White Paper

Braving The Complexities Of Immuno-Oncology Trials

scientist analyzing test tube of medicine in laboratory

ABSTRACT

Immuno-oncology trials are increasing in prevalence and, for many reasons, are much more complex than standard clinical trials. Shipping, with short timelines, strict conditions for maintaining sample integrity and the need for detailed, international tracking, is complicated. Sponsors must navigate unfamiliar area-specific standards and regulations to perform site development and local lab evaluations. Once the study is underway, large quantities of data must be processed and shared. Partnering with an experienced central lab can alleviate these challenges, create efficiencies and save researchers time and expense.

THE EVOLVING IMMUNO-ONCOLOGY INDUSTRY

Since 2011, when the FDA approved ipilimumab, the first checkpoint inhibitor, immuno-oncology (IO) has gained momentum and visibility in the industry. Harnessing a participant’s own immune system to destroy tumor cells improves the chance of therapeutic success through enhanced efficacy, increased tolerability and reduced toxicity compared with conventional treatments. Monoclonal antibody therapies, cancer vaccines, cytokine therapies and adoptive cell therapies, administered independently or in combination, are offering new hope to cancer patients. Even difficult-to-treat neoplasms ranging from melanoma, non–small cell lung cancers and kidney cancers to head and neck cancers, lymphoma and acute lymphoblastic leukemia (ALL) respond to this relatively new class of therapeutics. Consequently, because many of these therapies are considered breakthrough drugs or are fulfilling unmet needs in cancer treatment, they are eligible for fast-track FDA approval.

The statistics associated with the explosive growth of this treatment type are impressive. Between 2008 and 2017, the number of ongoing IO trials increased by approximately 17 percent each year. A January 2018 Annals of Oncology survey of ongoing IO research2 counted 940 clinical-stage IO agents, 3,042 immunotherapy trials and 1,105 anti-PD-1/L1 combination trials.

Unsurprisingly, the valuable work these numbers represent is not going unrewarded. In 2016, the cancer immunotherapy market was estimated at $41 billion. By 2025, it is expected to grow to nearly $119 billion,3 and FDA approvals for these agents will appear with unprecedented regularity.

COMPLEX IMMUNO-ONCOLOGY TRIAL DESIGNS DEMAND PRECISE EXECUTION

What is not apparent from this rush of activity is how challenging IO studies are to conduct and manage. Compared with a standard single-drug, double-blind clinical trial, IO studies are extremely complex and demand precise execution. Investigators are not working from a single protocol at a single center, collecting only a few sample types that can be stored for later batch shipping and processing at a single lab. Rather, they are coordinating variable protocols at multiple sites and collecting quantities of data from numerous samples that require esoteric testing at distant facilities. Early-phase IO studies are typically adaptive, multi-armed monstrosities testing large numbers of participants.

Additionally, because the field has become so large, satisfying participant enrollment is challenging and often demands a global reach. Exacting sampling procedures requires careful monitoring and, while routine tests can be done locally, sophisticated testing may only be available at a small number of labs. In many cases, the timeline for testing is short, requiring samples to be individually shipped and processed as soon as they are collected. The logistics of maintaining sample integrity and shipping to multiple labs from distant parts of the world are deeply complex and require specialized expertise. Sharing information among all stakeholders is an organizational puzzle.


Another critical consideration is that immuno-oncology studies generate vast quantities of data that must be compiled and analyzed frequently.


Accelerated FDA approval relies on intermediate endpoints showing clinical benefits. At the same time, adaptations based on safety and efficacy performance are expected, and real-time recognition of adverse trends also relies on continual analysis.

Today’s flexible, efficient IO clinical trials are designed to bring much-needed therapies to participants as quickly as possible, but they tend to complicate clinical trial management exponentially.

SPECIFIC CHALLENGES FACED BY IMMUNO-ONCOLOGY RESEARCHERS

Global project management
Immuno-oncology researchers face numerous challenges throughout the clinical trial period.6 In the competitive IO arena, one of the first such challenges is to quickly enroll study participants and set up investigator sites. Site personnel require significant training, as the esoteric testing typical of IO studies requires detailed sample management and, often, submission of multiple sample types kept under ideal conditions. At the same time, remote research sponsors are unable to monitor to what extent each clinical site is adhering to the study protocol until the test samples reach the lab.

