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Covid-19 HCQ update: Studies in France, Brazil, China raise more questions on its efficacy, safety

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.

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16 Apr 2020

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Chinese industrial activity revival at 98.6 percent, officials assure of API supplies

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.

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02 Apr 2020

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Hydroxychloroquine: Hype versus reality

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.

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23 Mar 2020

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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.

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04 Mar 2020

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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!

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26 Jul 2018

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Analyzing over US$ 90 billion of Medicare Prescription Drug (Part D) Spending in 2016

This week, PharmaCompass reviews the recently released data on prescription drugs paid for under the Medicare Part D Prescription Drug Program in the United States in calendar year 2016. But first, let’s understand what is Medicare. Medicare is the federal health insurance program in the US. In 2017, it covered 58.4 million people — 49.5 million aged 65 and older, and 8.9 million disabled. Prescription drug coverage under this program was started in 2006, and is known as Medicare Part D. As part of this coverage, the Centers for Medicare & Medicaid Services (CMS) contracts insurance companies and other private companies, known as plan sponsors, that offer prescription drug plans to their beneficiaries with varying drug coverage and cost-sharing requirements. In 2017, the Congressional Budget Office (CBO) had estimated that spending on Medicare Part D would reach US$ 94 billion, or about 16 percent of all Medicare expenditures for the year. Click here to access the compilation of Medicare Part D Prescriber Summary Report According to the CBO, Medicare Part D is the most significant expansion of the Medicare program since it was created by Congress in 1965. With more than 1.48 billion claims from beneficiaries enrolled under the Part D prescription drug benefit program under its umbrella, our analysis of Medicare Part D provides valuable insights into how elderly Americans use prescription drugs. Top 10 drugs by cost: The ones that bore the highest cost burden for Medicare As in 2015, in 2016 too Gilead’s Hepatitis C treatment — Ledipasvir/Sofosbuvir (Harvoni) — remained the single drug highest payout under the Medicare Part D Prescription Drug Program with a total cost of US$ 4.4 billion. As Gilead continued to face competition from AbbVie and Merck in the Hepatitis C space, the spending on Harvoni was down 37 percent from US$ 7.03 billion in 2015. Click here to access the compilation of Medicare Part D Prescriber Summary Report Celgene’s cancer treatment, Lenalidomide (Revlimid), Sanofi and Merck’s diabetes treatments and AstraZeneca’s Crestor (Rosuvastatin Calcium) for cholesterol followed Harvoni. All together, they cost the Medicare program over US$ 10 billion. Generic Name Number of Medicare Part D Claims Number of Medicare Beneficiaries Number of Prescribers Aggregate Cost Paid for Part D Claims (In USD) LEDIPASVIR/ SOFOSBUVIR (HARVONI) 141,665 52,782 12,097 4,398,534,465 LENALIDOMIDE 239,049 35,368 10,382 2,661,106,127 LANTUS SOLOSTAR (INSULIN GLARGINE, HUM.REC.ANLOG ) 5,028,485 1,075,248 245,447 2,526,048,766 SITAGLIPTIN PHOSPHATE 4,742,505 864,442 206,223 2,440,013,513 ROSUVASTATIN CALCIUM 6,012,444 1,560,050 249,981 2,322,724,007 FLUTICASONE/SALMETEROL 5,194,391 1,196,007 275,442 2,319,808,482 PREGABALIN 4,940,115 852,497 267,532 2,098,953,250 RIVAROXABAN 4,403,332 807,820 252,141 1,954,748,890 APIXABAN 4,455,782 826,969 231,631 1,926,107,484 TIOTROPIUM BROMIDE 4,153,162 903,494 235,564 1,818,857,361 Click here to access the compilation of Medicare Part D Prescriber Summary Report Top 10 drugs by claims: The most commonly used drugs of 2016 With 46.6 million claims, the thyroid hormone deficiency treatment — Levothyroxine Sodium — retained its position of being the most claimed product under Medicare’s Part D Prescription Drug Program in 2016. The number of Medicare Part D claims includes original prescriptions and refills. Following Levothyroxine Sodium was the lipid-lowering agent — Atorvastatin Calcium — which had 44.5 million Medicare Part D claims that were filed by almost 9.4 million beneficiaries. Generic Name Number of Prescribers Number of Medicare Part D Claims Number of Medicare Beneficiaries LEVOTHYROXINE SODIUM 669,999 46,617,109 8,091,785 ATORVASTATIN CALCIUM 494,973 44,595,686 9,435,633 AMLODIPINE BESYLATE 497,017 39,913,468 7,802,905 LISINOPRIL 490,452 39,469,840 8,009,954 OMEPRAZOLE 492,951 32,909,236 7,001,160 METFORMIN HCL 611,700 31,007,932 6,394,014 SIMVASTATIN 380,560 29,687,947 6,201,911 HYDROCODONE/ACETAMINOPHEN 660,617 28,595,150 7,265,882 FUROSEMIDE 488,352 27,878,243 5,421,598 GABAPENTIN 555,997 27,627,466 5,363,382 Click here to access the compilation of Medicare Part D Prescriber Summary Report Top 10 drugs by prescribers: Medicines that were most popular with doctors Among the prescribers, albuterol sulfate (salbutamol) and Diltiazem had over 900,000 unique providers (or doctors) prescribing the drug. Albuterol (salbutamol) is used to provide quick relief from wheezing and shortness of breath while Diltiazem is used to prevent chest pain (angina). Also on the list of popular drugs with prescribers is Hydrocodone-Acetaminophen. With more doctors prescribing Hydrocodone-Acetaminophen (an opioid) than commonly used antibiotics, such as Cephalexin, Ciprofloxacin and Amoxicillin, the series of new FDA initiatives to combat the epidemic of opioid misuse and abuse should change the position of opioids in the top 10 drugs by prescribers in the coming years. Click here to access the compilation of Medicare Part D Prescriber Summary Report Generic Name Number of Prescribers Number of Medicare Part D Claims Number of Medicare Beneficiaries ALBUTEROL SULFATE 985,427 13,100,354 5,417,718 DILTIAZEM HCL 931,159 8,142,004 1,982,550 POTASSIUM CHLORIDE 879,491 18,945,969 4,278,000 PEN NEEDLE, DIABETIC 677,210 5,281,778 1,795,046 LEVOTHYROXINE SODIUM 669,999 46,617,109 8,091,785 HYDROCODONE/ACETAMINOPHEN 660,617 28,595,150 7,265,882 METFORMIN HCL 611,700 31,007,932 6,394,014 CEPHALEXIN 597,647 5,603,879 3,933,373 CIPROFLOXACIN HCL 594,129 7,000,081 4,851,657 AZITHROMYCIN 591,028 7,958,625 5,734,122 What does the future hold? Although the Part D Prescriber PUF (public use file) has a wealth of information on payment and utilization for Medicare Part D prescriptions, the dataset has a number of limitations. Of particular importance is the fact that the data may not be representative of a physician’s entire practice or all of Medicare as it only includes information on beneficiaries enrolled in the Medicare Part D prescription drug program (i.e., approximately two-thirds of all Medicare beneficiaries). Click here to access the compilation of Medicare Part D Prescriber Summary Report Last month, the Office of the Inspector General (OIG) reviewed the Part D claims data for the years 2011 to 2015 for brand-name drugs. The OIG’s report found that the total reimbursement for all brand-name drugs in Part D increased 77 percent from 2011 to 2015, despite a 17-percent decrease in the number of prescriptions for these drugs. With soaring drug prices being an issue for regular debate in the Unites States and President Trump announcing that his team will use strategies to strengthen the negotiating powers under Medicare Part D and Part B, it remains to be seen how the data on prescription drugs paid for under the Medicare Part D Prescription Drug Program will change in the coming years. Click here to access the compilation of Medicare Part D Prescriber Summary Report

