Myeloma Combination Approval Shows How FDA's Real-Time Oncology Review Works

The Food and Drug Administration approved teclistamab (Tecvayli) in combination with daratumumab hyaluronidase-fihj (Darzalex Faspro) on March 5 for adults with relapsed or refractory multiple myeloma who have had at least one prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent, the Oncology Nursing Society reported. The approval was based on the randomized Phase 3 MajesTEC-3 trial, and it also converted teclistamab's 2022 accelerated approval as a single agent to a traditional approval.

The application was part of FDA's Commissioner's National Priority Voucher pilot and received priority review, according to the report. It also used three tools run by FDA's Oncology Center of Excellence: Real-Time Oncology Review, the Assessment Aid and Project Orbis. Each changes how a cancer application moves through the agency, not what it must prove.

Starting the review before the application is complete

FDA's Real-Time Oncology Review page says the program "facilitates earlier submission of topline efficacy and safety results, prior to the submission of the complete application." New drug applications for new molecular entities, original biologics license applications and supplemental applications with oncology indications may be eligible. FDA looks for drugs likely to show substantial improvement over available therapy or that meet criteria for its expedited programs, and for endpoints that are easy to interpret, such as overall survival or response rates.

A sponsor asks to take part when topline results from a pivotal trial are in. FDA says it generally decides within about 20 business days. If accepted, the sponsor can begin sending data two to four weeks after all patient data are locked in its database, bundled into at most three pre-submissions and a final submission. The pre-submission package includes key efficacy and safety datasets, the trial protocol and amendments, and a draft of the prescribing information.

The formal review clock starts only when the complete application arrives. FDA says the early look gives reviewers a chance to spot data quality or review issues sooner and to give early feedback. It also sets limits: acceptance "does not guarantee or influence approvability," and the program is not meant to produce a decision before the user fee goal date, although early approvals have occurred. FDA says RTOR applies only to drug applications submitted to its drug center, not to device applications.

A shared review document

The Assessment Aid is a voluntary document the applicant fills in using a template based on FDA's multidisciplinary review. Sections are split into the data, "The Applicant's Position" and "The FDA's Assessment," so reviewers can record where they agree or disagree with the company in the same file. FDA caps the applicant's portion at 100 pages for a new molecular entity and 75 pages for a supplement, and says companies that do not use it follow the usual process "with no impact on review timelines or benefit-risk decisions."

Reviewing with other countries

The Oncology Center of Excellence started Project Orbis in May 2019 to give cancer drug sponsors a framework for concurrent submission and review among international regulators. The first collaborative review involved FDA, Australia's Therapeutic Goods Administration and Health Canada; other agencies have since joined. FDA says the aim is to reduce delays in access in other countries, since pivotal cancer trials are often run internationally.

For the teclistamab application, FDA worked with Health Canada and Switzerland's Swissmedic, according to the nursing society's report, which noted that the applications may still be under review at those agencies. Each regulator makes its own decision under its own law.