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Top drugs and pharmaceutical companies of 2019 by revenues
Acquisitions and spin-offs dominated headlines in 2019 and the tone was set very early with Bristol-Myers Squibb acquiring New Jersey-based cancer drug company Celgene in a US$ 74 billion deal announced on January 3, 2019. After factoring in debt, the deal value ballooned to about US$ 95 billion, which according to data compiled by Refinitiv, made it the largest healthcare deal on record. In the summer, AbbVie Inc, which sells the world’s best-selling drug Humira, announced its acquisition of Allergan Plc, known for Botox and other cosmetic treatments, for US$ 63 billion. While the companies are still awaiting regulatory approval for their deal, with US$ 49 billion in combined 2019 revenues, the merged entity would rank amongst the biggest in the industry. View Our Interactive Dashboard on Top drugs by sales in 2019 (Free Excel Available) The big five by pharmaceutical sales — Pfizer, Roche, J&J, Novartis and Merck Pfizer continued to lead companies by pharmaceutical sales by reporting annual 2019 revenues of US$ 51.8 billion, a decrease of US$ 1.9 billion, or 4 percent, compared to 2018. The decline was primarily attributed to the loss of exclusivity of Lyrica in 2019, which witnessed its sales drop from US$ 5 billion in 2018 to US$ 3.3 billion in 2019. In 2018, Pfizer’s then incoming CEO Albert Bourla had mentioned that the company did not see the need for any large-scale M&A activity as Pfizer had “the best pipeline” in its history, which needed the company to focus on deploying its capital to keep its pipeline flowing and execute on its drug launches. Bourla stayed true to his word and barring the acquisition of Array Biopharma for US$ 11.4 billion and a spin-off to merge Upjohn, Pfizer’s off-patent branded and generic established medicines business with Mylan, there weren’t any other big ticket deals which were announced. The Upjohn-Mylan merged entity will be called Viatris and is expected to have 2020 revenues between US$ 19 and US$ 20 billion and could outpace Teva to become the largest generic company in the world, in term of revenues.  Novartis, which had followed Pfizer with the second largest revenues in the pharmaceutical industry in 2018, reported its first full year earnings after spinning off its Alcon eye care devices business division that had US$ 7.15 billion in 2018 sales. In 2019, Novartis slipped two spots in the ranking after reporting total sales of US$ 47.4 billion and its CEO Vas Narasimhan continued his deal-making spree by buying New Jersey-headquartered The Medicines Company (MedCo) for US$ 9.7 billion to acquire a late-stage cholesterol-lowering therapy named inclisiran. As Takeda Pharmaceutical Co was busy in 2019 on working to reduce its debt burden incurred due to its US$ 62 billion purchase of Shire Plc, which was announced in 2018, Novartis also purchased the eye-disease medicine, Xiidra, from the Japanese drugmaker for US$ 5.3 billion. Novartis’ management also spent a considerable part of 2019 dealing with data-integrity concerns which emerged from its 2018 buyout of AveXis, the gene-therapy maker Novartis had acquired for US$ 8.7 billion. The deal gave Novartis rights to Zolgensma, a novel treatment intended for children less than two years of age with the most severe form of spinal muscular atrophy (SMA). Priced at US$ 2.1 million, Zolgensma is currently the world’s most expensive drug. However, in a shocking announcement, a month after approving the drug, the US Food and Drug Administration (FDA) issued a press release on data accuracy issues as the agency was informed by AveXis that its personnel had manipulated data which the FDA used to evaluate product comparability and nonclinical (animal) pharmacology as part of the biologics license application (BLA), which was submitted and reviewed by the FDA. With US$ 50.0 billion (CHF 48.5 billion) in annual pharmaceutical sales, Swiss drugmaker Roche came in at number two position in 2019 as its sales grew 11 percent driven by its multiple sclerosis medicine Ocrevus, haemophilia drug Hemlibra and cancer medicines Tecentriq and Perjeta. Roche’s newly introduced medicines generated US$ 5.53 billion (CHF 5.4 billion) in growth, helping offset the impact of the competition from biosimilars for its three best-selling drugs MabThera/Rituxan, Herceptin and Avastin. In late 2019, after months of increased antitrust scrutiny, Roche completed its US$ 5.1 billion acquisition of Spark Therapeutics to strengthen its presence in gene therapy. Last year, J&J reported almost flat worldwide sales of US$ 82.1 billion. J&J’s pharmaceutical division generated US$ 42.20 billion and its medical devices and consumer health divisions brought in US$ 25.96 billion and US$ 13.89 billion respectively.  Since J&J’s consumer health division sells analgesics, digestive health along with beauty and oral care products, the US$ 5.43 billion in consumer health sales from over-the-counter drugs and women’s health products was only used in our assessment of J&J’s total pharmaceutical revenues. With combined pharmaceutical sales of US$ 47.63 billion, J&J made it to number three on our list. While the sales of products like Stelara, Darzalex, Imbruvica, Invega Sustenna drove J&J’s pharmaceutical business to grow by 4 percent over 2018, the firm had to contend with generic competition against key revenue contributors Remicade and Zytiga. US-headquartered Merck, which is known as MSD (short for Merck Sharp & Dohme) outside the United States and Canada, is set to significantly move up the rankings next year fueled by its cancer drug Keytruda, which witnessed a 55 percent increase in sales to US$ 11.1 billion. Merck reported total revenues of US$ 41.75 billion and also announced it will spin off its women’s health drugs, biosimilar drugs and older products to create a new pharmaceutical company with US$ 6.5 billion in annual revenues. The firm had anticipated 2020 sales between US$ 48.8 billion and US$  50.3 billion however this week it announced that the coronavirus  pandemic will reduce 2020 sales by more than $2 billion. View Our Interactive Dashboard on Top drugs by sales in 2019 (Free Excel Available)  Humira holds on to remain world’s best-selling drug AbbVie’s acquisition of Allergan comes as the firm faces the expiration of patent protection for Humira, which brought in a staggering US$ 19.2 billion in sales last year for the company. AbbVie has failed to successfully acquire or develop a major new product to replace the sales generated by its flagship drug. In 2019, Humira’s US revenues increased 8.6 percent to US$ 14.86 billion while internationally, due to biosimilar competition, the sales dropped 31.1 percent to US$ 4.30 billion. Bristol Myers Squibb’s Eliquis, which is also marketed by Pfizer, maintained its number two position and posted total sales of US$ 12.1 billion, a 23 percent increase over 2018. While Bristol Myers Squibb’s immunotherapy treatment Opdivo, sold in partnership with Ono in Japan, saw sales increase from US$ 7.57 billion to US$ 8.0 billion, the growth paled in comparison to the US$ 3.9 billion revenue increase of Opdivo’s key immunotherapy competitor Merck’s Keytruda. Keytruda took the number three spot in drug sales that previously belonged to Celgene’s Revlimid, which witnessed a sales decline from US$ 9.69 billion to US$ 9.4 billion. Cancer treatment Imbruvica, which is marketed by J&J and AbbVie, witnessed a 30 percent increase in sales. With US$ 8.1 billion in 2019 revenues, it took the number five position. View Our Interactive Dashboard on Top drugs by sales in 2019 (Free Excel Available) Vaccines – Covid-19 turns competitors into partners This year has been dominated by the single biggest health emergency in years — the novel coronavirus (Covid-19) pandemic. As drugs continue to fail to meet expectations, vaccine development has received a lot of attention.  GSK reported the highest vaccine sales of all drugmakers with total sales of US$ 8.4 billion (GBP 7.16 billion), a significant portion of its total sales of US$ 41.8 billion (GBP 33.754 billion).   US-based Merck’s vaccine division also reported a significant increase in sales to US$ 8.0 billion and in 2019 received FDA and EU approval to market its Ebola vaccine Ervebo. This is the first FDA-authorized vaccine against the deadly virus which causes hemorrhagic fever and spreads from person to person through direct contact with body fluids. Pfizer and Sanofi also reported an increase in their vaccine sales to US$ 6.4 billion and US$ 6.2 billion respectively and the Covid-19 pandemic has recently pushed drugmakers to move faster than ever before and has also converted competitors into partners. In a rare move, drug behemoths  — Sanofi and GlaxoSmithKline (GSK) —joined hands to develop a vaccine for the novel coronavirus. The two companies plan to start human trials in the second half of this year, and if things go right, they will file for potential approvals by the second half of 2021.  View Our Interactive Dashboard on Top drugs by sales in 2019 (Free Excel Available)  Our view Covid-19 has brought the world economy to a grinding halt and shifted the global attention to the pharmaceutical industry’s capability to deliver solutions to address this pandemic.  Our compilation shows that vaccines and drugs for infectious diseases currently form a tiny fraction of the total sales of pharmaceutical companies and few drugs against infectious diseases rank high on the sales list. This could well explain the limited range of options currently available to fight Covid-19. With the pandemic currently infecting over 3 million people spread across more than 200 countries, we can safely conclude that the scenario in 2020 will change substantially. And so should our compilation of top drugs for the year. View Our Interactive Dashboard on Top drugs by sales in 2019 (Free Excel Available)   

