new drug approvals in mid-2020. But our mid-2020 recap published in July, which
looked at new drug approvals by the US Food and Drug Administration (FDA) and European Medical Agency (EMA),
found that the FDA had approved 33 new drugs by the end of June. This put the
approvals within the ballpark of the past two years.
This week, we bring you a roundup of 2020, a tumultuous year when 58 drugs (53 approvals by the Center for Drug Evaluation and Research and 5 by the Center for Biologics Evaluation and Research) bagged FDA’s new drug approvals. While this number is lower than the number of drugs approved in 2018 (62), it is higher than the number for 2019 (54). Out of this, while 23 approvals were in the field of oncology, 9 were for infectious diseases and infections, 8 for genetic diseases, 7 for neurology, 3 for immunology and 2 for gastroenterology.
View New Drug Approvals in 2020 with Estimated Sales (Free Excel Available)
A year marked by EUA
With the pandemic raging across the world, emergency use authorizations (EUAs) dominated news headlines in 2020 — the FDA issued 10 EUAs, with the most
prominent being those issued to Pfizer-BioNTech and Moderna for their Covid-19 vaccines.
EMA was busy as well since they issued 75 positive opinions
with Novartis leading
the pack with 8, followed by Pfizer and Sanofi which received 4 each.
The EUAs came with their own set of controversies. In March,
the FDA had issued an EUA “for oral formulations of chloroquine phosphate and hydroxychloroquine sulfate
for the treatment of” Covid-19. However, by June, FDA had revoked the EUA,
as the agency determined that chloroquine and
hydroxychloroquine were not likely to be effective in treating Covid-19 for the
authorized uses in the EUA.
Amongst treatments for Covid-19, in May the FDA
authorized the emergency use of Gilead’s antiviral
drug remdesivir. In our mid-2020 recap, Gilead’s remdesivir was on top of
our list of top-selling drugs after it received an EUA from the FDA.
In October, remdesivir became the first drug to
be approved by the FDA for treatment of Covid-19 patients requiring
hospitalization. While analysts predicted US$ 3.5 billion in revenue in early
October, the future of this drug as a treatment for Covid-19 in hospitalized
patients remains uncertain, especially in wake of results from the World Health
Organization (WHO)-led Solidarity Trial that said Gilead’s remdesivir
had little or no effect on the 28-day mortality or length of hospital
stays for Covid-19 patients. The FDA approved remdesivir for
hospitalized patients a week after the WHO results.
View New Drug Approvals in 2020 with Estimated Sales (Free Excel Available)
Gilead US$ 21 billion Immunomedics acquisition
Immunomedics' antibody-drug conjugate (ADC) — Trodelvy (sacituzumab govitecan-hziy) — was approved by the FDA in April this year for the treatment of adult patients with metastatic triple-negative breast cancer who have received at least two prior therapies for the disease. Such tumor types account for 15 to 20 percent of breast cancers. Trodelvy follows remdesivir in our list of FDA approved drugs in 2020 with the highest sales potential. The current forecast for Trodelvy sales is US$ 2.151 billion by 2026.
In
September, Gilead made a big move and acquired biotech company
Immunomedics Inc for US$ 21 billion. The
transaction, which was completed in October, will strengthen Gilead’s cancer portfolio and add another potential blockbuster to it.
Immunomedics
plans to submit a supplemental Biologics License Application (BLA) to support
full approval of Trodelvy in the US over the next quarter. According to a statement, Immunomedics
is also on track to file for regulatory approval of the drug in Europe in the
first half of 2021. Moreover, ongoing studies are also evaluating the potential
of Trodelvy as a treatment for non-small cell lung cancer and other types of
solid tumors.
View New Drug Approvals in 2020 with Estimated Sales (Free Excel Available)
Roche-PTC Therapeutics’ risdiplam bags approval
Following
Troveldy in sales potential for drugs approved by the FDA is Roche and PTC Therapeutics’ drug Evrysdi (risdiplam), the first oral medicine approved for the
rare genetic disease, spinal muscular atrophy, which until four years ago had
no available treatments.
