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Over the last decade, many initiatives sponsored by various entities, including academic and clinical research centers have focused on efforts to streamline clinical trial eligibility and data collection. Oncology trial design is no exception as endpoints and eligibility criteria have also changed with the value of the data generated in early phase studies.
Over the last decade, many initiatives sponsored by various entities, including academic and clinical research centers [e.g., American Society of Clinical Oncology (ASCO), Friend of Cancer Research (FOCR)], pharmaceutical companies, patient advocacy groups, global regulatory and government agencies; have focused on efforts to streamline clinical trial eligibility and data collection as presented in a transformational ASCO 2011 campaign entitled “Accelerating Progress Against Cancer–ASCO’s Blueprint for Transforming Clinical and Translational Cancer Research.” Other important efforts are the 2012 passage of the Advancing Breakthrough Therapies for Patients Act which created expedited pathways for patient access to new drugs, and the 2014 21st Century Cures Initiative that focused on modernizing clinical trials with digital tools to facilitate data sharing to achieve rapid development of drugs and devices for unmet medical needs. To parallel these efforts, the FDA updated their guidance documents and rolled out expanded access and breakthrough therapy designation programs by explaining how single-arm trials may be used to support approval. During the Conference on Clinical Cancer Research in 2015, Dr. Richard Pazdur, Director of FDA Office of Hematology and Oncology Products, expressed his strategic vision to improve navigation through the drug approval process within the expanded access system in order to improve the informed consent processes, the need for eligibility criteria justified by science to improve patient access and develop best practices for big data and data sharing.
Modernizing Eligibility Criteria
Clinical trials designed for regulatory approval are usually drug centric with restrictive eligibility criteria. The concept is to enroll a narrowly defined homogenous patient population by limiting variables that could impact the efficacy endpoint and provide a better chance for drug approval; albeit, a narrowly indicated population for labelling. A more patient centric approach has an expanded eligibility criteria where more patients are eligible for study participation, which results in faster study enrollment, exposes more patients to study drug treatment and data generalized to more patients.
As oncology clinical study designs now center on selecting the right therapy for the right patient in a variety of different adaptive designs, such as basket and umbrella trials, the trial endpoints and eligibility criteria have also changed along with the value of the data generated in early phase studies. Regulatory agencies have streamlined pathways to move drugs with enhanced activity on progression free survival (PFS) and response endpoints to ultimately reach patients faster by accelerating approval and breakthrough status programs. An example of a streamlined pathway is the accelerated approval of Keytruda® (pembrolizumab) based on the results from a single biomarker-based Phase IB study (KEYNOTE-001).
As cancer care paradigms have evolved, so too have clinical trial designs evolved to include these complex strategies, striking the balance between having too permissive or too restrictive eligibility criteria that can impact study success and timely completion. A recent Journal of Clinical Oncology (JCO) special article entitled “Modernizing Eligibility Criteria for Molecularly Driven Trials” by Edward S. Kim, MD et al1 reviewed trial eligibility requirements in the era of personalized medicine. The paper reported enrollment in oncology trials is poor, with only 5% to 8% of eligible patients participating in research studies-that number, as well as the complexity of eligibility criteria, has increased over time. For example, 13 eligibility categories were utilized in cytotoxic or non-molecularly targeted therapy protocols as compared to 32 eligibility categories were found in targeted therapy protocols, which has affected enrollment pace and the duration of the enrollment period. Kim pointed out, “many eligibility criteria are grandfathered into clinical trial protocols, not because they are appropriate for the trial, but because they were carried over from previous protocols written for similar study populations. This potentially leads to an additive effect in the number of criteria.” Following the practice can complicate the interpretation of study data and impact the applicability of the results to the intended population. The working group recommended study teams construct eligibility criteria in the context of: meeting scientific objectives, generalized to non-study populations, related to patient safety and drug toxicity concerns, and review and revise eligibility criteria on a periodic basis. These cooperative working groups plan to release several manuscripts later this year at the Fall Friends of Cancer Research (FOCR) meeting in November, which will include expanded template eligibility criteria for implementation across clinical protocols to accelerate and advance cancer care.
