On November 13, 2019, Teva announced that it will resume the production of vincristine, a drug that has served as the backbone of many anti-cancer treatment regimens for several decades. Earlier this year, Teva informed the FDA that it had made a business decision to stop manufacturing the drug. Only 1 other US pharmaceutical manufacturer (Pfizer) produces vincristine, and when this company met unexpected manufacturing delays in the fall, the life-saving drug was in short supply.
Vincristine is critically important for the treatment of a variety of malignancies and is included on the World Health Organization’s lists of essential medicines and essential medicines for children.
The shortage of vincristine affected patients across the country whose cancer treatment relies on the drug and led to a widespread backlash by physicians and patient representative groups who quickly responded with petitions and calls to the government to intervene with measures to ameliorate the current shortage and to prevent such events in the future.
Teva maintains that it could not have anticipated the shortage, as it only produced 3% of the market supply, and that it was not aware of the challenges faced by the other manufacturer when it decided to stop producing the drug. In a company media communication, Teva announced that their product will be available in the United States as early in 2020 as possible.
Generic drugs are widely used in cancer treatment, but some generic drugs, such as vincristine, which has been off patent for decades, are difficult to produce and have a narrow profit margin, making them unattractive to manufacturers.
As stated in an e-mail from the FDA’s Division of Drug Information, drug shortages are a “significant public health issue” with potentially serious consequences for patients who may experience delays in treatment, forgo treatment altogether, or receive alternative and less effective therapies. In response to a request by the US Congress to help address the shortage crisis, the FDA formed the Drug Shortages Task Force to explore shortages in generic drugs and to seek remedies for the problem. The task force issued a report on October 29, 2019, that identified 3 main reasons for chronic drug shortages: (1) a lack of financial incentive for manufacturers; (2) limited ability for the marketplace to recover from shortages caused by outside challenges; and (3) a manufacturing and supply chain that tends toward innovation and improvement, but which leaves mature drugs sidelined. In this report, the task force also addressed solutions to combat the drug shortage, including FDA initiatives.
On November 19, 2019, the FDA’s Division of Drug Information will host a continuing education webinar titled “FDA Drug Topics: Drug Shortages: FDA Efforts, Current Challenges and Future Goals.” This webinar will introduce the agency’s Drug Shortage Program, explain how it is addressing drug shortages, and explore the various challenges that lead to drug shortages.
Click here for webinar registration information.
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On November 11, 2019, the FDA granted breakthrough therapy designation to Bristol-Myers Squibb’s supplemental biologics license application for the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) for the treatment of patients with advanced hepatocellular carcinoma who have been previously treated with sorafenib (Nexavar; Bayer). The PDUFA goal date for this application is March 10, 2020.
The approval was based on data from the nivolumab plus ipilimumab cohort of the phase 1/2 CheckMate-040 clinical trial, an ongoing, open-label, multicohort study investigating nivolumab and nivolumab-based combinations in patients with advanced hepatocellular carcinoma previously treated with sorafenib.
Primary end points include safety and tolerability, and objective response rate based on investigator assessment using Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included disease control rate, duration of response, overall survival, time to response, time to progression, and progression-free survival. In the nivolumab plus ipilimumab cohort of patients, the objective response rate was 31% with a median duration of response of 17.5 months.
Ian M. Waxman, MD, Development Lead, Gastrointestinal Cancers, Bristol-Myers Squibb, said in a company press release, “The FDA’s acceptance of our application for Opdivo plus Yervoy represents important progress for patients with liver cancer in the United States, where hepatocellular carcinoma is the fastest rising cause of cancer-related death.”
Hepatocellular carcinoma is often diagnosed at an advanced stage and is associated with poor prognosis. Most cases of hepatocellular carcinoma are caused by hepatitis B virus or hepatitis C virus infections; however, metabolic syndrome and nonalcoholic steatohepatitis rates are rising and expected to contribute to increased incidence of the disease.
On November 14, 2019, the FDA granted accelerated approval to zanubrutinib (Brukinsa; BeiGene) for the treatment of patients with mantle-cell lymphoma who have received at least 1 prior therapy.
“Mantle cell lymphoma usually responds well to initial treatment, but eventually returns or stops responding, and the cancer cells continue to grow. This is a life-threatening condition,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence and Acting Director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research. “Clinical trials showed that 84% of patients saw tumor shrinkage with this therapy. For patients whose disease relapses or becomes refractory, secondary therapies may be successful in providing another remission, and today’s approval will provide patients with another treatment option,” he said.
The efficacy of zanubrutinib was assessed in 2 clinical trials. In the phase 2, multicenter, single-arm BGB-3111-206 trial, 86 previously treated patients with relapsed or refractory mantle-cell lymphoma who had ≥1 previous therapies received 160 mg of zanubrutinib orally twice daily until disease progression or unacceptable toxicity. In the phase 1/2, dose-escalation, multicenter, single-arm BGB-3111-AU-003 trial of B-cell malignancies, 32 previously treated patients with mantle-cell lymphoma received 160 mg of zanubrutinib orally twice daily or 320 mg once daily.
The primary efficacy end point in both trials was overall response rate as assessed by an Independent Review Committee. In the BGB-3111-206 trial, the overall response rate was 84% (95% confidence interval [CI], 74-91), with a complete response rate of 59% (95% CI, 48-70) and a median response duration of 19.5 months (95% CI, 16.6-not estimable). In the BGB-3111-AU-003 trial, the overall response rate was 84% (95% CI, 67-95), with a complete response rate of 22% (95% CI, 9-40) and a median response duration of 18.5 months (95% CI, 12.6-not estimable).
The most common (≥20%) adverse reactions included decreased neutrophil count, decreased platelet count, upper respiratory tract infection, decreased white blood cell count, decreased hemoglobin, rash, bruising, diarrhea, and cough. Serious adverse reactions were reported in 31% of patients. The most frequent serious adverse reactions were pneumonia in 11% and hemorrhage in 5% of patients. Of the 118 patients with mantle-cell lymphoma who received zanubrutinib in the 2 trials, 7% discontinued treatment because of adverse reactions. The most frequent adverse reaction leading to treatment discontinuation was pneumonia, occurring in 3.4% of patients.
Fatal events within 30 days of the last dose of zanubrutinib occurred in 7% of the 118 patients with mantle-cell lymphoma in the 2 trials. Fatal cases included 2 patients with pneumonia and 1 patient with cerebral hemorrhage.
Because zanubrutinib was granted accelerated approval, which allows faster approval of drugs for serious conditions to fill an unmet medical need, further clinical trials may be required to verify and describe the drug’s clinical benefit.
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