The approval of Evrysdi presents patients and their families with a unique choice between a one-time gene therapy, an RNA-based drug infused three times a year at the doctor’s office and a daily medicine taken at home.
Roche priced the drug by patient weight, with a maximum cost of US$ 340,000 per year — substantially lesser than the competing (and approved) therapies from Biogen and Novartis.
View New Drug Approvals in 2020 with Estimated Sales (Free Excel Available)
Vertex’s Kaftrio bags EMA approval
Earlier
this year, PharmaCompass had published its compilation of sales
forecasts for the new drugs approved by the FDA in 2019. The list was led by Vertex’s cystic
fibrosis treatment — Trikafta — which was expected to have sales of US$ 3.935 billion by 2024.
Trikafta
is a combination of ivacaftor, tezacaftor and elexacaftor and its
stellar clinical data made the FDA approve the drug within three months of
Vertex’s application
filing and five months before FDA’s action date.
In
June 2020, EMA’s CHMP adopted a positive opinion, recommending the granting of a marketing authorization for
Vertex’s
combination, which will be marketed as Kaftrio.
View New Drug Approvals in 2020 with Estimated Sales (Free Excel Available)
A year
of multiple setbacks
Not everything went smoothly in 2020. In fact, the year saw several setbacks — almost 44 drugs were not granted approval by the FDA. Bristol Myers Squibb was one such company that
received setbacks. As part of Bristol’s US$ 74 billion acquisition of Celgene, the New
York-headquartered drug company offered Celgene shareholders Contingent Value Rights or
CVRs. But to realize the US$ 9-a piece payment, approvals for three
ex-Celgene drugs must meet their pre-specified deadlines.
While in March, the FDA approved Bristol’s ozanimod, a sphingosine-1-phosphate receptor agonist for the treatment of relapsing multiple sclerosis, well ahead of the December 31, 2020 deadline, in May, Bristol Myers Squibb and bluebird bio, Inc announced
that they have received a Refusal to File letter from FDA regarding the Biologics License Application (BLA) for their CAR-T therapy — idecabtagene vicleucel
(ide-cel) — for patients with heavily pre-treated relapsed and refractory multiple myeloma, which was submitted in March 2020. Upon preliminary review, the FDA
determined that the Chemistry, Manufacturing and Control (CMC) module of the
BLA requires further details to complete the review.
This was
followed by Bristol Myers announcing that the FDA has extended the action date
by three months for the BLA for lisocabtagene maraleucel (liso-cel), a
CD19-directed CAR-T therapy for the treatment of adults with relapsed or
refractory (R/R) large B-cell lymphoma after at least two prior therapies. The
FDA had then set the new Prescription Drug User Fee Act (PDUFA) action date as
November 16, 2020. However, on that day, FDA informed the company that its
review of the BLA for liso-cel will not be completed by November 16.
The FDA
approval of liso-cel by December 31, 2020 is one of the required remaining
milestones of the CVRs issued upon the close of the Celgene acquisition in the
fourth quarter of 2019. The other is FDA approval of ide-cel by March 31, 2021.
FDA declines approval to Novartis’ inclisiran: Recently, there was news that
the FDA declined to approve Swiss drugmaker Novartis AG’s lipid-lowering therapy, inclisiran (branded as Leqvio). The drug came to Novartis' fold through the
US$ 9.7 billion acquisition of The Medicines Company last year. The drug has been cleared by the European Commission.
In a statement, Novartis said the
FDA has not raised any concerns
related to the efficacy or safety of inclisiran. The complete
response letter (CRL) is due to unresolved facility inspection-related
conditions. No onsite inspection was conducted by the FDA, the company said.
View New Drug Approvals in 2020 with Estimated Sales (Free Excel Available)
Our
view
Like the
drug companies, regulators across the world also worked at a frenetic pace in
order to accelerate EUAs and drug approvals, especially for treatments and
vaccines for Covid-19.