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05 Jul 2018

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Drug costs and prescription trends in the United States: Analyzing Medicare’s $121 billion spend

In less than three weeks, Donald Trump will assume office as the President of the United States. He has mentioned that he wants Medicare (a national social insurance program) to directly negotiate the price it pays for prescription drugs. Medicare provides health insurance to Americans aged 65 or more, who have worked and paid into the system through the payroll tax. It also provides health insurance to younger people with some disabilities or end-stage renal disease and amyotrophic lateral sclerosis. In 2015, Medicare provided health insurance to over 55 million Americans — including 46 million people aged 65 or more, and nine million younger people. As we flag off the New Year, PharmaCompass provides insights into drug prices and prescription patterns in the US in order to help professionals make informed decisions. We believe that the cost of medicines in the US, which have been a subject of much public outcry and discussions in the recent years, will continue to be scrutinized during 2017. Medicare data for 2014 Medicare Part D, also known as the Medicare prescription drug benefit — the program which subsidizes the costs of prescription drugs and prescription drug insurance premiums for Medicare beneficiaries — published a data set (for calendar year 2014) which contains information from over one million healthcare providers who collectively prescribed approximately US $121 billion worth of prescription drugs paid for under this program. For each prescriber and drug, the dataset includes the total number of prescriptions that were dispensed (including original prescriptions and any refills), and the total drug cost. The total drug cost includes the ingredient cost of the medication, dispensing fees, sales tax, and any applicable administration fees. It’s based on the amounts paid by the Part D plan, the Medicare beneficiary, other government subsidies, and any other third-party payers (such as employers and liability insurers). The total drug cost does not reflect any manufacturer rebates paid to Part D plan sponsors through direct and indirect remuneration or point-of sale rebates. In order to protect the beneficiary’s privacy, the Centers for Medicare & Medicaid Services (CMS) did not include information in cases where 10 or fewer prescriptions were dispensed. Top Ten Drugs by Cost, 2014 [Most expensive for Medicare] Drug Name Total Claim Count Beneficiary Count Prescriber Count Total Drug Cost Sofosbuvir 109,543 33,028 7,323 $3,106,589,192 Esomeprazole Magnesium 7,537,736 1,405,570 286,927 $2,660,052,054 Rosuvastatin Calcium 9,072,799 1,752,423 266,499 $2,543,475,142 Aripiprazole 2,963,457 405,048 130,933 $2,526,731,476 Fluticasone/Salmeterol 6,093,354 1,420,515 281,775 $2,276,060,161 Tiotropium Bromide 5,852,258 1,211,919 253,277 $2,158,219,163 Lantus Solostar (Insulin Glargine) 4,441,782 972,882 224,710 $2,016,728,436 Sitagliptin Phosphate 4,495,964 789,828 190,741 $1,775,094,282 Lantus (Insulin Glargine) 4,284,173 787,077 223,502 $1,725,391,907 Lenalidomide 178,373 27,142 9,337 $1,671,610,362 View the Medicare Part D National Prescriber Summary Report, Calendar Year 2014 (Excel version available) for FREE! Top Ten Drugs by Average Cost per Claim, 2014 [Most expensive drugs] Drug Name Total Claim Count Beneficiary Count Prescriber Count Total Drug Cost Average Cost Per Claim Adagen 13 $1,224,835 $94,218 Elaprase 100 $6,560,225 $65,602 Cinryze 1,820 194 196 $96,155,785 $52,833 Carbaglu 60 $2,901,115 $48,352 Naglazyme 129 $6,189,045 $47,977 Berinert 538 73 68 $25,685,311 $47,742 Firazyr 1,568 269 232 $70,948,143 $45,248 H.P. Acthar 9,611 2,932 1,621 $391,189,653 $40,702 Procysbi 314 41 47 $12,542,911 $39,946 Folotyn 15 $598,210 $39,881 Top Ten Drugs by Claims, 2014 [Most Commonly Used by Patients] Generic Name Total Claim Count Beneficiary Count Prescriber Count Total Drug Cost Lisinopril 38,278,860 7,454,940 464,747 $281,614,340 