Challenges in initiating and conducting personalized cancer therapy trials: perspectives from WINTHER, a Worldwide Innovative Network (WIN) Consortium trial

Abstract

Advances in 'omics' technology and targeted therapeutic molecules are together driving the incorporation of molecular-based diagnostics into the care of patients with cancer. There is an urgent need to assess the efficacy of therapy determined by molecular matching of patients with particular targeted therapies. WINTHER is a clinical trial that uses cutting edge genomic and transcriptomic assays to guide treatment decisions. Through the lens of this ambitious multinational trial (five countries, six sites) coordinated by the Worldwide Innovative Networking Consortium for personalized cancer therapy, we discovered key challenges in initiation and conduct of a prospective, omically driven study. To date, the time from study concept to activation has varied between 19 months at Gustave Roussy Cancer Campus in France to 30 months at the Segal Cancer Center, McGill University (Canada). It took 3+ years to be able to activate US sites due to national regulatory hurdles. Access to medications proposed by the molecular analysis remains a major challenge, since their availability through active clinical trials is highly variable over time within sites and across the network. Rules regarding the off-label use of drugs, or drugs not yet approved at all in some countries, pose a further challenge, and many biopharmaceutical companies lack a simple internal mechanism to supply the drugs even if they wish to do so. These various obstacles should be addressed to test and then implement precision medicine in cancer.

Keywords: biomarker; clinical trials; personalized cancer therapy.

Figure 1.

Design of WINTHER trial. In the WINTHER trial [14], each patient undergoes a biopsy of the tumor (or metastasis) and normal tissue from the organ of origin of the tumor. A complete biological profiling of DNA and RNA is undertaken. The choice of therapy is rationally guided either by matching actionable targets (mutations, amplifications, gene rearrangements) found in the tumor (arm A) or the tumor gene expression with the algorithm-predicted sensitivity of the drug based on the WINTHER algorithm (arm B). Launched by the WIN Consortium (Worldwide Innovative Networking Consortium in personalized cancer medicine), it is an international effort with six centers participating in the trial from five different countries, and three laboratories analyzing samples (Foundation Medicine in the United States for NGS; Gustave Roussy Cancer Campus in France and Ambry Genetics in the United States for transcriptomics). It uses two different platforms and knowledge bases as well as a clinical management committee that functions like a molecular tumor board for treatment decisions, and considers both FDA-approved and experimental drugs as potential options for patients. The bioinformatic analysis (WINTHER algorithm) is being carried out jointly by Gustave Roussy Cancer Campus and Ben Gurion University, Israel, and the WINTHER algorithm will be improved and developed together with Ariana Pharma, Paris, France. T, tumor biopsy; N, normal tissue biopsy; PFS, progression-free survival; TTP, time to progression.

Figure 2.

Timeline for WINTHER Activation by Country and Process (analysis as of September 2014). IRB approval times (from submission of the protocol to approval) ranged from 1 month in France to 10 months at MD Anderson in the United States. Delays in regulatory approval in the United States were mainly due to requirement for CLIA and, most importantly, FDA oversight. The dark grey (blue online) bars: timing of the different processes in project development. The black (green online) bars: timing of United States-specific processes in project development. The light grey (pink online) bars: timing of the project implementation in each country (from protocol availability to activation of the site in the site initiation visit). The latter includes the time required for IRB and Health Authority review that are further described in the embedded table. Some processes may occur in parallel and, in some institutes, additional processes beyond IRB and health authority approval were needed before activation could occur. CLIA, Clinical Laboratory Improvement Amendments; IDE, Investigational Device Exemption. Single asterisk: ‘Process for Health Authority approval’ denotes initial time from investigator decision to ask health authorities what kind of approval was needed to final Health Authority deliberation. The time for Health Authority approval may overlap with time from protocol submission to IRB approval at least in part, as processes were carried out in parallel. Double asterisk: The initial protocol had to be amended following FDA specifications. It therefore took 36 months to have a final regulatory-approved protocol after concept initiation. Triple asterisk: Total time added to study process by need for FDA oversight was 16 months including: 1 month to plan risk assessment request, 12 months for FDA to approve study (includes initial assessment as significant risk necessitating submission of IDE, preparation of IDE, rejection of FDA by IDE, re-evaluation of risk assessment by FDA with new determination of nonsignificant risk, and amendment of protocol per FDA request).