Managing Multi-Arm Studies

Transcription

1 White paper Managing Multi-Arm Studies in an Evolving Immuno-Oncology Landscape Immuno-oncology studies are getting increasingly complex, but sponsors can minimize risks by working more collaboratively with CROs and trial sites. Jennifer Cubino, MA, CCRA, Senior Director, Customer Operations, Customer Solutions Management Group Peter Fredette, Associate Site & Patient Networks Director, Oncology Kerry Gorman, Associate Director, Quintiles Site Management and Therapeutic Strategy Terry Murdock, MS, Vice President and Global Head, Oncology Center of Excellence Special contributors: Sarah Cannon Research Institute, Clinical Operations Group

2 TABLE OF CONTENTS Introduction 3 A paradigm shift in early phase oncology trial design 3 Call to action for closer collaboration 4 Case study: Adapting to new cohorts at Sarah Cannon Research Institute 5 How to prepare for a complex immuno-oncology study 6 Key takeaways 8 References 9 About the authors 12

3 Introduction Immunotherapy has begun to revolutionize cancer treatment by introducing therapies that target the host immune system, not the tumor. Advances in cancer vaccines, CAR T-cell therapy, checkpoint inhibitors, cytokines, interferons, and other therapies are transforming standards of care for cancer patients and in some cases dramatically improving survival rates. 1 50% Cancer immunotherapy drugs share of the overall oncology market These successes have spurred a wave of excitement and investment in immuno-oncology research. In 2015 alone, the U.S. Food and Drug Administration (FDA) approved several cancer immunotherapies, 2 including the first immunotherapies for lung cancer 3 and children with cancer. 4 Cancer immunotherapy drugs currently represent roughly 50 percent of the overall oncology drugs market, generating about $41.0 billion in 2014 alone, and by 2020, the market is expected to double, generating in excess of $80 billion for the biopharmaceutical industry. 5 The medical and clinical impact of these therapies promises to be enormous. As the industry improves its understanding of how these agents work, innovations will continue to emerge, particularly in the use of combinations of these immunotherapies, which may be additive or even synergistic. A paradigm shift in early phase oncology trial design These advances in immunotherapy development are adding tremendous complexity to the clinical trials supporting this research, particularly in the way that early phase oncology trials are planned and managed. Many of these projects utilize adaptive Phase I study designs that support the FDA accelerated approval pathway, as well as trial designs that can reduce development timelines and avoid the need to conduct multiple trials replicating earlier findings. These trials are often substantially larger and more complex than traditional Phase I efforts, with the potential to include 1,000 or more patients. The rapid advances in clinical development of immunotherapies across multiple indications is also causing parallel shifts in standards of care and to the research landscape. As a result, trial leaders need to be ready to shift direction mid-stream by changing control arms, or expanding the number of arms when early results suggest these agents might be applicable for different tumor types and patient populations. Challenges of a shifting landscape When research sites are expected to manage multiple arms of a research protocol each with a unique schedule, protocol, lab requirements and monitoring needs it gets increasingly difficult for them to meet the day-to-day goals of the trial. These are exciting developments for cancer care and cancer research, but it can be extremely challenging for all stakeholders conducting these clinical trials. When research sites are expected to manage multiple arms of a research protocol each with a unique schedule, protocol, lab requirements and monitoring needs it gets increasingly 3