Sample tracking, chain of custody, and logistics
IO studies require the collection of many samples, all of which must be labeled and shipped multiple times, usually individually. For biologics in particular, timelines are short and each sample must be maintained under optimal conditions. In the case of chimeric antigen receptor (CAR) T-cell therapy, the T-cell sample must be kept at -150°C.7 Equally important, once processed, an autologous therapy must go back to the source participant; maintaining a solid chain of custody throughout its journey is paramount to success. Investigator sites are tasked not only with obtaining samples, such as non-trivial, CAR-T requiring apheresis, but also with performing all necessary labeling and shipping to specification.

Specimen processing, complex testing, and laboratory selection
Once a sample leaves the investigator site, it must be tracked to its destination — usually a lab. Further contributing to IO trials’ complexity, the labs themselves require consideration. One test or procedure may only be available at certain labs, in which case maintaining the sample’s integrity while in transit is a primary concern. Other tests required for the same study may be offered locally. If multiple facilities are engaged to perform equivalent testing, procedures and results may require harmonization to ensure the results from all labs are comparable.

Data integration, interim assessment, and reporting
Finally, handling the quantity of IO study data generated is difficult and requires seamless communication among sponsors, investigators, labs, shipping vendors and suppliers. The data should be accessible to multiple stakeholders and easily categorized. Critically important, the researchers must generate interim reports regarding safety, efficacy, biomarkers and more to guide the rest of the study and to be considered for fast-track FDA approval.

PROCESS PITFALLS AND ERROR POTENTIAL IN IMMUNO-ONCOLOGY CLINICAL TRIALS

Unfortunately, highly complex studies are prone to error, especially when the proper processes are not in place. For example, in recent occurrences, study teams have lost large percentages of their samples through processing errors, and physician groups have produced unusable genomic data by storing their clinical samples in incorrect buffers. Without systematic organization, such as that provided by an experienced central lab, IO studies can encounter a gamut of difficulties — some catastrophic.

First, working with sites in various foreign locations often results in slow setup, enrollment and staffing because the team is not familiar with the local people, customs or regulations. This lack of experience can cause study delays. Also, with sub-par communication, protocols may not be performed with 100 percent precision, varying from site to site.


The sample management required for esoteric testing and multi-arm trials is complex enough that even the best of sites can make mistakes — either one-off, or systematic.


With no simple steps and without tracking visibility before shipping, a sponsor might be inadvertently collecting false data, leading to unfounded conclusions. Or, if the error is apparent, having no insight into investigator site activities makes the mistake hard to correct.

Second, imperfect shipping or tracking can mean losing a packaged sample. It can also result in oversights going undetected, such as failure to ship or failure to hold a specific specimen at the required temperature. Sample integrity is at risk with any time delay or failure to maintain required conditions. The chance of delays under stressful conditions is greatest when the investigator site and the shipping company fail to work together. A poor tracking system can cause a break in the chain of custody — terrible in the case of a much-needed autologous anti-cancer agent — or waste many man-hours as staff members try to reconcile shipped versus received samples and locate missing packages. Errors in laboratory testing can devastate a trial. Failure to harmonize tests across labs or failure to screen labs for quality performance or calibration can result in unusable and inaccurate data.

Last, with no systematic help to format the reams of data IO studies produce, researchers can waste countless hours trying to consolidate data from multiple sites. This time-consuming transfer of data may also introduce errors. Sorting through disorganized data based on any particular criterion is difficult, so collecting covariates, recognizing adverse trends or submitting interim or final FDA reports may be delayed.

MANY SOLUTIONS IN ONE FOR COMPLEX CLINICAL TRIALS

With challenges arising from lost samples, compromised samples, data entry errors, hard-to-compile data from disparate sources, noncomparability of tests from different labs, staffing problems, delays in interim submissions and delays in adverse trend recognition, the complexity of IO trials can seem impenetrable. Is there a solution? Yes — a high-performing central lab with a global presence can serve as a central coordinator and perform many customized, integral services to keep complex studies on course, saving time and funds while helping to ensure data collected is of high quality.

Working with a central lab and dedicated experts who understand IO trials’ complexities is vitally important.


The best central lab partner will be able to provide agile project management oversight, understanding that the immuno-oncology space contains many moving components and that each trial is different.


Dedicated project managers can help facilitate logistics and manage multiple independent labs, vendors, transfers and timelines on a day-to-day basis. Central labs provide skilled professionals experienced in operational management, documentation, lab oversight, vendor management and logistics to facilitate studies.

