This year’s Friends of Cancer Research (Friends) Annual Meeting started with a morning keynote by Anna Abram the Deputy Commissioner for Policy, Planning, Legislation and Analysis at the U.S. Food and Drug Administration (FDA). Abram discussed many different initiatives that have been led by Friends over the years including the breakthrough therapy designation, FDA Oncology Center of Excellence, updating product labels, and expanding clinical trial eligibility criteria. She noted that half of the approvals from the breakthrough therapy designation are for oncology and how the Oncology Center of Excellence has already yielded results for patients. Abram went on to note that clinical trials are getting increasingly more complex and costlier to administer, which could deter enrollment and delay completion. To help counteract this, Abram discussed a pilot program at FDA that will give sponsors the opportunity to discuss study designs with FDA. Abram announced during her keynote that for 2019 FDA will have the funds to tackle labeling updates. This will include timely inclusion of data into labels, particularly for generic drugs and labels out of date. This relates to a recent study conducted by Friends that demonstrates many FDA-approved cancer drug labels are missing critical information on drug effectiveness. Senators Hatch (R-UT) and Bennet (D-CO) recently introduced a legislative solution, Making Objective Drug Evidence Revisions for New Labeling Act or MODERN Labeling Act, to the Senate. Abram concluded her keynote by noting how at the end of the day, all of the work done by those attending the Friends Annual Meeting and at FDA is for patients.
Panel 1: Augmenting Randomized Confirmatory Trials for Breakthrough Therapies with Historical Clinical Trials Data
The first panel explored the opportunity of utilizing historical clinical trials data to support oncology drug development and assess treatment effect size. While randomized controlled trials (RCT) remain the gold standard, conducting randomized confirmatory trials in rare cancers or for therapies that have demonstrated large treatment effect over available therapies can introduce ethical concerns or loss of clinical equipoise that may interfere with the continued drug development. Elizabeth Stuart from Johns Hopkins University moderated the panel discussion and outlined the need and challenge of using historical comparison data within a clinical trial. Andrea Ferris of LUNGevity noted that such analyses could allow for more patients to receive a potentially beneficial therapy and would allow an opportunity for additional information to be extracted from single arm studies.
Two case studies were presented to explore whether historical comparison data can be matched to a randomized control arm and yield similar outcomes. Ruthie Davi, Vice President of Data Science at Medidata, presented a case study in non-small cell lung cancer (NSCLC) to assess whether a synthetic control arm can be created to replicate the outcomes of a traditional randomized control. Pallavi Mishra-Kalyani from the FDA presented a second case study in melanoma that assessed overall survival and progression free survival when the randomized control arm was replaced with an historical control arm. Both case studies showcased the potential utility of these analyses, which represents an important step to understanding how to overcome challenges associated conducting a randomized controlled trial in difficult to study indications.
Antoine Yver from Daiichi Sankyo and Joohee Sul from the FDA noted the regulatory implications and opportunities of using this type of data in clinical trials and were optimistic and encouraged by the case studies presented at the meeting. Raji Shridhara at FDA noted that the sources of data (e.g., registries, electronic health records, and historical clinical trials) would determine potential use and the compatibility of endpoints, temporality of data, and idiosyncrasies are other factors to consider. All the panelists stressed the need to proceed but to proceed with caution. Several next steps include assessing whether the treatment effect can be replicated with the use of an historical comparison arm, optimize matching methods and analyses, and explore additional indications.
This year’s lunch conversation was between the Director of the FDA Oncology Center of Excellence (OCE), Dr. Richard Pazdur and FDA’s Dr. Gideon Blumenthal and Dr. Amy McKee. The conversation focused on the OCE and how it is revolutionizing and streamlining cancer product review. There was a focus by all three participants in cultivating disease experts since it assists with internal communication and functions at FDA and allows for consistent advice to be disseminated to industry across therapeutic areas. There was also an emphasis on the need to get the OCE “right” since it is the pilot project for other Centers of Excellence at FDA, and it was stated that so far, the Center has run well and accomplished what it set out to do: yield results for patients in an efficient and streamlined manner.
Panel 2: Identifying and Establishing the Role of Circulating Tumor DNA in Cancer Drug Development
The second panel discussed the role that liquid biopsies, more specifically, circulating tumor DNA (ctDNA), may have on monitoring a patient’s tumor response, and how this tool may be relevant in cancer drug development.