Apart from
Covid-19, the year saw wider adoption and
approvals for cell and gene therapies along with approvals of several innovative medicines like relugolix (the first
oral gonadotropin-releasing hormone receptor antagonist for the treatment of
adult patients with advanced prostate cancer), berotralstat
the first oral once daily plasma kallikrein inhibitor to prevent attacks of
hereditary angioedema in adults and pediatric patients 12 years and older,
lumasiran (an HAO1-directed small interfering
ribonucleic acid indicated for the treatment of primary hyperoxaluria type 1 to lower urinary oxalate levels in pediatric and adult
patients) and osilodrostat for the treatment of adults with Cushing’s disease).
Moreover, there were several interesting ‘non-Covid’ medical breakthroughs that took place during 2020. One such breakthrough is a single pill that combines four medications meant to
lower blood pressure and cholesterol and aspirin that was found to cut the risk
of heart disease.
While the agility shown by pharma companies and regulators was
undoubtedly quite impressive, with many countries granting EUA to vaccines for
Covid-19, the ongoing pandemic did put mankind in a bind for several months.
And if the words of the WHO director general Tedros
Adhanom Ghebreyesus are to be believed, the
coronavirus crisis will not be the last pandemic and attempts to improve human health are “doomed” without tackling climate change and animal welfare.
If that really proves to be the case, the pharma industry has a lot to learn from this pandemic, and science has a lot to demonstrate if mankind is to emerge unscathed from such adversities.
View New Drug Approvals in 2020 with Estimated Sales (Free Excel Available)
Impressions: 6862
https://www.pharmacompass.com/radio-compass-blog/new-drugs-approvals-by-fda-and-ema-2020-recap
#PharmaFlow by PHARMACOMPASS
31 Dec 2020
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: 3585
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
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: 1614
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: 7620
https://www.pharmacompass.com/radio-compass-blog/hydroxychloroquine-hype-versus-reality
#PharmaFlow by PHARMACOMPASS
23 Mar 2020
This week, Phispers brings you news on J&J’s plans to acquire Actelion and Teva’s new medical cannabis inhaler due for launch in Israel. There are pharma deals from across the globe, such as Roche’s decision to sell its South Carolina plant and Catalent’s acquisition of Accucaps.M&A Compass: Roche sells API plant; Catalent laps up
Accucaps; Teva
announces layoffsSwiss drug maker Roche is selling its
active pharmaceutical ingredients (API) plant in South Carolina (US) to Patheon NV, a
leading global provider of high-quality drug development and delivery solutions
to the pharmaceutical and biopharma sectors. The deal will save 200 jobs in South Carolina. Patheon has also
entered into a multi-year supply arrangement with Roche. Meanwhile, Catalent, Inc has acquired Accucaps Industries Limited, a Canada-based developer and manufacturer of over-the-counter (OTC), high potency and conventional pharmaceutical softgels. The acquisition is subject to approval by the Canadian government. It will substantially complement Catalent’s global OTC and prescription pharmaceutical softgel capabilities and capacity.While Patheon and Catalent are making acquisitions, Teva
announced layoffs, and Pfizer cancelled its expansion plans in Ireland. Two
ministers of Malta announced that Teva
Pharmaceutical Industries will be laying off over 200 workers before the end of 2017.