Levothyroxine Sodium 37,711,869 6,245,507 416,518 $631,855,415 Amlodipine Besylate 36,344,166 6,750,062 451,350 $303,779,661 Simvastatin 34,092,548 6,768,159 387,651 $346,677,118 Hydrocodone-Acetaminophen 33,446,696 8,005,790 677,865 $676,296,988 Omeprazole 33,032,770 6,707,964 475,122 $529,050,385 Atorvastatin Calcium 32,603,055 6,740,061 419,327 $747,635,818 Furosemide 27,133,430 5,176,582 456,047 $135,710,772 Metformin HCl 23,475,787 4,509,978 364,273 $203,948,989 Gabapentin 22,143,641 4,298,609 486,754 $492,557,255 View the Medicare Part D National Prescriber Summary Report, Calendar Year 2014 (Excel version available) for FREE! Top Ten Drugs by Prescribers, 2014 [Most Popular with Doctors] Generic Name Total Claim Count Beneficiary Count Prescriber Count Total Drug Cost Hydrocodone/Acetaminophen 33,446,696 8,005,790 677,865 $676,296,988 Ciprofloxacin HCl 7,253,018 4,926,835 568,201 $46,728,353 Amoxicillin 6,298,980 4,384,899 557,614 $31,193,739 Cephalexin 5,040,219 3,529,303 557,048 $36,987,401 Azithromycin 7,339,954 5,274,010 544,625 $70,699,119 Prednisone 11,032,986 4,505,821 536,108 $86,537,932 Tramadol HCl 14,250,227 4,272,724 515,816 $125,343,514 Sulfamethoxazole /Trimethoprim 4,833,758 3,090,944 500,790 $29,231,511 Gabapentin 22,143,641 4,298,609 486,754 $492,557,255 Amoxicillin/Potassium Clav 3,551,452 2,710,244 478,361 $61,713,432 The findings from CMS data The CY 2014 data represented a 17 percent increase compared to the 2013 data set and a substantial part of the total estimated prescription drug spending (as estimated by the Department of Health and Human Services Office of the Assistant Secretary for Planning and Evaluation, or ASPE) in the United States — at about US $ 457 billion in 2015, which was 16.7 percent of the overall personal healthcare services. Of that US $ 457 billion, US $ 328 billion (71.9 percent) was for retail drugs and US $ 128 billion (28.1 percent) was for non-retail drugs. The drug pricing process in the US is complex and reflects the influence of numerous factors, including manufacturer list prices, confidential negotiated discounts and rebates, insurance plan benefit designs, and patient choices. An IMS study found that across 12 therapy classes widely used in Medicare Part D, medicine costs to plans and patients in Medicare Part D are 35 percent below list prices. View the Medicare Part D National Prescriber Summary Report, Calendar Year 2014 (Excel version available) for FREE! While the CMS does not currently have an established formulary, Part D drug coverage excludes drugs not approved by the US Food and Drug Administration, those prescribed for off-label use, drugs not available by prescription for purchase in the US, and drugs for which payments would be available under Parts A or B of Medicare. Part D coverage excludes drugs or classes of drugs excluded from Medicaid coverage, such as: Drugs used for anorexia, weight loss, or weight gain Drugs used to promote fertility Drugs used for erectile dysfunction Drugs used for cosmetic purposes (hair growth, etc.) Drugs used for the symptomatic relief of cough and colds Prescription vitamins and mineral products, except prenatal vitamins and fluoride preparations Drugs where the manufacturer requires (as a condition of sale) any associated tests or monitoring services to be purchased exclusively from that manufacturer or its designee Our view The Medicare program is designed such that the federal government is not permitted to negotiate prices of drugs with the drug companies, as federal agencies do under other programs. For instance, the Department of Veterans Affairs — which is allowed to negotiate drug prices and establish a formulary — has been estimated to pay (on an average) between 40 to 58 percent less for drugs, as opposed to Medicare Part D. If Trump administration kick starts direct negotiations on Medicare drug prices with drug companies, 2017 will surely turn out to be a year for the pharmaceutical industry to remember. View the Medicare Part D National Prescriber Summary Report, Calendar Year 2014 (Excel version available) for FREE!

