Drospirenone/Ethinyl Estradiol/Levomefolate Calcium

Pictured: Packs of birth control pills/iStock, towfiqu ahamed At the end of July, Lupin Pharmaceuticals recalled two batches of Tydemy, a birth control drug that the company produces in India, when it was found to have reduced effectiveness. It was the company’s eighth product recall in just 18 months. Lupin was also forced to stop production at one of its Indian plants in 2022 after the FDA issued a warning letter last fall. Around the same time, another generics manufacturer, Intas Pharmaceuticals, made headlines over a failed FDA inspection at a manufacturing plant in Gujarat, India, leading the company to cease operations there. At a moment when drugs already are in short supply, these disruptions are reducing availability even more, putting entire supply chains at risk and forcing doctors and patients to make difficult, life-changing treatment decisions. “It’s hard to know” how the issues at Intas and Lupin will influence drug availability in the future, Erin R. Fox, associate chief pharmacy officer of Shared Services at the University of Utah Health and adjunct professor at the University of Utah College of Pharmacy, told BioSpace via email. “The initial stoppages have contributed [and] created shortages, but as time goes by, other suppliers may be able to ramp up, so it really depends on what the other suppliers are able or willing to do.” In 2020, over 90% of drugs prescribed in the U.S. were generics. Indian companies alone supply 40% of these drugs, The Wall Street Journal reported. Yet, according to a ProPublica investigation into FDA oversight of Indian and Chinese drug factories, only 6% of generic drug manufacturers in these two nations received FDA inspections in 2022. Now, the FDA is under pressure to balance the demands of a desperate healthcare system with the need to ensure that imported products are safe and effective. Issues Leading to Lupin’s Recall Lupin has been the subject of FDA scrutiny since October 2022, receiving several warnings about five of its 12 Indian manufacturing plants within just a few weeks. For example, one of the company’s plants in Pune was cited for 18 violations that month, many pertaining to quality control. In March 2023, a plant in Pithampur received a recommendation for voluntary action from the FDA when an inspection determined that employees were not keeping adequate data records during manufacturing processes. The biggest recent news, however, is Lupin’s voluntary recall after unspecified impurities were found in the oral contraceptive Tydemy. Lupin distributed the two bad batches of Tydemy in the U.S. between June 2022 and May 2023, totalling over 4,000 boxes. On July 28, the company issued a statement announcing the recall as the FDA warned patients that the drug might not work. So far, no adverse medical effects have been reported due to the ineffective drugs, and affected patients have been urged to continue taking the recalled Tydemy until other medication can be obtained. In parallel, Intas Pharmaceuticals faced problems of its own, catapulting the oncology field into severe shortages when manufacturing was shut down at one of its factories. In one case, a Sanand facility was discovered to have destroyed records related to current good manufacturing practice by dumping acetic acid on them. In the face of the resulting shortages, some oncology wards have been forced to ration cancer therapy. Solutions on the Table Tinglong Dai, a professor at Johns Hopkins Carey Business School, told Biospace by email that the failures of Lupin and Intas highlight a bigger problem with overseas generics manufacturing. “There are definitely broader, industry-specific issues, and these aren’t isolated cases,” he said. “We rely on an incredibly extensive global generic supply chain network that we simply don’t have the resources, capabilities or track record to successfully oversee.” Fox said that shortages are likely to continue “until we change incentives for companies to improve quality and for hospitals to purchase based on quality.” She pointed to research by Marta Wosińska of the Brookings Institute that proposed a multi-pronged solution to the shortage problem, including a government-run buffer inventory of critical drugs and a program that incentivizes hospitals to prepare for potential drug shortages. Another approach is to push the FDA to improve its inspection of foreign-made generic drugs. Dai noted that lax adherence to FDA standards—and the consequent recalls and production stoppages—is acutely harming supply at the moment. He suggested that systemic changes, such as providing information about where the drugs they prescribe are manufactured, could allow prescribers to make informed decisions. During the COVID-19 pandemic, the FDA was unable to complete in-person inspections of Indian facilities, an agency spokesperson told BioSpace. Instead, the agency relied on “alternative inspectional tools” when necessary, including “remote interactive evaluations, record requests, and leveraging information from trusted regulatory partners.” This allowed the agency to maintain oversight on “more than 25% of drug manufacturing facilities in India” since the onset of the pandemic, the spokesperson said, emphasizing that the FDA is now returning to normal inspection operations. In the short term, however, the messaging around generic drugs should change, Dai said. “Until the FDA can step up its inspection of foreign generic drug manufacturers, it should stop claiming that generic drugs are as safe and effective as brand-name drugs,” he said. “We are living in an extremely dangerous and dire situation, and it is simply a crime if we don’t do something now to fix it.” Andy Gooding-Call is a freelance science writer based in Northampton, Massachusetts. Reach him at andygoodingcall.com.