Impressions: 54653

https://www.pharmacompass.com/radio-compass-blog/top-drugs-and-pharmaceutical-companies-of-2019-by-revenues

#PharmaFlow by PHARMACOMPASS
29 Apr 2020
COVID-19: India restricts drug exports amid rising prices of essential bulk drugs; FDA announces first drug shortage
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: 8150

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

#Phispers by PHARMACOMPASS
04 Mar 2020
cGMP Non-Compliance Recap 2019
In 2019, concerns over quality of medicines continued to dominate news headlines. The ‘sartan’ recall saga, which was triggered in July 2018 after the European Medicines Agency (EMA) began reviewing medicines containing valsartan, for the presence of the carcinogenic impurity N-nitrosodimethylamine (NDMA), continued well through the year and had a major impact on the global pharmaceutical industry. View our Interactive 2019 cGMP Compliance Recap Dashboard (Free Excel Available) In 2019, French drugmaker Sanofi announced it would recall popular heartburn medicine Zantac in the United States and Canada, after medicines containing the active ingredient ranitidine were also linked with the presence of NDMA. Several generic drugmakers followed suit and as concerns mounted over cancer-causing impurities in commonly used antacid, diabetes and blood pressure medicines, the EMA’s human medicines committee (CHMP) requested that marketing authorization holders (MAHs) for human medicines containing chemically synthesized active substances review their medicines for the possible presence of nitrosamines and test all products at risk. The review will include all generics and over-the counter (OTC) products. View our Interactive 2019 cGMP Compliance Recap Dashboard (Free Excel Available)  In Spain, a drug mixup caused children to develop a form of werewolf syndrome (a rare and curious condition that causes excessive hair growth) after they were given a wrong medication to treat heartburn. Swiss drugmaker Novartis battled data manipulation allegations involving its US$ 2.1 million gene therapy Zolgensma and a new book titled ‘Bottle of Lies’, by investigative journalist Katherine Eban revealed how quality and efficacy of generic drugs is being compromised by companies in India and China, the two main countries that produce these drugs for the US consumer. The book release sent the FDA in damage control mode, with senior officials issuing statements supporting the agency’s generic drug framework. Inspection statistics PharmaCompass reviewed the FDA and EDQM’s inspection statistics for the calendar year 2019 and found that the FDA’s Drug Quality Assurance division conducted 1,138 inspections with 2,280 inspections being performed by the member states of the EDQM.  The FDA was the most active in the United States with 478 inspections followed by India where the inspection count was 193 and then in China where the count stood at 117. With regard to non-compliance, there were 73 inspections which were classified as OAI (6.4 percent of the total number of inspections) by the FDA while the EDQM issued 20 non-compliance reports (0.87 percent of all inspections).  The highest number of facilities which failed to meet FDA’s standards were in the United States (29), followed by India (18) and then China (13). From an inspection success rate perspective, firms in the United States passed 94 percent of their inspections while the success rates in India and China were 91 percent and 89 percent respectively. View our Interactive 2019 cGMP Compliance Recap Dashboard (Free Excel Available)  FDA investigators have identified persistent challenges while conducting foreign inspections, raising questions about the equivalence of foreign to domestic inspections. For example, while domestic inspections are almost always unannounced, FDA’s practice of pre-announcing foreign inspections up to 12 weeks in advance gives manufacturers the opportunity to fix problems.  A US Government Accountability Office preliminary analysis of FDA data revealed that from fiscal year 2012 through 2016, the number of foreign drug manufacturing establishment inspections increased. However, from fiscal year 2016 through 2018, both foreign and domestic inspections decreased—by about 10 percent and 13 percent, respectively. FDA officials attributed the decline, in part, to difficulty in filling jobs abroad and on the paucity of inspectors. View our Interactive 2019 cGMP Compliance Recap Dashboard (Free Excel Available) While the FDA is actively working on increasing the number of inspectors, according to FDA officials, it could take two to three years before the new staff is experienced enough to conduct foreign inspections. Concerns over manufacturing quality in India re-emerge In 2019, there was a surge of OAI classifications and FDA warning letters issued to the manufacturing sites of many major Indian pharmaceutical companies. The FDA issued warning letters to Aurobindo Pharma, Cadila Healthcare, Emcure Pharmaceuticals, Glenmark, Indoco Remedies, Jubilant, Lupin, Mylan, Strides and Torrent Pharmaceuticals. There are more warning letters expected as Form 483s issued after inspections at the facilities of Sun Pharma, Cipla and Lupin continue to reveal problems. View our Interactive 2019 cGMP Compliance Recap Dashboard (Free Excel Available)   The Form 483 issued by the FDA, following the inspection at Sun Pharma’s Halol facility, highlighted that Sun “failed to establish and implement controls which ensure data integrity” while Cipla’s finished pharmaceuticals manufacturing facility in Goa got classified as Official Action Indicated (OAI) by the FDA following a September 2019 inspection in which the FDA investigators had issued a 38-page Form 483. Regulatory actions lead to potential supply disruptions into US These regulatory actions have now begun to impact the supplies of generic pharmaceuticals into the United States. Injectable drugs, which constantly feature on the drug shortage list, had Cadila and Pfizer announce the discontinuation of their supplies to the United States. Following FDA’s warning letter to Cadila, the firm informed the FDA that it would permanently cease production of injectable drug products for the United States.  