Kathleen Zajd

	Oncology products are expected to reach approximately $75 billion in global spending by 2015.

 This therapeutic dominance depends on the success of novel cytotoxics and targeted therapies now in development-if they prove safe and effective in clinical trials.

	Because of the many challenges facing Phase I oncology trials, small- to mid-sized oncology focused pharmaceutical and biotechnology companies must consider multiple factors, including medical and scientific knowledge, regulatory intelligence, site and investigator engagement, and trial and data management.

	Patients often present the first challenge in oncology trial design and execution, as Phase I trials must be performed in patients who usually have advanced disease. The evolution of pipeline agents from conventional cytotoxics to novel molecular targeted therapies requires development, validation, and adoption of new assays for trials. Additional complexities are presented by the US Food and Drug Administration or the European Medicines Agency regulations and data collection from the complex and dynamic networks that comprise most trials. These challenges are daunting. But the right tools and talents can surmount these hurdles and yield benefits into Phase II and beyond.

	Protocol design is paramount to a good trial, as amendments cost time and money. The Tufts Center for the Study of Drug Development calculates an added two months and an average of about $454,000 per amendment regardless of trial phase.

 Notably, Tufts reports, 52 percent of amendments in Phase I studies happen prior to the first volunteer receiving the first dose. Therefore sponsors must anticipate and eliminate protocol errors and flaws as early as possible. For example, are all of the protocol-defined procedures appropriate for collecting data that will support a new drug application or investigational medicinal product dossier?

	While first-in-man studies are designed to identify the maximum tolerated dose, newer investigational agents may require optimal biological dose endpoints. Consequently, the protocol for a new agent-such as monoclonal antibodies, signal transduction pathway inhibitors, or antisense molecules-needs to define how to determine the recommended Phase II dose and to describe new assays or procedures to measure biologic endpoints as well as capture safety assessments.

	The complex health of patients with advanced cancer plays a significant role in protocol design, and trial management. Understandably, these patients usually have comorbid conditions requiring numerous medications. The protocol should strive to make such disease and concomitant medications effects distinct from the tested therapy.

	Site selection should begin with sites that are both competent and capable of enrolling appropriate patients, have good clinical practice facilities and procedures, and employ sufficient and available qualified staff.

 Familiarity with each site's standard operating procedures (SOPs) creates substantial efficiencies in getting a trial up and running. These SOPs include institutional contracting procedures, scientific and ethics review boards practices, and documentation requirements.

	Sponsors must ensure compliance for each site regarding good clinical research and safety practices, from patient education to trial inspections. Sites also most operate with compliance to federal, local, and institutional regulations to protect and care for patients. The International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use guidelines provide guidance to standardize the conduct of clinical trials across the United States, European Union, and Japan.

 Contingency planning and risk mitigation also are essential for sponsors.

Trials must enable verification of data integrity-sponsors are accountable for the quality of data and analyses. Using vetted, oncology trial-tested resources to implement the initial trial infrastructure goes a long way toward facilitating efficient data management and validation. Templates and libraries of standards reduce drafting, review, and finalization cycles while improving quality. Because of similarities across Phase I oncology trials, template-reporting mechanisms that summarize holistic patient results can simplify and expedite dose-escalation decisions.

	Proficient use of eClinical technologies permit data capture at enrollment and during monitoring as well as ongoing analysis that recognizes emergent adverse events with accurate grading and attribution. Such eClinical technologies include electronic data capture (EDC), and software for adjudication, clinical trial management, and safety databases. EDC expedites real-time alignment of data with patient profiles, visits, and cohort assessments. Moreover, EDC affords immediacy in safety reviews, whether on site or remote, just as it provides for data cleaning and trial conduct transparency.

	The relative speed of patient accrual depends on the dose-escalation protocol and patient consent/availability/site capacities. Planning adjustments keeps enrollment on track from the first-patient/first-visit onwards. However, assignments are not solely made on availability of the next dose level. They also stem from vacancies created by patients who become ineligible or patient mortality. Tracking participants and assignments requires near constant communication between trial and on-site managers, and the assignment plan must be deemed fair by all sites to succeed.

	Most seasoned sponsors have multiple considerations for early phase oncology trials, from patients' health to management of biological samples to slot assignments to data validation. Quality Phase I results lay the foundation for advanced efficacy trials in the most appropriate oncology patients, particularly when acquired in a time- and cost-effective manner.

 is Vice President, Oncology Clinical Development at Novella Clinical, 4309 Emperor Boulevard, Suite 400, Durham, NC, 

	1. IMS Institute for Healthcare Informatics, "The Global Use of Medicines: Outlook Through 2015," May 2011, 

	2. K. A. Getz, "Protocol Amendments: A Costly Solution," 

	3. M. D. Forster, et. al., "Performing Phase I Clinical Trials of Anticancer Agents: Perspectives from within the European Union and Japan," 

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Optimizing early phase trials key to the success of novel cytotoxics and targeted therapies.

Kathleen Zajd

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Early Phase Trials