4 difficult for them to meet the day-to-day goals of the trial. Interviews with site research coordinators involved in these studies have surfaced frustrations with cumbersome form changes, the need for additional training, difficulty determining availability for patients in different arms, shifting budget requirements, and regulatory challenges driven by the complex adaptive trial designs. Lack of communication and transparency can further aggravate the process, requiring the research sites to deal with often unnecessary obstacles. These might include overlapping data deadlines, insufficient lab kits to meet new amendment requirements, and/or confusion about which protocol arms have openings. This can cause delays or errors in data collection, improperly managed samples, and even cause patients to miss out on trial participation. But it doesn t have to work this way. Call to action for closer collaboration Better strategy begins with choosing partners that have the expertise and experience to manage complex immuno-oncology trials covering multiple indications, and who can access additional staff and resources to respond and adapt when trials evolve. To best prepare for this complex trial environment, sponsors should involve research sites and CRO partners early in the planning process, and seek out their feedback on best practices for managing the inevitable changes these adaptive trials undergo. Even relatively simple changes, such as consolidating and coding lab kits for easy use, creating formal plans for enrolling patients into new arms, and utilizing easy-to-use cohort management tools to track enrollment status across multiple arms in real-time can help to manage these changes effectively. Taking the time up front to assess potential risks and identify mitigation strategies can reduce confusion and frustration and ultimately improve a complex trial s probability of success. Taking the time up front to assess potential risks and identify mitigation strategies can reduce confusion and frustration and ultimately improve a complex trial s probability of success. CROs and sponsors can also work more closely with sites to assess feasibility on an ongoing basis. With so many changes likely to occur over the course of a trial, it becomes essential to more frequently assess recruitment potential and shifts in patient treatment pathways in relation to the trial at hand. Sites can also take these opportunities to reassess infrastructure, resources and budgetary items, so that they can proactively identify the need to expand or contract in response to shifting site trends. Transparency and communication in these exercises allow for CROs and sponsors to better plan budgets and timelines for things such as potentially bringing on new sites or closing some down, providing additional training or tools, or meeting additional site resource needs. Properly preparing for and accommodating these needs can help improve efficiency and speed in the overall process. The following case study and more specific examples will help highlight some key efforts in better strategic collaboration in planning for successful completion of complex, adaptive clinical trials: 4

5 CASE STUDY: Adapting to new cohorts at Sarah Cannon Research Institute A world class site leader reflects on the value of collaboration for multi-arm, complex Phase 1b study designs. As the research arm of HCA s Global Cancer Institute, Sarah Cannon Research Institute (SCRI) understands the complexity of multi-arm, complex Phase 1b studies. Based in the community, SCRI physicians see all types of patients and can successfully enroll them across multiple tumor types, making them perfectly positioned to work on these types of multi-arm, complex Phase 1b studies. The organization has led more than 220 first-in-man clinical trials since its inception in 1993, and has been a clinical trial leader in more than two-thirds of approved cancer therapies over the last 10 years. SCRI s experience in oncology research, broad network of experts and trial sites, and proven history of success make it an ideal partner for running multi-arm Phase 1b studies. However, working with a world-class site network is only one step in achieving success on these types of trials. To be as efficient as possible, all the stakeholders need to work more collaboratively so they can address problems as they arise. These issues are not insurmountable, but they do require a lot more up-front planning, says Amanda Bilbrey, senior director of clinical operations at SCRI. When we have early conversations, we can plan for all of the expectations and operational concessions that will need to be made. Having a more collaborative environment also leads to better communication, especially during times of change, so that all parties understand how trial expansion will impact aspects such as site operations, budget, timeline, staffing and monitoring requirements. When the trial design changes, the site has to adapt with it, Bilbrey says. For example, timing, duration and overlap of serial pharmacokinetic (PK) testing, and the additional infrastructure sites need to manage new samples can be difficult to adapt to without prior warning. When the sponsor is first considering a new cohort, it is a good time to talk with investigators and site staff about the feasibility of the addition, Bilbrey says. That gives the site team time to discuss key considerations, such as whether to amend procedural requirements, and/or whether certain cohorts might be best served through expansion to additional trial sites so that they can access new patient populations, infrastructure and staff. When we collaborate early, we can provide feedback on the best approach before protocols are amended, Bilbrey adds. This process helps minimize the disruption, and provides sponsors and CROs with valuable insight on how to address these changes most effectively. 5

6 Having advanced notice of new cohorts can also help with recruiting. When our team is notified at an early stage, we can begin generating excitement about the new opportunity, says Cassie Lane, program manager of Phase 1B trials at SCRI. The extra time can help launch recruiting efforts, and allow site leaders to adapt their processes to accommodate simultaneous enrollment for multiple patient populations. The more sites are able to collaborate with CROs and sponsors, the easier it is for everyone to address specific concerns that could affect the study. It is the best way to set the trial up for success, Bilbrey concludes. How to prepare for a complex immuno-oncology study Sponsors face a host of challenges on these complex trials, but they can mitigate their impact by following these four tips: 1. Stay ahead of evolving standards of care. Every time one of these groundbreaking immuno-oncology products comes to market, it has the potential to change the standard of care for patients, which can complicate the issue of selecting appropriate controls and determining whether patients are available for the study. Such changes are unavoidable, but sites and sponsors can prepare themselves for these changes during the planning stage of the trial by developing a communication plan and clear chain of command to quickly amend protocols if the need arises, and to communicate those changes to all stakeholders, from sponsors to patient-facing staff. They may also want to provide additional training and ongoing support to site monitors and investigators on advanced safety signal monitoring, evolving toxicity management guidelines, and the importance of tracking immuno-related events as evidence of progression. Trial teams should stay abreast of industry trends, tracking development projects that could potentially impact their research process if new products come to market, and consider if any of their targets are vulnerable to rapidly evolving standards of care, such as with chronic lymphocytic leukemia (CLL) and second line non-small cell lung cancer (NSCLC). By staying attuned to changes in the market, trial leaders are better positioned to proactively adapt, with minimal disruption to trial progress and to the sites, while also reducing any chance of increased burden to the patients and their caregivers. By staying attuned to changes in the market, trial leaders are better positioned to proactively adapt with minimal disruption to the trial, site and patients. 2. Be ready to adapt to enrollment peaks and valleys. Preparing for rapid enrollment is key for all the study stakeholders. Plans need to be made and implemented to keep data analysis up-to-date, as well as proactive planning with all team members about how to adapt if enrollment rates surge. Identifying back-up staff to perform rapid data entry and query resolution and conduct ongoing site monitoring is key. Site leaders should also consider cross training key staff so they have the flexibility to fill-in where necessary to keep project timelines and data delivery on track and assist teams that need additional help. 6