In 2019, Pfizer announced that two manufacturing sites in India, which it had acquired through its US$ 17 billion acquisition of Hospira, will cease manufacturing operations. The sites located near Chennai (Irungattukottai) and Aurangabad employed 1,700 people. View our Interactive 2019 cGMP Compliance Recap Dashboard (Free Excel Available) The Irungattukottai site received an FDA warning letter in 2013 and in 2016, Pfizer halted production at the plant after a PIC/S (short for Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme) joint inspection with regulators from four international agencies — MHRA (Medicines and Healthcare products Regulatory Agency of the UK), USFDA (United States Food and Drug Administration), TGA (Therapeutic Goods Administration of Australia) and Health Canada — found various quality control problems. Firms like Vital Laboratories and Alchymars ICM SM Private Limited, which had been issued warning letters in the past, were placed on import alert by the FDA. Concerns over operations at firms responsible for valsartan recalls The FDA and EDQM both raised concerns over the operations at Lantech Pharmaceuticals Limited, a firm which undertakes contract solvent recovery for valsartan API manufacturing operations. Solvents recovered by Lantech and samples collected from Lantech’s equipment were found to contain mutagenic impurities. Inspections at Lantech revealed that the firm failed to implement a procedure for investigating unknown peaks in recovered solvent chromatograms observed during analytical testing — an oversight which had led to the cancer-causing impurities not being detected in the ‘sartan’ APIs. View our Interactive 2019 cGMP Compliance Recap Dashboard (Free Excel Available) The FDA also raised data-integrity concerns at the facility as it was “routinely deleting recovered solvents gas chromatography (GC) data older than three months permanently, without any backup” and adequate controls. As a fallout of the “sartan” recall, warning letters were issued to Mylan and Jubilant over their valsartan manufacturing operations. Novartis’ data manipulation scandal In a shocking announcement, the US Food and Drug Administration (FDA) issued a press release on data accuracy issues with Novartis’ gene therapy — Zolgensma. Zolgensma was acquired by Novartis in April 2018 when in a bid to secure its leadership position in gene therapy, Novartis struck a deal to acquire Illinois-based AveXis Inc for US$ 8.7 billion. The gene therapy, intended to treat children less than two years of age with the most severe form of spinal muscular atrophy (SMA), is priced at US$ 2.1 million, making it the world’s most expensive drug. View our Interactive 2019 cGMP Compliance Recap Dashboard (Free Excel Available) On May 24, 2019, the FDA approved Zolgensma and a month later, on June 28, the agency was informed by AveXis (the product's manufacturer) that its personnel had manipulated data from an in-vivo murine potency assay. The FDA used this information to evaluate product comparability and nonclinical (animal) pharmacology as part of the biologics license application (BLA), which was submitted and reviewed by the FDA. According to information shared by the FDA, the product that was administered in the Phase 1 clinical trial was manufactured by a different process than the product that was administered in the Phase 3 clinical trial and the animal toxicology studies. Because the manufacturing processes were different, interpretation of the overall clinical trial and nonclinical study results depends on understanding the characteristics of the Phase 1 version of the product in relationship to the characteristics of the Phase 3 version of the product. View our Interactive 2019 cGMP Compliance Recap Dashboard (Free Excel Available) AveXis’ investigation report revealed that the firm became aware of the data manipulation as early as on March 14, 2019, more than two months prior to the BLA approval. However, AveXis did not inform the FDA of the issue until over a month after the BLA approval. If AveXis had informed FDA of this issue prior to the BLA approval, there was a possibility that the approval would have been delayed beyond the PDUFA goal date of May 31, 2019. The FDA assessment, however, stated that although the BLA would have eventually been approved, it is carefully assessing this situation and remains confident that Zolgensma should remain on the market. While managing the crisis, Novartis CEO Vas Narasimhan acknowledged that the company could have handled the furor surrounding Zolgensma better. Novartis’ AveXis fired its former chief scientific officer Brian Kaspar in connection with the data manipulation scandal, although Kaspar’s lawyer said he did nothing wrong and is ready to defend his name as needed. The Swiss drugmaker could face possible civil or criminal penalties, the FDA has said. Our view Over the past years, PharmaCompass has provided on-time coverage of quality concerns that have emerged at manufacturing operations around the world. With the widespread use of generic drugs and the majority of them being manufactured in India and China, data-integrity within manufacturing operations and assurance of product quality continue to remain key concerns. View our Interactive 2019 cGMP Compliance Recap Dashboard (Free Excel Available)   While streamlined, compliant operations still seem like a distant dream, in 2019, the former promoters of Ranbaxy, the Singh brothers were finally arrested for misappropriating funds. The legal action was in connection with their stake sale in the Indian drug behemoth to Japanese drugmaker Daiichi Sankyo for US$ 2.4 billion. The sale took place in 2008, months before the US Food and Drug Administration (FDA) banned imports from two of Ranbaxy’s Indian plants as a result of widespread data falsification by the firm. That was the start of troubles for the duo, as Daiichi later took them to court for allegedly suppressing and misrepresenting facts at the time of sale. We hope there is a lesson in this for the industry so that companies improve their practices of falsifying data and the focus shifts towards patient safety rather than minimizing cost and maximizing profit. View our Interactive 2019 cGMP Compliance Recap Dashboard (Free Excel Available)  