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05 Jan 2017

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China shuts plants of major antibiotic producers to fight pollution; more troubles for Teva

This week, Phispers has lots on generics. While the global leader Teva has more troubles at hand, generic players in the US face fresh lawsuits, and Sanofi plans to sell its European generic unit. There is also talk of Novartis buying America’s generic-drugs maker Amneal. In other news, oncologists find problem with clinical trials, and China shuts plants to curb pollution Teva braces declining sales, lawsuits and closure of its Mexico plant There is more bad news from Israel’s Teva Pharmaceutical Industries. First, its Rimsa plant in Mexico is said to be shut, and a lot of employees have been (reportedly) laid off. As per a news report, it’s difficult to make the Rimsa plant operational anytime soon. Teva had invested US $ 2.3 billion in the facility. There are reports that the company may make a write-down on its investment in Rimsa. In September, the global leader in generics had claimed that the Espinosa brothers, who had controlled Rimsa until its sale to Teva, had deceived the regulatory authorities and patients for years and sold defective and illegal drugs. Teva’s troubles don’t end there. The company is also setting aside US $ 520 million in its bid to settle allegations of paying bribes in Russia, Mexico and Ukraine. In its latest earnings report released Tuesday, Teva noted that “advanced discussions” are under way with the federal courts in the US to resolve the incidents, which took place between 2007 and 2013. Teva has completed 12 acquisitions worth US $ 46 billion in the last four years. Teva’s blockbuster Copaxone, which brings in 19 percent of its overall sales, has lost several patent challenges in the US and is likely to face generic competition early next year, putting more than US $ 4 billion in sales at risk. Even without a generic competitor, sales declined 2.2 percent year-on-year in the third quarter this year. To control pollution, north China industrial hub curbs drug production If you live in Delhi, and are coping with the hazardous pollution levels, here’s something that will interest you. A wide-ranging ban has been imposed in a northern Chinese industrial hub on production at drug plants, steel mills and other businesses. This is a last-ditch attempt by the government of Shijiazhuang city to meet this year’s pollution control target — to reduce the levels of PM 2.5 (fine particles that pose a risk to human health) by 10 percent. Shijiazhuang is the capital of the northern Hebei province, which reported economic growth of 6.8 percent in the first three quarters of this year. Last week, the government of Shijiazhuang city said for the remaining 45 days of the year, it will curb output at thermal power plants, halt all production at industries such as steel and cement, and limit manufacturing of pharmaceuticals, chemicals and even furniture. In 2014, President Xi Jinping had responded to public outrage over high smog levels. As a result, local officials are trying hard to strike a balance between pollution control and economic growth. Shijiazhuang is home to major active pharmaceutical ingredient (API) producers such as North China Pharmaceutical, CSPC Zhongnuo Pharmaceutical, CSPC Ouyi Pharmaceutical and many others. These companies are critical to the global antibiotic supply chain as they provide the building blocks for antibiotic manufacturing, such as 6-APA and 7-ACA, along with commonly used antibiotics such as Penicillin, Amoxicillin, Amipicillin and Azithromycin. PharmaCompass has been routinely covering the Chinese bulk drug industry and its impact on the environment. In April this year, PharmaCompass had reported how school children in China were wearing gas masks due to pollution concerns. And prior to that, we had carried an article on how dependent the world has become on bulk drugs from China. More trouble for generic drug-makers in the US as unions file lawsuits In a fresh salvo at the generic drug industry, a union representing sergeants of the New York Police Department is attempting to hit some companies with civil penalties. The generic industry is already facing charges from a two-year US Justice Department antitrust probe. The union has filed two lawsuits against two groups of drug-makers, which includes Novartis AG’s generic drug unit, Ireland-based Perrigo Co., India’s Wockhardt and Taro Pharmaceutical Industries (Israeli subsidiary of India’s Sun Pharma). The union has alleged that the companies colluded to raise prices of two dermatological creams by as much as 1,000 percent since 2013. Besides this, at least four other unions have filed lawsuits of their own, with two of them adding Actavis Inc., acquired in August by Teva, to the list of defendants. All the unions manage health benefits for their members. The unions say they overpaid for the drugs due to the price collusion. They point to data that the drug-makers took price hikes on certain medicines by nearly the same amounts within months of each other. A lawyer for the New York sergeants’ union said he expects a judge will call a conference in December to decide if the cases can be combined. Novartis may buy generic drug-maker Amneal for US $ 8 billion Swiss healthcare major Novartis AG is in talks to acquire American generic-drugs maker Amneal Pharmaceuticals. Through this acquisition, Novartis plans to strengthen its Sandoz business. According to Bloomberg, Novartis and Amneal may reach an agreement soon. Amneal makes the antiviral acyclovir (to treat herpes) and gabapentin (for epilepsy and pain). The acquisition could cost Novartis around US $ 8 billion. Amneal is a family-owned business led by co-founders Chintu and