The working group developed a white paper that laid the rationale for the use of ctDNA as a feasible and less-invasive method to assess treatment response in patients with cancer. The white paper proposed the development of a proof-of-concept study, or pilot project, where ctDNA and treatment response data from several clinical trials testing PD-(L)1 inhibitors would be prospectively collected, aggregated, and analyzed to assess how feasible it is to use ctDNA as a monitoring tool in drug development.
The main themes of the white paper were presented by the moderator, Geoffrey Oxnard of the Dana-Farber Cancer Institute, who provided a robust rationale for the need to operationalize ctDNA in drug development. Dr. Oxnard observed that many clinical trials already collect ctDNA material, so the standardization of data analyses would greatly benefit the field. Jean-Charles Soria of MedImmune and David Shames of Genentech – a member of the Roche Group, agreed that ctDNA is already being collected and used in clinical trials, and that its operationalization as a monitoring tool in drug development would promote faster turn-around times for defining treatment response, which would greatly help patients and clinicians in decision-making and treatment selection.
Panelists representing the FDA included Julia Beaver of the Center for Drug Evaluation and Research (CDER) and Reena Philip of the Center for Devices and Radiological Health (CDRH). They encouraged for (1) more research to be conducted to understand and properly validate the assay that measures ctDNA in blood; (2) to further refine what is being measured and analyzed when assessing ctDNA and patient response; and (3) to continue collecting high-quality data that could be used to test the feasibility of using ctDNA as a primary endpoint in a clinical trial. Darya Chudova of Guardant Health shared that other organizations are already working on setting standards on the analytical validation of ctDNA assays and ctDNA measurements, which will promote greater recognition of ctDNA as a valid tool in drug development.
Drug sponsor representatives showed collective interest in participating in the pilot project that would collect data from ongoing and planned clinical trials in a standardized way and were amenable to keep exploring the idea of sharing and aggregating ctDNA data. Jamie Holloway, a patient advocate who provided the crucial patient perspective commented on how patients would be happy and willing to help in these efforts by providing blood that will help to better understand ctDNA as a tool. The panelists recognized that this is ongoing work and that there are many more questions that need to be addressed and refined to fully understand the usefulness of ctDNA in drug development.
As a next step, Friends is creating a consortium that will seek to address these questions through the implementation of the pilot project and thus, generate high-quality and standardized data that may be used to accelerate drug development and inform the use of ctDNA to measure response to therapies.
Panel 3: Real-time Oncology Review: Streamlining Data Submissions and Ensuring Data Quality
The afternoon keynote, featuring Janet Woodcock, Director, CDER, FDA, set the stage for the third panel discussion on Real-time Oncology Review (RTOR). During her address, Dr. Woodcock proposed “for us all to get together… to look at every single part of the regulatory process and think about how it could be done better.” She opined that regulatory agencies around the world still rely on “digitized paper” where submissions in the form of PDFs hamper the regulatory process and praised the RTOR pilot as an innovative effort that is helping to remove artificial barriers for certain regulatory submissions.
Katherine Couvillon, breast cancer survivor and patient advocate, explained to the audience why the last panel of the day, Real-Time Oncology Review: Streamlining Data Submissions and Ensuring Data Quality, was an important one as she shared her own story of battling cancer and the breakthrough therapy that enabled her to continue the fight. As Katherine poignantly said, “One month can make a huge difference for a patient.”
The RTOR panel was moderated by Michael McCaughan of Prevision Policy and opened with a presentation from Qi Liu, FDA, describing the RTOR pilot and the first two RTOR supplemental approvals as case studies. The panel featured discussion from FDA and industry representatives involved in the first two RTOR approvals who described the experience with the pilot as very innovative on the part of FDA and sponsor that streamlined and improved the efficiency and quality of the review process. The panel acknowledged that the ultimate benefit of RTOR will be realized by expanding beyond simple supplemental applications. Moving forward, considerations regarding inclusions of manufacturing components and companion diagnostic claims will need to be identified.
Media Coverage of Friends Annual Meeting 2018
Off The Clock? The New Timelines Of “Real-Time Review” – Pink Sheet (11/27)
Woodcock Pushes for Major Digital Shift in Regulation – Regulatory Focus (11/14)
Reliance On ‘Digitized Paper’ Is Slowing Drug Development – US FDA’s Woodcock – Pink Sheet (11/14)
FDA Begins Updating Generic Chemotherapy Labels – Regulatory Focus (11/13)