Earlier this year, Teva had acquired Actavis Generics and recently informed the government of its decision to start “consolidating production” around its 30 plants in Europe and that it would also lay off workers in Malta.Meanwhile, Pfizer has cancelled a planned US $ 425 million
expansion of its Grange Castle plant in Dublin, a development which would have
led to permanent employment for 350 people and 1,250 jobs during construction.Pfizer is one of Ireland’s largest private sector employers. It had sought permission earlier this year for a major extension to the plant. However, the plans have been shelved due to failure of a high-profile, late-stage pipeline drug to lower cholesterol.Teva to market medical
cannabis inhaler in Israel
For the first time, the medical cannabis sector managed to comply with the pharmaceutical standards for inhalation. Israel’s Teva Pharmaceuticals has partnered with Tel Aviv-based Syqe Medical to market medical cannabis in Israel for pain management. The dose is administered with the help of an inhaler — the most efficient means of administering cannabis.Teva will be the exclusive marketer and distributor of the inhaler in Israel. The inhaler, which is pending approval from Israel’s ministry of health, will be available for home use.J&J approaches Actelion for acquisition; Actelion says no
guarantee of the deal
Last week, Switzerland’s leading biopharmaceutical company — Actelion Ltd — confirmed that it has been approached by the US healthcare titan Johnson & Johnson for a possible takeover. Actelion is focused on the
discovery, development and commercialization of innovative drugs, and is a
leader in the field of pulmonary arterial hypertension (PAH).However, Actelion said there is no guarantee of the deal. Actelion chief executive Jean-Paul Clozel desires
to keep the company independent after building it from scratch. And news
reports say J&J will have to pay a steep premium if a takeover is to
succeed.Actelion's rare-disease focus makes it an attractive target,
since its drugs face less price pressure than other more widely used medicines.
There are other reasons why the takeover looks improbable. First, Actelion’s market capitalization far outstrips its net present value. Second, President-elect Donald Trump’s proposed repatriation holiday may come in the way of J&J making the acquisition.Drugs in India fail quality standards; Vietnam bans major
Indian manufacturersThis was a bad week for Indian pharma. Drug regulators of seven
Indian states alleged that 27 medicines — sold by 18 major drug companies — are of “substandard” quality. These were cited with false labelling, wrong quantity of ingredients, discoloration, moisture formation, failing dissolution test and failing disintegration test.The tests on the 27 medicines were done by drug regulators of
Maharashtra, Karnataka, West Bengal, Goa, Gujarat, Kerala and Andhra Pradesh.
The drug makers include Abbott India, GSK India, Sun Pharma, Cipla and Glenmark Pharma, Alkem Labs, Cadila Healthcare, Emcure Pharma, Hetero Labs, Morepen Labs, Macleods Pharma, Wockhardt Pharma and Zydus Healthcare.The drug brands alleged to be substandard are: antipsychotic drug
Stemetil
and antibiotic drug Pentids
from Abbott India, anti-bacterial medicine Althrocin
by Alembic Pharma, migraine medication Vasograin by Cadila Pharma, cough syrup Ascoril by Glenmark Pharma, worm infection drug Zentel
by GSK India, arthritis medication Hydroxychloroquine
(HCQS) by Ipca Labs, anti-inflammatory medication Myoril
by Sanofi Synthelabo, and Torrent Pharma’s hypertension drug Dilzem.In Parliament, the minister of state for health said that drugs,
which are banned in other countries, have been allowed to be sold in India subject to
certain provisions. The drugs which have been allowed in India are nimesulide, analgin and pioglitazone. What was worse, Vietnam blacklisted 39 Indian drug companies,
including Aurobindo Pharma, Cadila and Macleods Pharmaceuticals for
quality standard violations. The Vietnamese drug regulator has also banned
companies in Bangladesh and South Korea. The regulator has listed the names of
blacklisted companies on its website.FDA’s quality metrics programme to be voluntary till 2018Last week, the US Food and Drug Administration (FDA) released a revised version of its proposal to
collect quality metrics data from drug manufacturers in response to protests
from the industry.As per the revised draft, the program will begin with a voluntary
phase that will run into 2018, after which the FDA intends to make the program mandatory.The revised draft guidance also narrows the scope of the program by
cutting the number of metrics the agency plans to ask for. It also grants more
flexibility with quality metrics to drug companies that are reporting by both
product and site."The revised draft guidance includes the following changes
from the earlier draft guidance: Adoption of a phased-in (voluntary) approach,
reduction in the number of data elements requested (i.e., reduction in
reporting burden), support for both product reports and site reports,
modifications to the quality metrics data definitions, addition of clarifying
examples for the definitions, addition of comment fields, and clarification of
special considerations for non-application and OTC (over-the-counter) product
reporting," the FDA said.EMA publishes results of two more clinical studiesThe European Medicines Agency (EMA) has published clinical data for two more medicines — Armisarte and Caspofungin — on its clinical data website. The clinical data website was launched on October 20, 2016, when the EMA had added clinical data for Kyprolis
and Zurampic.