Chirag Patel and has operations in North America, Australia, Europe and Asia. Its portfolio of generic treatments includes around 115 approved molecules in the US. Sanofi to sell off European generic drug unit French drug maker Sanofi confirmed it has decided to sell off its generic drug unit in Europe. The decision will affect two manufacturing plants in the Czech Republic and Romania. Sanofi CEO Olivier Brandicourt recently informed investors that the company has “made a definitive decision to initiate a carve-out process and divest the generics portfolio in Europe.” The move is part of the company’s 2020 strategic roadmap. He, however, did not provide details. Sanofi had acquired Zentiva, a Czech generic business, in 2008 for US $ 2.6 billion. And Sanofi’s generic business is centered around this acquisition. The business is particularly strong in the Czech Republic, Romania and Turkey. On Monday, Zentiva Romania informed the Bucharest Stock Exchange that its majority shareholder Sanofi has decided to sell its Romanian generic drug plant as part of a major divestment plan of its EU generic drugs business. A company spokesperson said the planned scope of the divestment is the generics business “related to Europe,” so it excludes Russia, the Commonwealth of Independent States (CIS) and Turkey. And it includes the two “dedicated manufacturing sites producing and distributing generics for the European market,” one in Prague (Czech Republic), and the other in Bucharest (Romania). Former Valeant executives arrested for fraud Last week, two former executives of Valeant Pharmaceuticals — Gary Tanner and Andrew Davenport, who had been the CEO of Philidor — were arrested on charges of running a fraud scheme that swindled millions of dollars out of Valeant. The fraud was allegedly conducted with the help of a mail-order pharmacy, that is now defunct. According to Preet Bharara, US Attorney for the Southern District of New York, the arrests were part of an ongoing probe of the scheme. The criminal complaint alleges that Tanner and Davenport conspired to enrich themselves with Valeant funds. The two helped Valeant set up Philidor in early 2013, which was primarily a vehicle to market and distribute Valeant drugs. According to the complaint, Tanner focused on building Philidor’s business, resisted his superiors’ directives to line up other distributors for Valeant’s products and ultimately received a US $10 million kickback from Davenport. The complaint alleges that in 2014, the two orchestrated Valeant’s agreement to buy an option to purchase Philidor, which cost Valeant at least US $ 133 million. More than US $ 40 million of that went to shell companies controlled by Davenport. One such shell company — called ‘End Game LP — gave a kickback of US $10 million to Tanner. Homeopathy products in the US may carry caveats soon In a report on homeopathic advertising, the Federal Trade Commission (FTC) in the US said that homeopathic drugs should “be held to the same truth-in-advertising standards as other products claiming health benefits.” Only the US Food and Drug Administration (FDA) can prevent homeopathic marketers from selling their products. The FTC has no teeth in the matter. But very soon, homeopathic products could include statements such as ‘there is no scientific evidence backing homeopathic health claims’ and ‘homeopathic claims are based only on theories from the 1700s that are not accepted by modern medical experts.’ However, this may not affect sales of homeopathic products. There are claims that such statements could backfire because homeopaths and those who believe in homoeopathy don’t trust modern medicine. They could also believe that if homeopathy has been around for that long, it must work. This is not the first-time homeopathic medicines would carry caveats. In 1988, the FDA had struck a deal where it agreed that homeopaths could be self-regulating, if they include a disclaimer that their claims haven’t been evaluated by the FDA. In February this year, PharmaCompass had carried a news nugget on Professor Paul Glasziou, a leading academic in evidence-based medicine at Bond University, who had declared homeopathy as a “therapeutic dead-end” after a systematic review concluded the controversial treatment was no more effective than placebo drugs. Cancer clinical trials exaggerate benefits of new drugs, say oncologists Two cancer physicians argue that large clinical trials — required for approval of new cancer drugs in the US — often overstate the effectiveness of the treatment in the real world. During cancer clinical trials, some volunteers take the experimental drug, while others receive standard care with existing drugs. The groups are then compared to see if their tumors have shrunk, how long it takes for the tumors to return, and how long do the patients survive. This way, the trial sees whether the experimental drug is safe and effective and can be sold to patients in the US. The process is based on the premise that trials give an accurate indication of safety and efficacy among cancer patients in general, and not only those who are eligible for and selected for the trial. The trouble is, participants in clinical trials are unlike the overall cancer population, point out oncologists Dr. Sham Mailankody of Memorial Sloan Kettering Cancer Center and Dr. Vinay Prasad of the Oregon Health and Science University in JAMA Oncology. They’re younger, healthier, wealthier, better plugged in to the healthcare system, and better educated. According to these oncologists, if cancer patients are similar in age, socio-economic status, have presence of other (similar) illnesses, and other characteristics as those in a clinical trial, they might do as well. But for everyone else, the trial results probably promise more than the drug can deliver.

