Safety will be the central focus Tuesday as the FDA’s Oncologic Drugs Advisory Committee meets virtually to discuss the benefit-risk profile of Glaxosmithkline plc’s belantamab mafodotin as a fifth-line therapy for adults with relapsed or refractory multiple myeloma. While the FDA said the 31% overall response rate in the DREAMM-2 trial with the 2.5-mg/kg belantamab mafodotin dose may be beneficial in a heavily treated population, the agency is concerned about the antibody-drug conjugate’s ocular toxicity, which is unique among anti-myeloma agents. According to the briefing document for the meeting, trial results showed an overall incidence of ocular toxicities of 71%, with 44% of patients experiencing at least one episode of severe keratopathy at the 2.5-mg/kg dose. Trial results also showed a clinically significant decline in visual acuity, including severe vision loss.

How a surrogate endpoint plays out in a real-world benefit could play a heavy role Wednesday when the FDA’s Cardiovascular and Renal Drugs Advisory Committee meets virtually to weigh in on Mallinckrodt plc’s terlipressin as a treatment for hepatorenal syndrome (HRS) type 1. The drug – a synthetic 12-amino-acid peptide analogue of vasopressin – already has received two complete response letters, with the first dating back to 2009. In each letter, the FDA required another trial, saying the results of the previous trial were not statistically significant. The adcom will focus on the results of a third randomized, blinded, placebo-controlled trial, CONFIRM, which was conducted under a special protocol assessment agreement. The trial met its primary endpoint with 29% of patients in the terlipressin arm compared with 16% of patients in the placebo arm achieving verified HRS reversal. Although the FDA agreed to the endpoint, the agency stressed that it was a surrogate endpoint that would have to be born out in clinical outcomes. HRS-1 is associated with high mortality and patients also may require renal replacement therapy (RRT). According to the FDA briefing document for the adcom, RRT-free survival was slightly greater in the terlipressin arm as compared with placebo, but terlipressin was not associated with improved survival. The proportion of patients who died was slightly greater numerically in the terlipressin arm than in the placebo arm.

When it comes to developing COVID-19 vaccines, a phase III trial must enroll “many thousands of participants, including those with underlying medical conditions, to generate relevant data for key target populations,” according to a report from the International Coalition of Medicines Regulatory Authorities. Regulators from around the world who participated in a recent workshop on COVID-19 vaccine development broadly agreed that clinical studies should be designed with stringent success criteria that would allow a convincing demonstration of the efficacy of a vaccine. Trials should be diverse in terms of race, ethnicity and age, and sponsors should have plans for pediatric assessments and accruing data of use in pregnant women. The report also advised that all COVID-19 vaccine trials use the same endpoint, include a placebo or comparator control, and provide at least one year of follow-up.

With the goal of restarting on-site, prioritized domestic inspections next week, FDA Commissioner Stephen Hahn said that, for the foreseeable future, FDA inspections will be pre-announced and they will depend on the COVID-19 trajectory in a given state and locality, as well as the rules and guidelines put in place by those state and local governments. The agency’s ability to resume inspections, which were halted in March when COVID-19 hit pandemic levels, will be impacted by the availability of such services as public transportation that also have been affected by the spread of the coronavirus infections. Giving advance notice of an inspection “will help assure the safety of the investigator and the firm’s employees, providing the safest possible environment to accomplish our regulatory activities, while also ensuring the appropriate staff are on-site to assist FDA staff with inspection activities,” Hahn said.

The FDA finalized several guidances on eligibility criteria for cancer trials, with the aim of broadening the eligibility criteria to maximize the generalizability of trial results and the ability to understand a drug’s benefit-risk profile across the patient population. In finalizing the guidances, the agency acknowledged that some “eligibility criteria have become commonly accepted over time or used as a template across trials without clear scientific or clinical rationale.” That can be a problem for sponsors and cancer patients, as “unnecessarily restrictive eligibility criteria may slow patient accrual, limit patients’ access to clinical trials, and lead to trial results that do not fully represent treatment effects in the patient population that will ultimately use the drug,” the agency added. Released as drafts in March 2019, the final guidances address trial inclusion of cancer patients with brain metastases, HIV and hepatitis B and C infections, and organ dysfunction or prior/concurrent malignancies. A fourth guidance discusses minimum age considerations for inclusion in pediatric cancer trials.

The FDA’s Center for Biologics Evaluation and Research (CBER) is now supporting the current version of the Clinical Data Interchange Standards Consortium (CDISC) standard for the exchange of nonclinical data (SEND) and an update to the FDA Data Standards Catalog. The standard applies to the electronic submission of nonclinical data in generic and new drug applications, certain biologics license applications and certain investigational new drug applications. While sponsors are encouraged to begin using CDISC SEND for CBER applications, the center won’t require the SEND standard until March 15, 2023, according to a notice to be published in Tuesday’s Federal Register.

The U.K.’s National Institute for Health and Care Excellence (NICE) last week signed a memorandum of understanding with Colombia’s Institute of Health Technology Assessment (IETS) to share expertise in developing guidance for health technology assessments (HTAs). The two organizations also will exchange their experience in developing specific clinical guidelines, quality standards and other guidance, according to NICE. IETS said the agreement will serve as a steppingstone in boosting Colombia’s HTA process. In addition, it will open a door for NICE to share its knowledge with other HTA agencies in Latin America.

The EMA finalized an opinion requiring drug companies to have appropriate control strategies to prevent or limit the presence of nitrosamines, a probable carcinogen, and improve their manufacturing processes, where necessary. Companies also will have to evaluate the risk of the impurities being present in their drugs and to conduct appropriate tests if a risk is identified. The EMA said detailed information for companies, including timelines, will soon be available on its nitrosamine impurities webpage. Meanwhile, the U.S. Pharmacopeia released six new reference standards to support manufacturers and regulators in analyzing and monitoring nitrosamine impurities in the drug supply chain.

The U.S. Circuit Court of Appeals for the Federal Circuit last week further finetuned the timing of the 180-day notice of commercial marketing required by the Biologics Price Competition and Innovation Act (BPCIA). Affirming a lower court decision in Genentech Inc. v. Amgen Inc., the Federal Circuit said Amgen’s Oct. 6, 2017, commercial marketing notice for Mvasi, a biosimilar referencing Genentech’s Avastin (bevacizumab), satisfied the BPCIA requirement, even though Amgen later filed supplements to add a manufacturing facility and to change the biosimilar’s label. Genentech, part of the Roche Group, had argued that the supplements resulted in new, distinct applications that required Amgen to send a new commercial marketing notice. Not so, the Federal Circuit ruled, noting that the supplements didn’t change the product, for which Amgen had provided the required marketing notice.

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