Pharmaceutical Technology Editors

 on conducting remote inspections, or, as the agency is calling them, “voluntary remote interactive evaluations (VRIEs)” at pharmaceutical and biologics facilities, using videoconferencing software, 360-degree video inspection, and other tools. The agency had been criticized for failing to take a stand on the use of remote inspection technologies in light of a growing backlog of plant inspections and delays in new drug approvals due to concerns about putting inspection staffers at risk of contracting COVID-19.

The guidance’s wording makes it clear that the agency views use of these technologies as a temporary measure, only for as long as US health authorities continue to define the COVID-19 pandemic as a public health emergency. However, it also suggests that FDA may use remote technologies in the post-COVID-19 world, as a way to supplement inspections, gain additional insights into issues found during a traditional inspection, or clarify questions or support a new drug application. The guidance also hints that technology may be used as a preliminary step, to better define the scope, depth, and timing required for future in-person inspections.

The guidance was issued without the customary public comment period, although FDA’s conservative approach and silence on the subject of remote technology had been discussed widely in the press and at industry events. Remote interactive evaluations would be used for pre- and post-approval inspections, surveillance inspections, follow-up and compliance visits, and bioresearch monitoring inspections.

FDA will use risk-management tools to determine when to ask a facility to participate, and may requests records or ask the company to take part in a VRIE before an on-site inspection.The agency also emphasized that it will not accept requests from facilities to perform inspections remotely, but will notify the facility if it wishes to set up a VRIE. FDA will contact the company and ask for information required to plan the evaluation ahead of time.

In order to prepare for the evaluation, FDA will schedule a brief meeting with the company to discuss staffing, key contacts and roles, logistics, expectations, and to outline key responsibilities. It will also ascertain any time zone differences and needs for interpreters.

Among the issues to be examined would be the facility’s capacity to host such evaluations, specifically the host facility’s internet access and its ability to live stream video and audio during an actual inspection. Discussions will come to an end if it is found that there is insufficient bandwidth or that remote video will not give adequate visibility into the operations or segments of the facility being evaluated.

FDA also says that it will not issue a Form 482 for these evaluations and that it will use its own government-issued Microsoft Teams, Zoom, and Adobe Connect platforms. It also asks that facilities be sure to make electronic documents accessible for sharing.

FDA also asks that facilities that are still using paper documentation ensure that it is scanned into PDFs when possible.

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The agency will use technology for “voluntary remote interactive evaluations” for pre- and post-approval and other types of inspections.

FDA Weighs in on Remote Inspections

Bristol Myers Squibb (BMS) has announced, in an April 14, 2021 press release, that the European Commission (EC) has approved Opdivo (nivolumab) in combination with Cabometyx (cabozantinib) for the first-line treatment of adults with advanced renal cell carcinoma (RCC).

EC’s decision was based on Phase III trial results demonstrating superior efficacy of the combination treatment versus sunitinib in progression-free survival, objective response rate, and overall survival. Additionally, the combination treatment was found to be well-tolerated with a low rate of treatment related adverse events leading to discontinuation.

“With this approval, we can now offer patients two different Opdivo-based combinations that have demonstrated significant survival benefits versus sunitinib,” said Dana Walker, vice-president, development program lead, genitourinary cancers, BMS, in the press release. “Today’s milestone builds on our heritage of developing and delivering novel treatments for patients with advanced RCC, first with the only dual immunotherapy option, Opdivo plus Yervoy, and now with a new immunotherapy and tyrosine kinase inhibitor regimen.”

“The combination of nivolumab and cabozantinib pairs two proven agents for advanced RCC that together have shown superior efficacy across key endpoints and subgroups of patients compared to sunitinib in the CheckMate -9ER trial. Additionally, the combination’s safety profile was manageable with known protocols, leading to a low rate of treatment-related discontinuations,” added Marc-Oliver Grimm, professor of medicine and urology department head, Jena University Hospital, in the press release. “With today’s approval, clinicians in the EU will be able to offer patients with advanced RCC an additional combination therapy that may help them achieve early control of their disease and improve survival outcomes.”

The European approval is for a flexible dosing regimen of the combination therapy—either using Opdivo 240 mg intravenously every two-weeks or 480 mg intravenously every four-weeks in combination with Cabometyx 40 mg, administered orally once a day. The combination therapy was approved by the US FDA in January 2021, further applications are under review with other regulatory bodies worldwide.

BMS has announced that the EC has approved Opdivo in combination with Cabometyx for the first-line treatment of adults with advanced renal cell carcinoma.



EC Approves BMS’ Opdivo in Combination with Cabometyx for Advanced RCC

The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) is continuing its review of very rare cases of unusual blood clots in the US, following administration of Janssen’s COVID-19 vaccine.