Bristol Myers Squibb and BeiGene's settlement, Sumitomo Pharma and Otsuka's trial flops, and AstraZeneca CEO's recent remarks made our news this week. Bristol Myers Squibb and BeiGene have settled their Abraxane feud by terminating their three-drug licensing deal altogether. Sumitomo Pharma's Otsuka-partnered schizophrenia candidate ulotaront filed in a pair of phase 3 trials. AstraZeneca CEO responded to a report about the company's plan to spin out its China business. And more.  1. Bristol Myers, BeiGene end legacy Celgene deal with settlement years after China ban Bristol Myers Squibb and BeiGene have decided to terminate their China licensing deal originally signed in 2017 by Celgene around the cancer drugs Revlimid, Abraxane and Vidaza. The settlement puts an end to a feud that stemmed from a Chinese import and sale ban on Abraxane. Chinese authorities placed the ban in 2020 after noticing manufacturing problems at a BMS contract manufacturing facility in the U.S. 2. Sumitomo-Otsuka schizophrenia drug flunks pair of phase 3 trials amid 'high placebo response' A pair of phase 3 studies for Sumitomo Pharma and Otsuka’s schizophrenia candidate ulotaront missed their primary endpoints. Compared with placebo, the AAR1 agonist showed slightly better results on improving schizophrenia symptoms on a severity scale. But the results failed to meet statistical significance. The pair suggested that placebo overperformance may have masked the drug’s therapeutic effect. 3. AstraZeneca forecasts stronger China sales as CEO tries to clear the air on spinoff report In response to a question about a recent Financial Times report that AstraZeneca has crafted plans to spin out its China operations in case of rising geopolitical tensions, AstraZeneca CEO Pascal Soriot said the company studies many business scenarios. The company studies many potential situations that never become reality, he explained during a press call. The British pharma also dialed up its revenue projection for its China business for the year. 4. Biogen looks at selling biosims unit to longtime ally Samsung Bioepis: reports It wasn’t long ago that Biogen sold its stake in Samsung Bioepis to joint venture partner Samsung Biologics but kept rights to some biosimilars. Now, Biogen is reportedly in talks to offload the remaining biosimilar portfolio to Samsung Bioepis. Biogen CEO Chris Viehbacher had previously said that the company was examining strategic options for the biosimilar business. 5. Takeda's Exkivity sputters in lung cancer trial, with accelerated approval on the line Takeda’s targeted non-small cell lung cancer drug Exkivity has failed as a monotherapy in a phase 3 trial in newly diagnosed patients whose tumors bear EGFR exon 20 insertion mutations. The first-line flop puts Exkivity’s second-line accelerated approval in danger. News of Exkivity’s phase 3 flop came just days after Johnson & Johnson touted a win for its rival drug Rybrevant also in new patients. 6. Lupin Pharma recalls birth control pills deemed possibly ineffective Lupin is recalling two lots of the birth control drug Tydemy because they missed the mark on a 12-month stability test, suggesting they may not be effective in preventing pregnancy. Testing on one of the lots found low levels of an essential inactive ingredient, ascorbic acid, and high levels of an impurity. The affected lots were distributed from June 3, 2022, to May 31, 2023. Other News of Note 7. Lundbeck, Otsuka target Alzheimer's caregivers in ad for expanded Rexulti label 8. Daiichi Sankyo wins Japanese nod for homegrown mRNA COVID vaccine (Reuters)