Impressions: 12558

https://www.pharmacompass.com/radio-compass-blog/cgmp-non-compliance-recap-2019

#PharmaFlow by PHARMACOMPASS
13 Feb 2020
DMF submissions in 2019: India maintains bulk drug supply supremacy to US
At PharmaCompass, we highlighted the significance of India in the global active pharmaceutical ingredient (API) supply chain last week with our list of generic drug facilities registered with the US Food and Drug Administration (FDA). Our compilation revealed that India had 182 generic drug facilities registered with the FDA and this number was nearly as much as the corresponding numbers for China (100) and United States (84) put together. These 182 facilities paid a fee of US$ 59,400 each to the FDA. View FDA DMF Filings in 2019 (Power BI Dashboard, Free Excel Available)  This week, we review the API Drug Master Files (DMFs) submitted to the FDA in 2019. Expectedly, India also led the DMF submission list.  In 2019, there were 616 active DMF submissions to the FDA with Indian companies submitting more than half (331) of them. Submissions from India were a little less than double the number of DMF submissions made by Chinese (113) and the US (57) firms put together. Drug master files (DMFs) are submissions made to the FDA by manufacturers by providing the agency with confidential, detailed information about facilities, processes, or articles used in manufacturing, processing, packaging, and storing of human drug products. View FDA DMF Filings in 2019 (Power BI Dashboard, Free Excel Available)  MSN Labs leads total count of DMF filings The 616 active DMF filings to the FDA were quite diverse — they covered over 400 products, and over half (322) the filings were for unique products.  Among the products with multiple DMF filings, Sugammadex Sodium topped the list as it had 18 DMF filings. Sugammadex is the API used in Merck’s Bridion for the reversal of neuromuscular blockade induced by rocuronium and vecuronium in general anesthesia. The other products with over five DMF filings were for the APIs of Lundbeck and Otsuka’s antipsychotic drug Brexpiprazole, Novartis, Gilead and Intercept’s blockbuster products Sacubitril-Valsartan, Tenofovir Alafenamide Fumarate and Obeticholic Acid. View FDA DMF Filings in 2019 (Power BI Dashboard, Free Excel Available)  The year 2019 also witnessed continued DMF filings for Rivaroxaban, Sitagliptin Phosphate, Ticagrelor and Tipiracil Hydrochloride. These filings indicate that the companies currently developing these products should brace themselves for intense competition in the near future. India’s MSN Labs continued to lead the count of total DMF filings with 42, of which it had 17 filings where it was the only one submitting a DMF for a specific product in 2019. The leading Chinese company filing DMFs was Fuxin Long Rui Pharmaceutical with nine DMFs, followed by Brightgene Bio-Medical Technology Co with five. The API DMF is part of the final generic drug product submission to the FDA. Therefore, the owner of a DMF incurs a one-time fee (US$ 55,013 for FY2019, US$ 57, 795 for FY2020) the first time the generic drug submission references that DMF. View FDA DMF Filings in 2019 (Power BI Dashboard, Free Excel Available)  DMF holders may also pay the fee in advance in order to have their DMF subjected to an initial completeness assessment by the FDA. This would allow their DMF to be included on a publicly-available list of DMFs that have paid their fee and not failed the initial completeness assessment.  Aurobindo, Sun, Lupin lead DMF assessments  While reviewing the DMF submissions made in 2019, we found that a third (209 out of 621) of the DMFs were listed on FDA’s publicly-available list of DMFs that have paid their fee and whose initial assessment had been completed. This indicates that either companies may have been unwilling to pay the fee or the FDA’s review process found shortcomings in their applications. Major Indian generic drug companies like Aurobindo (16), Sun Pharmaceuticals (13), MSN Labs (12), Lupin (7) and Macleods (7) led the list of companies that had the maximum DMF assessments completed for their 2019 submissions. There are also DMF submissions for products which can sometimes indicate future drug approvals. View FDA DMF Filings in 2019 (Power BI Dashboard, Free Excel Available)  Sanyo Chemicals submitted a DMF for Ibudilast, an anti-inflammatory drug whose oral capsules are used in Japan for the treatment of asthma and its ophthalmic solution is used to treat allergic conjunctivitis. The product is currently not approved in the United States. New drug approvals in the future can also be expected for Tertomotide, Omarigliptin, Estetrol Monohydrate, Abametapir, Pirenzepine, Cortexolone Proprionate, Lurbinectedin, Terlipressin, Ethyl Olivetolate, Remimazolam and Triapine. These products are currently under clinical trials for a variety of indications. Our view After compiling the list of companies that have submitted DMFs to the FDA as well as the generic facilities that paid their user fees, it’s clear that the API industry is beginning to find a new equilibrium.  View FDA DMF Filings in 2019 (Power BI Dashboard, Free Excel Available)  Our compilations of the previous years have shown that there is a steady decline in facility registrations and DMF filings. Given the increasing costs involved, as well as scaled up regulatory requirements, it seems that companies are becoming more selective in their product development decisions and also their willingness to do business in the United States. While the number of Indian API facilities registered with the FDA has remained relatively unchanged, the number of Chinese sites that registered with the US has reduced by 35 percent over the past five years. Several factors are changing the landscape of the generic drug industry. For instance, environmental regulations in China are driving up the cost of raw materials. Quality issues — such as the valsartan impurities case — have increased regulatory scrutiny. Moreover, passing inspections continues to remain a challenge for many manufacturers. And generic drug product manufacturers are also facing margin pressures, which in turn is driving a lot of M&A activity. Given this scenario, the generic industry should brace itself for more challenges in 2020. View FDA DMF Filings in 2019 (Power BI Dashboard, Free Excel Available)   