According to an April 14, 2021 press release, as a result of six reported cases in the US of cerebral venous sinus thrombosis (CVST), which mostly occurred in instances where there were low levels of blood platelets (thrombocytopenia), Janssen has decided to delay the European rollout of its vaccine while investigations are performed. Janssen’s vaccine was authorized for use in the European Union (EU) on March 11, 2021, but widespread use of the vaccine has not yet started in the region.

EMA is working with the US FDA and other international regulators on the matter and will decide on whether regulatory action is necessary. The evaluation of all reported cases is being expedited and EMA expects recommendation on the matter to be issued within a seven-day period.

While the review is ongoing, EMA maintains that the benefits of the vaccine outweigh the risks of side effects.

EMA's Pharmacovigilance Risk Assessment Committee is reviewing very rare cases of unusual blood clots in the US, following administration of Janssen’s COVID-19 vaccine.

Safety Review of Janssen COVID-19 Vaccine Continues in Europe

The European Medicines Agency (EMA) has confirmed, in an April 14, 2021 press release, that it is continuing to monitor the incidences of very rare blood clots with low blood platelets occurring after vaccination with the AstraZeneca COVID-19 vaccine (Vaxzevria).

A continuation of the safety review is in line with a request from the European Union’s (EU’s) Commissioner for Health and Food Safety following a meeting of EU Health Ministers. Vaccination data and data on epidemiology will be reviewed by EMA.

Through the review, which will be performed by EMA’s Committee for Medicinal Products for Human Use (CHMP), the potential risks of Vaxzevria will be put into context of the benefits for ongoing vaccination campaigns. Additionally, considerations over whether or not recommendations for a second dose of the vaccine will be considered by CHMP.

Overall, EMA considers the benefits of Vaxzevria continue to outweigh any potential risks, the agency stated in the press release. Safety and effectiveness will continue to be monitored and any updates will be provided to the public by EMA.

EMA is continuing to monitor the incidences of very rare blood clots with low blood platelets occurring after vaccination with the AstraZeneca COVID-19 vaccine (Vaxzevria).



Further Context on AstraZeneca COVID-19 Vaccine Risks to be Provided by EMA

According to an April 15, 2021 press release, the European Medicines Agency (EMA) has started its review of monoclonal antibody VIR-7831 (also known as GSK4182136) as a treatment for patients with COVID-19.

VIR-7831 is an investigational dual action SARS-CoV-2 monoclonal antibody that has been developed through collaborative work by GlaxoSmithKline and Vir Biotechnology. The treatment is currently undergoing clinical trials to assess its efficacy and safety in the treatment of adults and adolescents (aged 12 years and older and weighing at least 40 kg) with mild-to-moderate COVID-19, who are at high risk of progressing to more severe COVID-19.

EMA’s review will include data from an interim analysis of the Phase III study, COMET-ICE (COVID-19 Monoclonal antibody Efficacy Trial—Intent to Care Early). The preliminary results indicate that VIR-7831 reduced the risk of hospitalization in patients studied by 85% when compared with placebo.

A more comprehensive rolling review of available data is expected to start prior to a possible application for marketing authorization, although the initial review will provide European Union-wide recommendations. EMA has revealed that it will provide communication on the outcome of the current review once it has been concluded.

EMA has started its review of monoclonal antibody VIR-7831 (also known as GSK4182136) as a treatment for patients with COVID-19.

EMA Review of VIR-7831 for COVID-19 Underway

HTL Biotechnology and Echelon Biosciences have formed a strategic partnership for the distribution of high-quality hyaluronic acid (HA) and glycosaminoglycan (GAG), and the co-development of novel GAG products. The partnership was revealed in an April 14, 2021 press release.

The partnership will enable academic research and pharmaceutical development laboratories to gain expanded access to good manufacturing practice (GMP)-grade, kit-packaged HA and GAG products. The goal of the partnership, and the provision of clinical grade products to early-stage researchers, is to bridge the gap between lab-based research, development, and commercialization.

“Innovation is at the heart of HTL’s DNA,” said Yvon Bastard, CEO, HTL, in the press release. “This growth opportunity reinforces our mission and vision to apply science for increased bio-compatibility and improved health outcomes around the world.”

“This new partnership offers scientists and researchers the key technologies to develop innovative biopolymer solutions for new medical applications in aesthetics, ophthalmology, rheumatology, tissue engineering, and drug delivery,” added Charles Ruban, deputy CEO, HTL, in the press release.

“Echelon has been granted the opportunity to expand its market-leading HA assays and extra cellular matrix product line with the supply of HTL’s HA and other GAG-derived products. HTL is recognized internationally for producing biopolymers of premium quality,” stated Bert Israelsen, president of Echelon Biosciences, in the press release.

HTL Biotechnology and Echelon Biosciences have formed a strategic partnership for the distribution of high-quality HA and GAG, and the co-development of novel GAG products. 