Executive Summary

The data may be different, but US FDA will consider real-world evidence to add a tissue-agnostic indication, as well as take it away.

Sponsors may be able to use real-world data to expand an oncology therapy to a tissue-agnostic indication, but a US Food and Drug Administration official warned that the data also could take that indication away.

The FDA recognizes that real-world data will not be the same as the data collected during a traditional cancer trial. However, Suparna Wedam, a medical officer in the Office of Hematology and Oncology Products’ Division of Oncology Products I, said real-world data, if gathered using rigorous techniques, should support the addition and removal of indications.

“The data’s going to be different, but I think there’s definitely an opportunity to go both ways from a tissue-specific indication to a tissue-agnostic or from tissue-agnostic and start peeling away ones that aren’t right to be in there,” she said during a 26 April workshop on development of tissue-agnostic, biomarker-based indications sponsored by the FDA, Friends of Cancer Research and American Society of Clinical Oncology.

The allure of real-world evidence in part stems from the potential to use electronic health record or claims data to support approval or labeling expansions at a lower cost and in much less time than traditional clinical trials.

Wedam said using electronic medical records and registries could be an option to expand to a tissue-agnostic indication. But she emphasized that “this shouldn’t be a data mining exercise.” Sponsors will need similar rigor to traditional clinical trials and plans laid out prospectively.

“We shouldn’t go digging for things, but you should really know what you’re looking for,” Wedam said. “In that case then maybe you could use it to expand from a specific indication to tissue-agnostic.”

Wedam also said that real-world data could illustrate problems with the product once it is available for marketing.

“If you start using it out in the real world and you start seeing that data, that may give us the opportunity to start carving out those indications,” she said. “I think we’re committed to using the real-world data and we know it is a huge opportunity.”

FDA officials at the workshop could not exactly describe for the evidence that would prompt moving a product to a tissue-agnostic indication or suggest moving back to a tissue-specific label. They stressed throughout the workshop that the agency will consider the totality of evidence.

Two tissue-agnostic indications have been approved by the FDA, allowing the drugs to be used for a form of cancer no matter the location of the tumor Merck & Co. Inc.’s Keytruda (pembrolizumab) gained the indication in 2017.  (Also see “Biomarker-Led Claim Is Small Step For Merck’s Keytruda, Giant Leap For Cancer Indications” – Pink Sheet, 23 May, 2017.)

Loxo Oncology Inc. and Bayer AG gained the second tissue-agnostic approval – the first for a novel product  prospectively developed for that purpose – for Vitrakvi (larotrectinib) in 2018. (Also see “Vitrakvi, Daurismo Approvals Put US FDA On Brink Of Another Record ” – Pink Sheet, 27 Nov, 2018.)

Sponsors employing real-world data in their drug development program should expect early involvement by the FDA. Beginning at the IND stage, the agency will be working with sponsors to ensure a scientifically-sound study. (See sidebar.)

RWE Could Address Uncertainty

The FDA’s acceptance of real-world evidence in the tissue-agnostic oncology indication space seems to stem in part from the inherent uncertainty that is associated with the approvals.

Martha Donoghue, a lead medical officer in OHOP’s Division of Oncology Products II, said during the workshop that the agency must accept that while sponsors must include enough data in their applications to extrapolate efficacy across several tumor types, the sponsor will not be absolutely sure of a drug’s effect for every biomarker-drug-tumor combination.

Donoghue said the agency is considering “how we can use real-world data to address this residual uncertainty that we have about the outcomes of patients who receive drugs on a tissue-agnostic basis.”

Donoghue also said the agency will address its uncertainty based on the data package in hand. A lack of evidence could mean carving out some tumor types or certain patient subsets from an approval.

The FDA’s Keytruda tissue-agnostic approval received accelerated approval, even though it could have gained a full approval, in part so the agency could mandate long-term follow-up of the response durability. (Also see “Supplemental Oncology Approvals: ‘Reverse Accelerated Approval,’ Not Lowering The Bar” – Pink Sheet, 27 Nov, 2017.)

Former FDA Commissioner Scott Gottlieb suggested that accelerated approval could be expanded in rare disease and other areas to confirm the benefit seen in small development stage clinical trials and allow marketing sooner. (Also see “‘Progressive Approval’ Coming? US FDA Considers Accelerated Approval Without Surrogates” – Pink Sheet, 30 Nov, 2017.)

Use Of Real-World Evidence Growing

While the FDA has used real-world data for safety-related changes, it also is working along several fronts to build confidence in real-world evidence and its use in drug development.

The agency is attempting to replicate 30 clinical trials by March 2020 using claims data (Also see “Real-World Data Could Get Boost From Trial Replication Project” – Pink Sheet, 26 Apr, 2018.), and has several other demonstration projects ongoing, including one involving a mobile app aiding patient data collection. (Also see “Real-World Evidence Demo Projects From US FDA To Include New Mobile App” – Pink Sheet, 6 Nov, 2018.)

In addition, the agency in December 2018 released its framework for how real-world evidence may support efficacy determinations (Also see “US FDA Is Hesitant About Using Observational Studies In Real-World Evidence Framework ” – Pink Sheet, 6 Dec, 2018.), although industry wants observational studies to receive more weight. (Also see “Real-World Evidence: Observational Studies Deserve More Respect In US FDA Framework” – Pink Sheet, 30 Apr, 2019.)

https://pink.pharmaintelligence.informa.com/PS125236/RealWorld-Evidence…