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.  

Impressions: 3614

16 Apr 2020
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.  

Impressions: 1626

02 Apr 2020
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.  

Impressions: 7663

23 Mar 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: 8246

04 Mar 2020
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: 9219

26 Jul 2018
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 8