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24 Nov 2016

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Sandoz, Mylan, Hetero, Lupin face the heat due to data manipulation at Semler

In April 2016, the US Food and Drug Administration (FDA) came down heavily on Semler Research Center over issues of data manipulation. The FDA had told drug firms that their applications seeking approvals on the basis of studies done by the Bangalore-based firm will not be accepted. It had also asked firms to furnish additional clinical research from other approved entities to get the FDA nod.The action had been taken as a result of an inspection of Semler's bioanalytical facility in Bangalore conducted between September 29, 2015, and October 9, 2015. Generics relying on data from Semler are not considered equivalent to the brand The FDA also changed the therapeutic equivalence (TE) rating in the Orange Book (also called the Approved Drug Product with Therapeutic Equivalence Evaluations) for any approved ANDA that relied on data from Semler to “BX.” A BX rating indicates that data reviewed by the agency are insufficient to determine therapeutic equivalence, i.e., substitutability, of the generic product to the drug it references.As drug regulators across the world invalidate clinical studies conducted at Semler Research that demonstrate equivalence of the generic drugs to branded products, PharmaCompass brings to you the impact of this scandal on various products and drug companies. Dr. Reddy’s generic Nexium gains as competitor gets impactedThe violations uncovered at Semler Research have impacted the global generic pharmaceutical business. While most companies have been adversely impacted by the Semler data integrity scandal, there are some that have gained as well. For instance, Dr. Reddy’s North American business has got an unanticipated sales boost due to the issues at Semler. This was because the FDA mandated that competitor Hetero’s generic Nexium (an acid reflux medication) repeat its bioequivalence trials to be considered as an equivalent generic of the brand drug. This reclassification of Hetero’s drug has increased market share gains for Dr. Reddy’s Esomeprazole Magnesium – a generic equivalent of Nexium launched in the US in September last year. 96 European marketing authorizations to get impactedPharmaCompass’ assessment has uncovered 96 marketing authorizations in Europe for which “clinical and bioanalytical parts of the bioequivalence studies were performed at the Semler Research Center (SRC)”. Of these, 20 marketing authorizations are in France alone, followed by 10 each in Germany, the Netherlands and the United Kingdom. Click here to receive your copy of the European Marketing Authorizations Landscape due to the data-integrity violations at Semler A marketing authorization application is an application submitted by a drug manufacturer seeking permission to bring a newly developed medicine or a medicinal product to the market.In all probability, the maximum fallout of the Semler episode will be on Sandoz, as 29 marketing authorizations of Sandoz are likely to be recommended for repeat studies by authorities. Other generic majors who will possibly repeat studies are Mylan (15 marketing authorizations), Teva (nine marketing authorizations), Ratiopharm (six marketing authorizations) and Venipharm (five marketing authorizations). Changes in therapeutic status of Hetero, Lupin’s drugsWhile Hetero has to repeat its studies for generic Nexium in the United States, six Hetero filings in Europe have been listed by authorities for which the clinical studies were conducted at Semler.In the United States, the FDA has also changed the therapeutic status of Hetero’s Losartan Potassium along with Lupin’s filing for the same product to one (i.e. BX) where the product is no longer considered equivalent to the brand. Lupin’s Azithromycin, Upsher-Smith’s Propranolol Hydrochloride and Unique Pharma’s Tinidazole are other products which have seen their therapeutic code category get changed (to one of not being bioequivalent) by the FDA in the past month.Click here to receive your copy of the European Marketing Authorizations Landscape due to the data-integrity violations at Semler WHO questions findings of Semler studiesWhile the FDA and European regulators are busy dealing with the aftermath of the problems at Semler, the World Health Organization (WHO) has also been very active. In the Notice of Concern (NOC) issued by the WHO to Semler, as an outcome of WHO’s own inspections and discussions, Semler acknowledged that “four FDA studies and one WHO study have questionable data”. The WHO recommended “an immediate stop for all submissions of dossiers relying in whole or in part on involvement from Semler”. The WHO has questioned the findings of 11 studies performed at Semler for products which meet WHO’s pre-qualification criteria. The studies were performed on behalf of Mylan (three studies), Lupin (five studies), Micro Labs (one study) and Strides Ltd (two studies). Additionally, the WHO has also revealed 12 studies for which the products are currently under assessment but not yet pre-qualified. Our viewSemler’s data integrity concerns have made drug regulators question the equivalency of over 110 generic drug applications. Concerns have been highlighted by the FDA, European Medicines Agency (EMA) and the WHO. And the steps taken by the regulators indicate the magnitude of the fallout of these inspections. For the generic pharmaceutical industry, life has become a lot more challenging. In addition to concerns about in-house manufacturing compliance problems, they also need to worry about data integrity issues at clinical research firms. Clinical trial falsification issues at the laboratories of Quest Life Sciences, GVK Biosciences, Alkem Laboratories and Semler indicate that a sustained supply of generics can no longer be taken for granted.Click here to receive your copy of the European Marketing Authorizations Landscape due to the data-integrity violations at Semler