The website is in line with the EMA’s policy on the publication of clinical data.Armisarte,
a hybrid product (a product that is similar to its reference product but is
available in a different pharmaceutical form), is indicated for the treatment
of malignant pleural mesothelioma lung cancer and advanced non-small-cell lung
cancer.Caspofungin Accord, a generic product, is indicated for the
treatment of invasive candidiasis, invasive aspergillosis and other fungal
infections when the patient is febrile and neutropenic.Pharmaceuticals most counterfeited category, says reportA new report cites pharmaceuticals as the most targeted category for
counterfeiting. Globalization and the booming use of the internet is giving a
boost to counterfeiting.The report has been launched by online brand protection firm, NetNames. Titled The Risks of
the Online Counterfeit Community, the report looks at online
counterfeiting. It warns that no brand can afford to underestimate the
sophistication of fraudsters in the digital world.The size of the counterfeit market for pharmaceuticals is
estimated at US $ 200 billion, followed by electronics (US $ 169 billion) and
food (US $ 49 billion). According to NetNames, one in six products bought online is fake. And one-third
of all counterfeit seizures in the EU are linked to internet distribution
channels.According to NetNames, there are up to 50,000 internet pharmacies
in operation. Around 95 per cent of
these do not comply with laws and industry standards. Meanwhile, 90 per cent of
drugs purchased online come from a different country than what the website
claims. According to the report, the internet provides counterfeiters
with anonymity, virtually no barriers to entry, low overheads, easier
distribution with more frequent, smaller consignments sent by mail, and fewer
risks of being caught. And the desire by consumers to seek out big brands
online at discount prices, is providing counterfeiters with a ready target
audience and the opportunity to further the fraudsters' reach and potential
profitability.Trump announces Tom Price as health secretaryThis week, America’s President-elect Donald Trump announced Republican US Representative Tom Price as his Health and Human Services
Secretary. Price is an orthopedic surgeon from Georgia.Seema Verma, the founder of a health policy consulting company,
will lead the Centres for Medicare and Medicaid Services, which is part of
Health and Human Services (HHS).Meanwhile, Trump is expected to name Steven Mnuchin, a former Goldman Sachs partner and Hollywood financier, as his nominee for the post of Treasury Secretary. Mnuchin, who spent 17 years at Goldman Sachs before leaving in 2002 to launch a hedge fund, served as Trump's campaign finance chairman. Billionaire investor Wilbur Ross, known for his investments in distressed industries, is expected to be named Commerce Secretary.
Impressions: 3269
https://www.pharmacompass.com/radio-compass-blog/teva-to-market-cannabis-inhaler-fda-makes-quality-metrics-voluntary
#PharmaFlow by PHARMACOMPASS
01 Dec 2016
Ipca Laboratories finished dosage facilities at Silvasa and
Pithampur (India) were put on the FDA Import Alert List this week, an outcome
of Ipca running into problems in yet another FDA inspection. The latest alert
comes after Ipca’s API facility in Ratlam (India) was banned from exporting to the
U.S. in January this year. However, when reviewing the details of Ipca’s alert,
is there a business opportunity which
can be capitalized upon?
The FDA Import Alert, while banning all imports from the Pithampur facility, has stopped everything coming out of the Silvasa plant except Hydroxychloroquine Sulfate & Propranolol Hydrochloride. Ipca’s Ratlam facility had received a similar exemption earlier for the following APIs: Sulfamethoxazole, Trimethoprim, Ondansetron, Hydroxychloroquine Sulfate, Propranolol Hydrochloride and Furosemide. Given all the details that have been published about the observations at Ipca’s various facilities, a complete shutdown of all imports into the U.S. would
have been expected.
Why did a few of Ipca’s products get an FDA import alert exemption?