Biomarkers Accelerate Data Understanding
Cancer heterogeneity plays a prominent role in determining which patients may benefit from particular cancer medicines while many advanced technologies or treatment approaches have evolved to serve as biomarkers for use in drug development and assist in patient treatment. In-vitro diagnostic tests, companion diagnostics (e.g., assay to detect tumor PD-L1 expression in metastatic non-small cell lung cancer [NSCLC]) and molecular marker-based imaging tests may serve as biomarkers for treatment prediction, response assessment, determination of pharmacodynamics effect or as a safety endpoint. Adaptive clinical study designs, with subgroups enriched or stratified according to biomarker test results (i.e., marker positive or negative groups), are useful to characterize drug performance, and to modify study designs when treatment is found to be futile or unsafe in the biomarker negative group. This approach was discussed in a recent Journal of the American Medical Association (JAMA) paper by Mark G. Kris, M.D. who reported matching cancer patients to targeted therapy-based on tissue biomarkers or plasma testing (e.g., digital or quantitative polymerase chain reaction [PCR] used to detect circulating tumor cells and cell free tumor DNA) have been shown to improve patient survival compared to patients assigned to non-matched targeted therapy2. More than 60 commercial products are available using these techniques (e.g., Biocept Oncotype IQ®, Liquid Genomics®). The advantages of using plasma-based testing over traditional tissue biopsy’s sampling (i.e., technique limitations include obtaining inadequate biopsy samples, potential procedural complications and costs) in future clinical studies include the ease of obtaining samples, faster reporting of results, and the ability to acquire serial samples with greater sensitivity to monitor therapy response and detect changes earlier, as compared to traditional CT or MRI-based imaging assessments3. As these tests gain more clinical validity, as represented by FDA’s recent approval on June 1, 2016 of the first blood-based test to detect EGFR mutations as a companion diagnostic for treatment with erlotnib [Tarceva®], clinicians and researchers will be able to use rapid testing when making treatment decisions for newly diagnosed or progressing patients.
Together with traditional anatomic imaging techniques (e.g., X-ray, CT, MRI, or US), which are very good at visualizing pathology or the extent of disease in terms of the number, size and overall appearance of tumors; the advance of imaging biomarkers (while using molecular tracers and advanced imaging techniques such as PET, SPECT, MRI or MR Spectroscopy) with greater sensitivity or better spatial resolution, provide a noninvasive tool to monitor anticipated drug related effects on tumors. Receptor level imaging biomarkers can target cell proliferation, apoptosis, glucose metabolism, amino acid or lipid synthesis, etc. and are useful across all phases of drug development to evaluate disease distribution, disease response and biological characterization. The following examples demonstrate how tumor evaluation with imaging biomarkers may be used in research.
Evaluating tumor angiogenesis and new vessel formation-related treatment changes may be imaged with perfusion CT, dynamic contract enhanced DCE MRI as well as PET imaging. Drugs that alter tumor cellular density may be quantitatively measured with diffusion weighted MRI (DWI MRI), which has been shown to be a sensitive predictor of overall response. Receptor level imaging can be performed with a variety of PET or SPECT techniques: cellular proliferation may be demonstrated with F-18 FLT PET, MR spectroscopy or DWI MRI and apoptosis may be evaluated with 18F- Annexin labeled PET or DWI MRI. The FDA has approved several molecular biomarkers such F-18 FDG, C-11 Choline, F-18 FACBC and many other tracers such as F-18 FLT, F-18 FDHT, F-18 NaF. F-18 FMISO, F-18 FETNIM, etc. are available in academic labs as well as in many countries outside the USA.
Biomarkers provide the diagnostic tools and information necessary for risk stratification, therapeutic response prediction and monitoring of response. Over the last decade there have been significant advances to qualify and validate the data in larger multicenter cohorts which have accelerated our understanding of their utility and relationship to traditional response measures in the cancer treatment paradigm, such as PFS or survival outcomes. Research efforts will continue to improve data collection methods and standardized protocols so that the interpretability of these methods can be applied to a greater number of patients and the data may play a more significant role in improving personalized medicine by selecting the appropriate drug for the right patient to achieve better overall outcomes.
Joseph Pierro, MD is chief medical officer of and Kelley Atherton, MA is a medical writer, both with Biomedical Systems.