Impressions: 8210

https://www.pharmacompass.com/radio-compass-blog/dmf-submissions-in-2019-india-maintains-bulk-drug-supply-supremacy-to-us

#PharmaFlow by PHARMACOMPASS
23 Jan 2020
FDA bans import of all APIs from Zhejiang Huahai; EU issues non-compliance certificate
In case you thought the US Food and Drug Administration (FDA) and EU’s actions against China’s Zhejiang Huahai Pharmaceutical (ZHP) for supplying commonly used blood pressure medicine valsartan with cancer-causing impurities, were over, you may want to think again. Regulators in both US and Europe have stepped up action against ZHP. Last week, Phispers had reported how the US Food and Drug Administration (FDA) had posted an 11-observation, highly redacted Form 483 issued to ZHP (post an inspection of its active pharmaceutical ingredient facility) on its website on September 21, 2018. Post that, on September 28, 2018, the agency placed the firm on import alert to “protect US patients while the active pharmaceutical ingredient (API) manufacturer fully determines how impurities were introduced into its API and remediates its quality systems.” Similarly, European regulatory authorities issued Zhejiang Huahai a non-compliance certificate that prohibits the supply of valsartan and its intermediates to the EU market. Import alert at Huahai to impact global API landscape   In 2007, Huahai became the first Chinese pharmaceutical manufacturer to receive FDA approval for a finished drug product (nevirapine). It continues to rank amongst the top Chinese drug master file (DMF) filers with the FDA. As you are aware, in July this year, valsartan produced by ZHP was found to contain traces of N-nitrosodimethylamine (NDMA), a probable human carcinogen, due to a production change in 2012. The findings have prompted recalls in more than 50 countries. Last month, FDA’s testing of products showed an additional unexpected impurity in three lots of Torrent Pharmaceuticals’ recalled valsartan drug products. This second impurity — N-Nitrosodiethylamine (NDEA) — is a known animal and suspected human carcinogen. These Torrent products were included in the company’s recall. NDEA too was detected in valsartan made by ZHP using its previous manufacturing process, before changes were introduced in 2012. The FDA announcement issued last week said: “The import alert stops all API made by ZHP and finished drug products made using ZHP’s API from legally entering the United States.” An import alert at ZHP’s facility is likely to have a significant impact on the global API supply landscape. The FDA site shows 60 API DMFs of Huahai are Available for Reference for Generic Drug Applications in the United States. With each DMF assessment now requiring the applicant to submit a fee of US$ 55,013, the level of activity ZHP’s APIs generate in the US market and around the globe is significant. EU issues non-compliance report   The FDA’s actions against ZHP weren’t isolated as an inspection by EU authorities in collaboration with European Directorate for the Quality of Medicines (EDQM) found that ZHP did not comply with Good Manufacturing Practice (GMP) in the manufacturing of valsartan at the site in Linhai, China. The European inspection came after the suspension of the company’s CEP (a certificate of compliance with European standards for quality testing) for valsartan in July 2018. The inspection continued to focus on the manufacturing of valsartan. The September 2018 inspection by investigators from the Italian Ministry of Health found nine “major” and eight “other” deviations at ZHP. The European authorities found that the investigation conducted in the context of the NDMA/NDEA contamination of valsartan showed significant flaws. Moreover, the risk assessment performed in the context of the development/implementation of the optimized valsartan process, conducted in July/August 2018 (post the announcement of the recall) was also not satisfactory. The regulator also raised data-integrity concerns in relation to GC-FID (gas chromatograph-flame ionization detector) analysis and found that the company conducted inadequate investigation of unknown peaks detected in GC-MS (gas chromatography–mass spectrometry) analysis of batches of valsartan manufactured with the new process. While the company has already been prohibited to supply valsartan API to the EU market, the non-compliance report mentions that the EDQM should consider actions related to other valsartan CEPs in which Huahai is mentioned as an intermediate manufacturer. The non-compliance certificate also prohibits the supply of valsartan intermediates to the EU market. ‘The responsibility is on the manufacturer’   In addition to the FDA’s change control guidance document, which was published last month, the FDA highlighted that manufacturers must recognize “that it is their responsibility to develop and use suitable methods to detect impurities, including when they make changes to their manufacturing processes. If a manufacturer detects new or higher levels of impurities, they should fully evaluate the impurities and take action to ensure the product is safe.” While the FDA has not announced additional product recalls other than those already in place for valsartan medicines (and same is the case in the EU), it remains to be seen if the problems at Huahai create significant disruptions to the global API supply chain.  