Business Standard reported, at the time of covering the initial Ratlam ban that “Given the acute shortage in the US, the
FDA, however, has exempted four APIs from the import ban.” The article also mentions the market growth of Hydroxychloroquine from $30 million to $120 million in the last few years. While the FDA hasn’t yet put Hydroxychloroquine on their drug shortage list, concerns regarding supply
disruption are already being felt.
Wyeth’s branded Propranolol Hydrochloride was a $215 million product in 2006, before intense generic competition reduced the market to about 10% of its original size in less than two years. While almost every major generic company has some variant of Propranolol Hydrochloride on the market, the number of API suppliers are extremely limited. Pharma Compass’ database shows that
as Ipca, Albemarle (USA) and Cosmo Spa (Italy) are the only active Drug Master
Files in the FDA database, capacity expansion constraints in Europe and United
States could provide an opportunity for compliant API manufacturing of
Propranolol Hydrochloride.
With API manufacturers looking for new horizons, Ipca’s exemptions of old products like Sulfamethoxazole, Trimethoprim, Ondansetron, Hydroxychloroquine
Sulfate, Propranolol Hydrochloride and Furosemide should provide an manufacturing
and marketing opportunity worth examining.
Search our database for Sulfamethoxazole, Trimethoprim, Ondansetron, Hydroxychloroquine
Sulfate, Propranolol
Hydrochloride and Furosemide
to study the competitive landscape of manufacturers, pricing information and a
lot more.
Impressions: 4258
https://www.pharmacompass.com/radio-compass-blog/the-silver-lining-in-ipca-s-import-alert-blues
#PharmaFlow by PHARMACOMPASS
27 Mar 2015
Canada based, Concordia Healthcare continued their buying spree of old, established drug brands by announcing the acquisition of commercial assets of Covis Pharma S.a.r.l and Covis Injectables, S.a.r.l for US $1.2 billion in cash. The Covis deal comes right after Concordia’s $329 million purchase of Donnatal (belladonna alkaloids, phenobarbital) in May 2014.
Concordia’s buy makes them add to their existing portfolio, 18 high-margin, branded and authorized generic pharmaceutical products from private-equity backed, Swiss-based, Covis.
Authorized and branded generics of the following drugs are all part of the deal:
Nilandron®, for the treatment of metastatic prostate cancer
Dibenzyline®, for the treatment of pheochromocytoma (neuroendocrine tumor)
Lanoxin®, for the treatment of mild-to-moderate heart failure and atrial fibrillation
Plaquenil®, for the treatment of lupus and rheumatoid arthritis
Lanoxin, Dibenzyline and Plaquenil have been on the market in the United States for over 60 years
Covis 2014 revenues were between US$140 and $145 million with a 90% gross margin, while 38% of approximate Concordia’s US$ 120 million revenues came from Donnatal.
In their conference call, Concordia supported paying almost 8.5 times revenues with the following rationale:
Lanoxin (Digoxin) – API and Finished Dosage manufacturing challenges have resulted in market supply shortages and the potential FDA implementation of NTI (Narrow Therapeutic Index) for Lanoxin can represent a future upside to this business.
DiBenzyline (Phenoxybenzamine Hydrochloride) – is the preferred agent of choice with no generic competition. The opportunity exists to develop new orphan indications.
Plaquenil (Hydrochloroquine) – API supplier to Ranbaxy, which held 90% market share, exited the market in 2014 due to a voluntary market withdrawal and currently competitors are not positioned well to meet the existing demand.
Nilandron (Nilutamide) – absence of generic competition due to strict ANDA guidelines coupled with excellent payer coverage.
Covis’ 2014 revenues contributions were:
Lanoxin 25%
Dibenzyline 17%
Nilandron 16%
Plaquenil 15%
So while pharmaceutical companies are looking at next generation molecules to grow their revenue streams, a look back in time may provide some worthwhile opportunities.
Impressions: 4862
https://www.pharmacompass.com/radio-compass-blog/with-a-1-2-billion-buy-concordia-re-affirms-that-old-drugs-are-indeed-gold
#PharmaFlow by PHARMACOMPASS
10 Mar 2015