In addition to routine testing, central labs can help sponsors ship, track and store samples with biospecimen management. Customized kits, lab manuals and the right clinical supplies simplify the process for clinical site personnel, as do tools for virtual accessioning and specially printed forms to capture data from the time specimens are collected. A way of accessioning samples at the point of collection and entering them into a tracking system that team members anywhere in the world may access is highly recommended. Sponsors’ real-time ability to “see” where a sample is and check the first data entered before the sample leaves the investigator site, or make sure the sample does leave the site, allows queries to be corrected in a timely fashion. A central lab with experience will build strong relationships with quality vendors and vet local labs around the world to ensure that all test procedures are completed accurately and that time-sensitive samples are processed promptly. The central lab should also offer biorepository services to maintain each sample’s integrity until batch-testing, or to hold samples indefinitely for future biomarker or other analysis.

At the same time, an important part of managing IO trials is handling the data produced. Some central labs offer data management to deliver superior data consistency, accuracy and usability for studies, as well as data integration services to provide consolidated data from multiple specialty labs into one dataset. Customized reports are easy to create based on real-time information, and participant subsets are readily identified. Data can be analyzed whenever necessary, whether it is near the beginning of the trial or at the end.

CONCLUSION

Immuno-oncology clinical trials are complex. Typical challenges include short timelines, maintaining sample integrity while shipping internationally, low sample visibility at the clinical site, lab differences and managing large quantities of data from disparate sites. Partnering with an experienced central lab with customization, flexibility and experience can overcome most of these hurdles, making IO trials more efficient and saving time and expense.

LABCONNECT’S IMMUNO-ONCOLOGY SUPPORT

LabConnect provides a full range of services to help navigate the complexities of immunooncology research. Our experienced, dedicated scientific project managers oversee testing, sample processing and logistics and laboratory operations. Our study-specific clinical supplies and collection kits, SampleGISTICS™ tracking system and specialized testing capabilities, such as PBMC processing, ensure that your samples are correctly maintained throughout transport, testing and storage in one of our tightly controlled biorepositories. Access to our global network of select laboratories and our expertise in country-specific requirements can simplify logistics and streamline studies. Furthermore, LabConnect’s data integration and management systems and BioVisualization programs ensure that your data is accessible, understandable and usable in real time.

REFERENCES
1. Immuno-oncology clinical trials increased at 17% average yearly growth between 2008 And 2017, says GlobalData. Clinical Leader website. https://www.clinicalleader.com/doc/immuno-oncology-clinical-trials-increased-average-yearly-growth-between-and-says-globaldata-0001. Accessed January 24, 2020.
2. Tang J, Shalabi A, Hubbard-Lucey VM. Comprehensive analysis of the clinical immuno-oncology landscape. Ann Oncol. 2018;29(1):84-91.
3. Cancer immunotherapy market size worth $126.9 billion by 2026. Grand View Research website. https://www.grandviewresearch.com/press-release/global-cancer-immunotherapy-market. Published February 2019. Accessed January 24, 2020.
4. U.S. Food and Drug Administration Website. Hematology/oncology (cancer) approvals & safety notifications. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174.htm. Published January 9, 2020. Accessed January 24, 2020.
5. Bhatt DL, Mehta C. Adaptive designs for clinical trials. New Engl J Med. 2016;375:65-71.
6. Golan T, Milella M, Ackerstein A, Berger R. The changing face of clinical trials in the personalized medicine and immuno-oncology era: report from the international congress on clinical trials in Oncology & Hemato-Oncology (ICTO 2017). J Exp Clin Cancer Res. 2017;36(1):192. doi: 10.1186/s13046-017-0668-0.
7. Bell J. CAR-T ups challenges in pharma supply chain. Biopharmadive website. http://biopharmadive.com/news/car-t supply-chain-celltherapy-challenges-pharma/521560. Published April 23, 2018. Accessed January 24, 2020.
8. Applied Clinical Trials. The local central lab model. http://www.appliedclinicaltrialsonline.com/local-central-lab-model-0?id=&sk=&date=&pageID=4. Published April 1, 2008. Accessed January 24, 2020.

ABOUT LABCONNECT

Connect with LabConnect — the preeminent provider of central laboratory support services for analytically and logistically complex studies such as immuno-oncology, cell and gene therapies, and rare and orphan diseases. We offer unique and innovative services that have been specifically designed to meet the exacting demands of today’s clinical trials. Our worldwide scope of services includes routine and specialized testing, real-time sample tracking, data integration, biorepository, sample processing, and specialized functional outsourcing. Leading the evolution in central laboratory services since 2002, our services are customized to fit the unique needs of your trial. Get connected by requesting a proposal at www.labconnect.com or via email at info@labconnect.com.