Impressions: 4520

https://www.pharmacompass.com/radio-compass-blog/fda-bans-import-of-all-apis-from-zhejiang-huahai-eu-issues-non-compliance-certificate

#Phispers by PHARMACOMPASS
04 Oct 2018
Mid 2018 – Recap of Warning Letters, Import Alerts and Non-Compliances
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). Click here to access 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. Click here to access all Mid-Year Non-Compliances 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. Click here to access all Mid-Year Non-Compliances 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. Click here to access all Mid-Year Non-Compliances 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. Click here to access all Mid-Year Non-Compliances in 2018 (Excel version) for FREE! 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. Click here to access all Mid-Year Non-Compliances in 2018 (Excel version) for FREE! 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.” Click here to access all Mid-Year Non-Compliances in 2018 (Excel version) for FREE! 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. Click here to access all Mid-Year Non-Compliances in 2018 (Excel version) for FREE! 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. Click here to access all Mid-Year Non-Compliances in 2018 (Excel version) for FREE!   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. Click here to access all Mid-Year Non-Compliances in 2018 (Excel version) for FREE!   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: 9156

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#PharmaFlow by PHARMACOMPASS
26 Jul 2018
Trumpcare receives a blow; EMA to suspend 300 drugs due to clinical data integrity violations in India
This week, Phispers takes you to the US, where President Trump’s efforts to repeal and replace Obamacare received a setback. There is also news that the EMA has recommended suspending over 300 drugs due to data integrity concerns at a CRO based in Chennai — Micro Therapeutics — along with news on drug makers like Teva, Pfizer and Stada. Read on.   More scrutiny for Pfizer as injectable facility in India comes under FDA lens   Pfizer’s fill/finish manufacturing facility in the United States recently received a warning letter from the US Food and Drug Administration (USFDA). In February 2015, Pfizer had acquired the site in McPherson (Kansas) through its US $17 billion acquisition of Hospira. Pfizer was aware of Hospira's manufacturing record when it struck the deal, as the company was issued FDA warning letters on four of the seven continents — Europe, North America, Asia and Australia.  Last week, a Hospira facility in Visakhapatnam in India, set up to manufacture specialty injectables at an anticipated cost of US $375-450 million, received 11 observations from the US drug regulator. An inspection by the US FDA took place at the sterile injectables manufacturing unit between March 9 and 17 this year. An initial audit had taken place in 2015, during which 14 observations had been found. The company responded to the observations in March 2015 and submitted additional support documentation by the end of May 2015. “The inspection was found to be acceptable following the FDA's review of the company's responses and support documentation. The company has begun limited commercial production at the facility,” the company had said. The latest list of FDA observations includes three repeat observations related to air supply, air sampling and the root cause for microbial contamination. Last year, Pfizer had to halt production at its Chennai plant, which was also obtained as part of the Hospira acquisition, due to quality concerns. EMA endorses suspending 300 drugs due to clinical data integrity pitfalls   Late last year, the European Medicines Agency (EMA) had raised data-integrity concerns over another contract research organization (CRO) in India — Chennai-based, Micro Therapeutics Research Labs. The concerns had regulators reviewing the data of over 300 generic medicines being sold across Europe. Last week, the EMA announced it is recommending the suspension of more than 300 approvals and applications for generic drugs for which bio-equivalence studies were conducted at Micro Therapeutic Research Labs. The review concluded that data from studies conducted at two sites between June 2012 and June 2016 was “unreliable and cannot be accepted as a basis for marketing authorization in the EU.” However, there is no evidence of harm or lack of effectiveness of these medicines. EMA’s list of drugs it is recommending for suspension covers just about every EU member state, including Austria, Belgium, Czech Republic, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Norway, Portugal, Spain, The Netherlands and the UK. Generic drugs recommended for suspension include those being marketed by Novartis’ Sandoz, Sanofi’s Zentiva, Teva, Aurobindo Pharma and others. It includes dosage forms containing the active substances bupropion, voriconazole, betahistine, amlodipine/valsartan, tadalafil and naproxen. Though not a manufacturing compliance issue, clinical data-integrity has made headlines recently as labs across India had their data invalidated due to data-integrity concerns. Clinical trial falsification issues at the labs of Quest Life Sciences, GVK Biosciences, Alkem Laboratories, Semler Research Center and now Micro Therapeutics indicate that a sustained supply of generics can no longer be taken for granted. Struggling Teva to slash jobs to improve profitability   Things haven’t been going right for the Israeli generic drug giant Teva for quite sometime now. First, it’s CEO Erez Vigodman left the company. Second, its books were debt-ridden post the acquisition of Allergan Plc in July 2015. Third, its R&D has not seen a breakthrough in years. And now, Teva is said to be going in for major layoffs. The Israeli newspaper Calcalist reported that Teva is planning to cut 6,000 staffers (or 11 percent of its global workforce) after Passover. The company, however, denied this by saying it won’t layoff thousands. Instead, Teva said it is ending certain activities, consolidating operations and freezing new recruitments. “The efficiency program is an integral part of Teva’s business reality. The program includes, among other things, ending unprofitable activities and consolidating functions, in addition to freezing recruitment and natural employee turnover,” the company said. Teva is also looking for a new CEO to turn around the business after its US $ 40.5 billion acquisition of Allergan’s generic business pushed it into debt.  Trump's plan to repeal and replace Obamacare suffers a major setback   For seven years, the Republican Party has pursued repealing Obamacare like an obsession. But on Friday last, Speaker Paul Ryan and US President Donald Trump withdrew the bill at around 3.30 in the afternoon. Ryan could not bridge the ideological gap between the center and the far right within the Republican Party. The first presentation of Trumpcare couldn’t pass, as it was not sufficiently hard-hearted for the far-right members of the Freedom Caucus. But Trump and Ryan kept tweaking the bill to appease the hardliners. They even did away with the essential benefit guarantees that health insurance plans in American must now cover. And then the bill lost supporters at the center. The Bill fell short of around a dozen votes to get a winning vote count. The Congressional Budget Office had said the bill would deprive 24 million Americans of insurance coverage, while only saving the federal government US $ 151 billion. Meanwhile, Trump sought to spread blame for the failure of his first attempt at replacing Obamacare. He said: “Bad things are going to happen to Obamacare.  There's not much you can do to help it”. On Sunday morning, Trump wrote on Twitter: “Democrats are smiling in DC that the Freedom Caucus, with the help of Club for Growth and Heritage, have saved Planned Parenthood & Obamacare.” However, latest reports signal that Trump hasn’t given up hope. On Tuesday, he spoke to a  “semi-bipartisan”  group of Democratic and Republican senators and their spouses in the White House, where he signaled support for another run at a new GOP health care bill. Trump hopes a second go-around will be more successful. Stada CEO finds his car bugged amid takeover talks   Germany’s Manager Magazin reported last week that the chief executive of German drugmaker Stada — Matthias Wiedenfels — found a bugging device in his car. Stada has faced pressure to overhaul its strategy and has also received two takeover approaches. Wiedenfels, who became the CEO of Stada last summer, also received anonymous letters containing photographs that depict him in private or confidential business situations, the magazine said. The magazine, which did not cite sources or give information on those behind the bugging, said the incidents took place in the second half of 2016. Stada, however, did not comment on this report. Stada is the subject of takeover approaches from two private equity consortia. It has postponed the structured auction to give the bidders a chance to improve their offers which last valued the company at $3.9 billion. Over 1,100 drugs in Australia to become cheaper from next month   From April 1, millions of Australians will benefit from reduced prices of more than 1,100 medicine brands. Vital drugs have been added to Australia’s Pharmaceutical Benefits Scheme (PBS). The price of drugs used in conditions like high cholesterol, Parkinson’s disease, depression, breast cancer, eczema and psoriasis will cost lesser. For instance, 467,000 Australians using rosuvastatin for high cholesterol will save 22 percent per script. According to Australia’s Health Minister Greg Hunt, “sick Australians will save $500 million (US $ 383 million) over four years and up to $200 (US $ 153 million) a year each on the cost of medicines.” The country also plans to list new drugs on its PBS. These include drugs for two rare cancers — Hodgkin’s lymphoma, and an advanced type of skin cancer — and treatments for psoriasis, arthritis, schizophrenia and iron deficiency. Hunt said the savings for patients would be "considerable".  