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02 Jun 2016

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Phispers: Pfizer-Allergan end megamerger, GSK wants to make copying its drugs easier & more

This week, the biggest news in the world of pharmaceuticals was the termination of the Pfizer-Allergan mega-merger due to new measures taken by the US government. Post that, Allergan signed a US $ 3 billion licensing deal with UK’s Heptares for a portfolio of neurological drugs. But a lot more happened last week – for instance, Pfizer and Celltrion won approval for a biosimilar of J&J’s Remicade, GSK said it wants to make it easier for manufacturers in least-developed countries to make its drugs and Valeant terminated the salesforce for its female libido pill. Pharmaceutical Whispers (Phispers) brings you the latest news from across the world. Pfizer-Allergan terminate merger; Allergan signs licensing deal with HeptaresOn Monday, the US Treasury announced new measures to curb tax-inversion deals. The measures seemed to specifically target the Pfizer-Allergan US $ 160 billion mega deal. And, by Wednesday, the US government had achieved its desired objective – Pfizer and Allergan announced their decision to mutually terminate the deal. Allergan, which is run from New Jersey but has a legal domicile in Dublin, last year agreed to merge with Pfizer. This mega-merger would have moved the Pfizer headquarters from New York to Dublin, saving the pharma behemoth billions of dollars in taxes. As per news reports, Pfizer will need to pay a US $ 400 million fee to Allergan for expenses relating to the deal. Though the US Treasury decision and the termination of the Pfizer-Allergan deal represents a victory for President Barack Obama, whose administration proposed tougher rules aimed at curbing tax inversions, Allergan is not wasting time. Just hours after Allergan backed away from the US $ 160 billion-merger with Pfizer, the company bounced back with a US $ 3.3 billion licensing deal for global rights to a portfolio of drugs for neurological disorders from the UK's Heptares. The deal sends a clear signal that Allergan CEO Brent Saunders plans to barrel ahead with new pacts to bolster the company's pipeline. Pfizer, Celltrion win approval for biosimilar of J&J’s RemicadeNot all news this week was negative for Pfizer as the FDA approved Celltrion’s biosimilar application of Johnson & Johnson’s Remicade. The product will be co-marketed by Pfizer in the United States, a relationship Pfizer accessed through its acquisition of Hospira last year. Celltrion’s application is only the second biosimilar approved by the FDA. However, unlike generic medicines, biosimilars which have been currently approved are not interchangeable with the reference drug. The European Medicines Agency also issued a positive opinion to the Bioepis copy of Remicade. Samsung Bioepis, a joint venture between a unit of the Samsung group and Biogen, has become a force in the biosimilar drugs industry. In fact, South Korea too is emerging as a hub for biosimilar production. Last week, Bioepis filed a lawsuit against AbbVie Inc., makers of the world’s best-selling rheumatoid arthritis drug – Humira – which generated sales of US $ 14 billion last year. In 2015, Johnson & Johnson’s Remicade sales were US $ 6.5 billion. Glaxo not to patent drugs in poorer countriesIn an unusual step, GlaxoSmithKline said it wants to make it easier for manufacturers in the world's 48 least-developed countries to copy its medicines. The company said it would not file patents in these countries in the hope that by removing the fear of patent litigation and by allowing independent companies to make and sell versions of its drugs in those areas, it would widen public access to these drugs. In countries classified as lower middle income countries by GSK, it will continue to file patents, but will grant licenses to generic manufacturers in exchange for a “small royalty”. Gilead has adopted a similar model, of granting generic licensing agreements in developing countries, for its blockbuster Hepatitis C treatment, Sovaldi. The end of the female Viagra?Valeant Pharmaceutical, still reeling from all its accounting and price-gouging problems, has terminated the sales force for the female libido pill that it acquired last year for US $ 1 billion. The drug – Addyi (flibanserin) – failed to gain traction in its first six months on the market. Valeant’s stock has plunged 90 percent since its peak in August last year. Valeant plans to relaunch its sales effort for Addyi with an internal team it will build in the coming months, says a Bloomberg news report. In the meantime, the drug will still be available. Along with the 140 contract workers that make up the Addyi sales force, Valeant is firing about 140 employees across its dermatology, gastrointestinal and women’s health divisions, with dermatology taking the biggest hit. Valeant has about 22,000 employees. Alkem, Rusan and Anuh Pharma – data-integrity issues raise its ugly head yet again in India Inspection at Alkem: In July 2015, the European Union banned the marketing of around 700 generic medicines for alleged manipulation of clinical trials conducted by India's pharmaceutical research company GVK Biosciences. And this year, another laboratory is under the lens of EU regulators.A routine inspection by the European Medicines Agency in March 2015 of the Department of Bioequivalence of Alkem Laboratories, a major generic drugs manufacturer in India, raised concerns regarding study data used to support the marketing authorization applications of some drugs in the EU. Rusan Pharma back in news: In an inspection conducted in 2010 at