7 3. Plan for new safety signals and combination therapies. Combination therapies can deliver improved results for cancer patients but they add further complexity to these already complicated trials. Site staff also have to be keenly attuned to adverse event risks and safety monitoring of these patients, as combination therapies have been known to generate unacceptable levels of toxicity, even when each compound on its own has been found to be minimally toxic. In response, site investigators must be trained to identify immune-related adverse events and have strategies in place to alert the CRO and sponsors as soon as any issues arise. Investigators and site staff also need to be prepared to look for early safety signals on these combination therapy trials which may lead to the need for rapidly redesigning protocols, clinical databases, electronic case report forms and downstream biostatistical analysis in response. These changes can require additional training and planning time, which sponsors should consider when planning their schedule and budget. 4. Clearly define processes for capturing and handling patient samples. Immunotherapy research requires experienced site staff who can rapidly submit priority samples and limit the number of missed critical samples. The complexity of managing multiple armed studies, each arm with different sampling requirements, represents a growing challenge for site research partners. In addition to effectively managing sample collection, the Sponsor or CRO should have developed a prospective plan to assess for missing samples, database reconciliation and any data cut-off requirements for sample handling. Thoughtfully developing a robust and well coordinated plan for biosample handling and management helps ensure that all data are carefully captured accurately and completely. We have found the best approach to managing this critical aspect of a clinical trial is to assign a Sponsor or CRO project management resource whose job is to follow up on all samples and to track collection, shipment and sample reporting. This dedicated resource will also work in close collaboration with the central lab provider and analysis vendors to prevent any mistakes. Sponsors also need to have a clear understanding of the patient and site impact of biomarker testing and devise a thorough trial plan that aligns the right tests and timing to trial arms. Sponsors should consider harmonizing lab kits across the study arms, whenever possible, to make sample collection easier to manage. This results in increased sample data quality and greatly reduces wasted laboratory kits and supplies. Effective tissue sampling and biomarker testing are a critical component of these trials, as they determine whether an agent is having the desired result, and which populations respond to certain treatments and why. Good testing supports faster decision making, and helps stratify patient populations based on initial results. Sponsors who identify these concerns in the planning stages, and work collaboratively with their CRO and research site partners, can overcome any challenges that arise and improve their probability of success. 7