Impressions: 2544

https://www.pharmacompass.com/radio-compass-blog/trumpcare-receives-a-blow-ema-to-suspend-300-drugs-due-to-clinical-data-integrity-violations-in-india

#Phispers by PHARMACOMPASS
30 Mar 2017
Will data integrity concerns on clinical trials done at GVK Biosciences go beyond Europe?
 Over 700 commonly used generic medicines were recommended for suspension by the European Medicines Agency (EMA) based on data integrity concerns, over clinical studies conducted at GVK Biosciences in Hyderabad, India.What will be the global fallout of the European decision? The European decision has impacted products from companies such as:Abbott Laboratories, Accord Healthcare (Intas), Actavis, Alembic, Apotex, Betapharm (Dr. Reddy’s), Brown & Burk UK, Fair Med Healthcare AG, Glenmark, Lupin, Micro Labs, Mylan, Orion Corporation, Ranbaxy, Ratiopharm, Sandoz, Sanofi-Aventis, Stada, Teva, Torrent, Wockhardt, Zydus… and many, many more.The original recommendation of suspending some of the medicines made in January 2015, was an outcome of an inspection of GVK Biosciences’ site in Hyderabad (GVK BIO is a Clinical Research Organization- CRO) by the French medicines agency (ANSM) through the EMA. The EMA stated in their official release: “The inspection revealed data manipulations of electrocardiograms (ECGs) during the conduct of some studies of generic medicines, which appeared to have taken place over a period of at least five years. Their systematic nature, the extended period of time during which they took place and the number of members of staff involved cast doubt on the integrity of the conduct of trials at the site.” 1000 drugs reviewed// 700 rejectedWhile over 1,000 pharmaceutical forms and strengths were reviewed at the GVK site, over 300 of them had sufficient supporting data available from other sources. As a result, these medicines were allowed to remain on the market in the EU.However, for the over 700 other medicines, the EMA after its second review, maintained its previous recommendation of January 2015, to suspend medicines, where no additional supporting data from other studies was available. Only one exception after that second review was spared from suspension, as the company was able to address the EMA’s concerns: it was Bivolet Nebivolol (5 mg tablets/ marketing authorisation holder: Neo Balkanika EOOD).While the agency noted that “there is no evidence of harm or lack of effectiveness linked to the conduct of studies by GVK Biosciences at Hyderabad. Some of these medicines may remain on the market” if they are of critical importance for patients. However, the recommendation will now be sent to the European Commission for a legally binding decision, which will apply to Member States regardless of the decision taken in the interim period.The updated list of medicines for which, the CHMP (Committee for Medicinal Products for Human Use) recommends suspension, is available on the EMA website. Companies are given 12 months to submit additional data. The potential global impact of the European suspensions?The GVK Biosciences scandal is almost as severe in magnitude and impact, as the data falsification concerns, which were discovered at Ranbaxy (Katherine Eban’s stunning investigation in Fortune, “Dirty Medicine” covers this extensively). One of the main promoters of GVK Biosciences is Mr. D.S. Brar who was CEO & Managing Director of Ranbaxy from 1999-2004. The impact of GVK Biosciences’ misdeeds is already being felt on new product launches. Mylan recently withdrew its European application for generic Abilify (aripiprazole) (2014 sales US$6.2x billion) citing “identification of major GCP issues (Good Clinical Practices).” What about the impact on the US market?In 2010, FDA discovered data integrity violations, which bankrupted clinical research organization, Cetero Research/PRACS. Based on the Cetero findings in the United States, the EMA suspended seven drugs. Now it remains to be seen, how the FDA will handle the data integrity concerns found in Europe since products like repaglinide & candesartan cilexitil (Mylan), levetiracetam (Dr. Reddy’s), clonazepam (Sandoz), metformin hydrochloride (Actavis), tacrolimus (Panacea Biotech) all have U.S. FDA approvals.  Leading GVK Biosciences’ defense is the Indian government, who warned last month that if the European Union does not reconsider their decision, it may go to the World Trade Organization. The Indian government’s position is based on an appeal by GVK Biosciences, which made the “Indian government set up a panel of experts last year to investigate the matter and found no manipulation”, GVK Biosciences CEO Manni Kantipudi told Reuters.However, globally reputed GMP expert, Lachman Consultants, believes that the GVK Bioscience episode “could potentially impact data integrity, similar to the Cetero/PRACS case”.It’s clear for us that this is not the end of the story… 