Rusan Pharma’s facility in Gandhidham (India), the UK’s Medicines and Healthcare Regulatory Agency (MHRA) uncovered “evidence of fraudulent presentation of data” and determined that the site did not comply with Good Manufacturing Practices (GMPs). The same year, another unit of Rusan, located in Ankleshwar (India), did not meet GMP compliance standards during an inspection conducted by Romania’s National Agency for Medicines and Medical Devices. This week, Rusan was back in news. In January 2016, re-inspection by UK’s MHRA of the Gandhidham site found the Pharmaceutical Quality System “not operating in an adequate manner”. In addition, the inspection report mentions “there was not adequate evidence that the root causes of critical data integrity issues raised at the last inspection had been addressed.” Non-compliant sourcing of drugs by Anuh Pharma: The French Health Agency’s inspection at Anuh Pharma’s facility in Boisar (India) revealed the firm was sourcing commonly used Azithromycin from a non-EU GMP compliant source (Hebei Dongfeng Pharmaceutical Company Limited, China), micronizing the product and then directly exporting it to Europe under the manufacturer name, Anuh Pharma. In addition, several documents were found within a pile of rubble which included an original batch repacking record. A large number of active substances were manufactured at the site, such as chloramphenicol, chloramphenicol palmitate, erythromycin, erythromycin ethylsuccinate, roxithromycin, ciprofloxacin HCl etc. Catalent’s compliance problems delay OPKO’s new drug launchWith more than 40 manufacturing facilities around the world, Catalent is a preferred manufacturing partner for several major pharmaceutical companies across the world. OPKO Health, Inc., one of Catalent’s customers submitted its application for RAYALDEE® (calcifediol) to the FDA. In the complete response letter (CRL) issued to the company, the FDA indicated observations of deficiencies at Catalent’s St. Petersberg, Florida, facility as a result of an FDA field inspection initiated on March 14, 2016, and had held up the new drug approval. According to a news report, OPKO revealed the deficiencies occurred at Catalent’s primary softgel development and manufacturing at St Petersburg, Florida, which was hit with a Form 483 being issued on March 25. Meanwhile, Catalent began production of essential drugs at its French plant, which had been suspended by France’s health regulator in November last year due to occurrence of out-of-place capsules in several product batches. Safety warnings for new age diabetes drugs -- saxagliptin and alogliptin Last year, the FDA had issued safety warnings on new age diabetes drugs called SLGT2 inhibitors (canagliflozin, dapagliflozin, and empagliflozin) and PharmaCompass had asked the question, “Diabetes: Which new drug is the safest?”. At the time Merck succeeded in demonstrating the cardiovascular safety of Januvia®, which was not the case for other products in the same categrory such as AstraZeneca’s Onglyza® (saxagliptin) and Takeda’s Nesina® (alogliptin). This week the FDA issued a safety warning on Onglyza® (saxagliptin) and Nesina® (alogliptin) as the evaluation of two clinical trials determined that more patients who received saxagliptin or alogliptin-containing medicines were hospitalized for heart failure compared to patients who received an inactive treatment called a placebo. Blockbuster drug approval expected soon for non-alcoholic fatty liver The FDA reviewed the application of Intercept Pharmaceuticals Inc's liver drug, Obeticholic Acid (OCA) and did not raise any major red flags indicating a high likelihood that it will get approved. While the drug is being reviewed for use in patients with primary biliary cirrhosis, a rare liver disease, late-stage studies are underway on the same drug to treat non-alcoholic steatohepatitis (NASH), which has no approved treatment. Obeticholic acid (OCA) is listed as one of the top 10 possible blockbuster drugs by FierceBiotech with an expected sales in 2020 of US $ 1.6 billion. Gilead is also actively building its liver disease pipeline and this week, the company paid US $ 400 million upfront to acquire an early-stage pipeline of liver disease drugs from privately held Nimbus Therapeutics. Heart-disease science turns over its headScience is supposed to be simple – for instance, LDL is bad cholesterol and HDL is good cholesterol. If a drug lowers the bad cholesterol and increases the good one, the risk of heart disease should reduce significantly. Specialists were stunned by the results of a study of 12,000 patients, announced on Sunday at the American College of Cardiology’s annual meeting: “There was no benefit from taking the drug, Evacetrapib.” The drug’s maker, Eli Lilly, stopped the study in October, citing futility, but it was not until Sunday’s meeting that cardiologists first saw the data behind that decision. As per the study, participants taking the drug saw their LDL levels fall to an average of 55 milligrams per deciliter from 84. Their HDL levels rose to an average of 104 mg per deciliter from 46. Yet 256 participants had heart attacks, compared with 255 patients in the group who were taking a placebo. Ninety-two patients taking the drug had a stroke, compared with 95 in the placebo group. And 434 people taking the drug died from cardiovascular disease, such as a heart attack or a stroke, compared with 444 participants who were taking a placebo.

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07 Apr 2016

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Find PharmaFlow Article for Azithromycin

Azithromycin

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