8 This evolving trial environment requires clear and frequent communication between all stakeholders, as well as a culture of flexibility wherein all staff are ready to adapt to new trial parameters on the fly. This is achieved through greater collaboration and more robust planning and management strategies, where stakeholders proactively identify the challenges and establish monitoring, communication and contingency strategies to rapidly adapt to the shifting demands. Key takeaways These projects take strong leadership and sophisticated site teams who are accustomed to adapting to changes while still adhering relentlessly to safety and data management requirements. To make the most of these trials sponsors should: 1. Build an experienced team. Sponsors need to work with CROs who ve done this before, because they are best positioned to understand the risks and how to deal with them. Sponsors should look for partners with: Specific experience running immuno-oncology trials. Proven strong leadership and project managers who are dedicated to the trial. Well-established relationships with leading sites and key opinion leaders that have experience in running immuno-oncology trials. This combination of experience and leadership should give sponsors the confidence they need that their team can manage even the most complicated trial environment. Planning ahead, choosing good partners, empowering site leaders, and cross-training staff will go a long way toward improving adaptability, which will further increase the chances of success. 2. Plan ahead. These are complicated trials, but most of the challenges trial leaders will face can be addressed through thorough up-front planning and risk management strategies. Whether it s cross-training site monitors, establishing a clear process and calendar for enrollment, or giving site staff a single database to track their supply chain, putting these solutions in place ahead of time can prevent endless headaches and mistakes down the line. 3. Create a culture of collaboration. It is not enough to choose good partners. Sponsors also need to work collaboratively with their CROs and site leaders to proactively identify and solve problems before they effect trial progress. In many cases the best ideas will come from the sites themselves, who are accustomed to dealing with the day-to-day operations and can identify simple changes to reduce the delays, quality errors and patient attrition that can often plague these projects. 4. Be flexible. In immuno-oncology research the only constant is change. For these trials to work, stakeholders have to be willing and able to adapt. Planning ahead, choosing good partners, empowering site leaders, and cross-training staff will go a long way toward improving adaptability, which will further increase their chances of success. 5. Harmonization. Harmonize design during the planning of the study arms, including the schedule of events, timing of samples, edc design and lab kits, to improve quality and decrease costs. 8

9 References usa-cancer-immunotherapymarket-analysis forecasts-to html 9

10 About the authors Kerry Gorman Associate Director, Quintiles Site Management and Therapeutic Strategy Kerry works closely with research sites to develop relationships that foster mutual engagement along with developing strategies that align organizations to increase efficiency in clinical study conduct. Over the past decade, Kerry has worked both on the site side and the CRO side of the research equation, developing relationships that provide the foundation for mutual success in research projects. Prior to working in clinical research, Kerry worked for large pharma in sales and helped launch and develop an on-line medical education site that provided expert opinions on current medical literature for peer education. Kerry received her Bachelor of Arts Degree from the University of Central Oklahoma. Peter Fredette Associate Site & Patient Networks Director, Oncology Peter Fredette has over 17 years of experience in the drug development industry, including pre-clinical toxicology and all phases of clinical research. He is most experienced in oncology but has worked across more than a dozen therapeutic areas. Peter s current responsibilities include site and patient feasibility for global and domestic oncology trials; supporting CRO-site alliances; and implementing strategies to improve quality and accessibility of clinical trials for cancer patients around the world. Prior to this, Peter has held a variety of roles at Quintiles over the last 15 years, including trial monitoring, project management, and site and investigator relations. 10

11 About the authors Jennifer Cubino, MA, CCRA Senior Director, Customer Operations, Customer Solutions Management Group Jennifer Cubino has worked in clinical research for 13 years and has held roles in strategy, innovation, site alliance management,precision medicine, operations, clinical trial management and monitoring. In her role at Quintiles, she ensures seamless oncology portfolio delivery for large pharma customers. She also provides strategic oversight and planning to project teams in developing biomarker, operational, site and patient recruitment strategies and effective risk mitigation. Her therapeutic expertise includes: oncology, infectious disease, respiratory and psychiatric studies in Phases I-IV. She is experienced in creating solutions for development of biomarker targeted molecules and CDx strategies cross therapeutically. Jennifer was an appointed member of the Tufts Medical Center IRB for seven years and completed her Bachelor of Science at Cornell University, College of Agriculture and Life Sciences and Master of Arts in Clinical Research at Boston University, College of Medicine. 11

12 About the authors Terry Murdock, MS Vice President and Global Head, Oncology Center of Excellence Terry L. Murdock is vice president and global head of the Oncology Center of Excellence at Quintiles. He focuses on developing insights and innovations that help improve the probability of success of Quintiles oncology customer development projects and programs. As part of a team, he provides customers with alternative and innovative design aimed to improve the efficiency of development of oncology assets. Terry has 20 years of work experience as a successful senior executive in the medical research industry, specializing in oncology, multiple sclerosis and other autoimmune diseases. He is experienced at establishing operational excellence within culturally diverse environments with a track record executing operational, clinical and commercial plans. Prior to joining Quintiles, Terry held senior positions focused on clinical drug development at Ergomed, Genzyme/Sanofi, ILEX Oncology and US Oncology. Terry earned his M.S. in biology and a B.S. in microbiology from the University of Texas at Arlington. He is a registered microbiologist for the American Society of Clinical Pathology and a registered medical technologist for American Medical Technologists. Contact us at Copyright 2016 QuintilesIMS. All rights reserved _QI