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https://www.pharmacompass.com/radio-compass-blog/will-data-integrity-concerns-on-clinical-trials-done-at-gvk-biosciences-go-beyond-europe

#Phispers by PHARMACOMPASS
28 May 2015
Dr. Reddy’s largest API facility maybe the next to get banned from exporting to the United States
Dr. Reddy’s largest active pharmaceutical ingredient (API) plant in Srikakulam (Andhra Pradesh, India) was inspected by the USFDA in November, 2014. The Srikakulam facility received nine inspectional observations and the company said, immediately after the inspection: “we will respond to the agency within stipulated timelines with our remedial plans and start implementing the necessary measures immediately”. The initial response indicated that the deficiencies at the Srikakulam plant were manageable. However, and in view of the recent USFDA import ban on the Ipca Laboratories’ facility in Pithampur (Madhya Pradesh - India), is it possible that Dr. Reddy’s Srikakulam facility could also be banned?  ENTER HEALTH CANADA The basis on which the USFDA could potentially ban the Dr. Reddy’s Srikakulam plant, is that the facilities of both Ipca and Dr. Reddy’s were put under an import ban on December 23, 2014 by Health Canada citing concerns of data integrity at both sites. Health Canada states in their release: “This action comes in light of recent information from a trusted regulatory partner that raises concerns about the reliability of the laboratory data generated at these sites.”  Health Canada also lists the products impacted by the quarantine to be Domperidone, Valsartan, Capecitabine, Naratriptan and Desloratadine. The Naratriptan ban is noteworthy as Teva & Sandoz, both who produce their product using Dr. Reddy’s API, are the only approved products on the Canadian market, and Naratriptan is now on the Canadian drug shortage list.  Following the Canadian alert, the Ministry of Health in the United Arab Emirates, also decided to stop the importation and distribution of the products from Ipca’s Pithampur and Dr. Reddy’s Srikakulam sites. US MARKET The magnitude of the inspection was revealed by Dr. Reddy’s Co-Chairman & CEO, GV Prasad, when interviewed by the business channel CNBC in January. He mentioned that the launch of both the generic Novartis’ Diovan (Valsartan - used to treat high blood pressure and congestive heart failure) and AstraZeneca’s Nexium (Esomperazole Magnesium – used to treat symptoms of conditions involving excessive stomach acid), would not occur unless the USFDA inspection report is closed. Almost immediately after the inspection, Dr. Reddy’s announced the possible shift of the manufacturing of some key products from Srikakulam; including Esomperazole Magnesium. Nexium sales in 2014 were $3.6 billion and currently only Teva’s subsidiary, Ivax, has an approved generic on the U.S. market ; so Esomperazole Magnesium is definitely a strategic growth driver for Dr. Reddy.  In view of all the available information, the challenges confronting Dr. Reddy’s Srikakulam facility are immense. However, Dr. Reddy’s has overcome an import alert for their Mexican facility in the past, and hopefully, will be able to overcome the problems at Srikakulam.  Also, a setback to Dr. Reddy’s, will further tarnish the image of the Indian pharmaceutical industry, which has had more than a dozen facilities receiving USFDA warning letters, because of data integrity concerns in the past two years.Click here to read the 9 observations at Dr. Reddy's Srikakulam API plant (source: Nomura).    

Impressions: 11179

https://www.pharmacompass.com/radio-compass-blog/dr-reddy-s-largest-api-facility-maybe-the-next-to-get-banned-from-exporting-to-the-united-states

#Phispers by PHARMACOMPASS
30 Mar 2015
USFDA observations at Dr. Reddy’s Srikakulam API plant
Update 2015 May 28:  Click here to see the orignal form 483 issued to Dr Reddy'sObservation 1Lab records don't include complete data derived from all tests. The inspectors indicate five instances where all the test failures were not documented and reported as per standard operating procedure (SOP). The reported results don’t contain the earlier sample analysis. Observation 2 The inspection highlights unauthorised access to computer system. An instance was noted where data was deleted by an unauthorised person. Observation 3 The Batch production and control records didn’t have the entries filled after each and every step as required by SOP. The data were filled simultaneously. Observation 4 Procedures regarding the issuance, revision, superseding and withdrawal of documents not followed. Observation 5 Water used in the manufacture of APIs is not established to be suitable for use. The microbiological test methods were not verified and validated. Observation 6 Record of training of operators not maintained properly. Observation 7 Failure to justify and follow up on deviations or batch failures: The inspectors made two observations where a batch has failed on certain parameters. Either the investigations are incomplete or the conclusion was not satisfactory. Observation 8 Process validations: The inspectors raised questions on the process validation approach that would ensure that the process can be performed effectively and reproduce the desired results. The inspectors highlight a case of significant numbers of reprocessing carried out by the company, raising questions on the process. Observation 9 Adequate and clean washing and toilet facilities are not provided for personnel. The inspectors highlight that toilet facilities are located at a long distance. Source: Nomura  

Impressions: 5507

https://www.pharmacompass.com/radio-compass-blog/usfda-observations-at-dr-reddy-s-srikakulam-api-plant

#Phispers by PHARMACOMPASS
30 Mar 2015
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