Oncology products dominate the global therapeutics market, and are on course to reach an estimated €56 billion in sales by 2015.1 While cultural differences in approaches to treatment and research into cancer undoubtedly exist between countries, investigators throughout the European Union have adopted similar approaches2
to the rigorous evaluations of novel oncology treatments in Phase I clinical trials. But such trials are not conducted without reference to a number of considerations.
Commencing with the patients themselves, these considerations include the evolution of agents from conventional cytotoxics to novel molecular targeted therapies, the need to adapt research protocols, and trial conduct within the context of changing regulatory environments such as new requirements from the European Medicines Agency (EMA)Committee for Medicinal Products for Human Use. Other considerations also stem from maintaining efficient data collection from the complex and dynamic network that comprises most trials.
This article explores an array of these considerations (often presenting as barriers to trial optimisation) and offers potential solutions as oncology drug development continues to flourish.
Collaboration on trial design can help control costs and time delays associated with protocol amendments. Nearly 60 percent of protocols used in Phase I, II and III clinical trials for new drugs are amended during a trial, according to a 2011 study of 3,410 protocols by the Tufts University Center for the Study of Drug Development.3
Tufts calculates just one amendment can,on average, add two months and about €340,000 in costs.4
In Phase I studies, Tufts found 52 percent of amendments occurred prior to the first study volunteer receiving the first dose.
Regardless of trial phase, Tufts found that most amendments resulted from new safety information, requests from regulatory agencies, changes in the study strategy or standards of care,or recruiting difficulties.
Therefore, sponsors should anticipate potential protocol problems, flaws or errors, even via pilot testing with a small group of patients, so changes occur before the trial formally begins. For example, are
all of the protocol-defined procedures appropriate for collecting data that will support an investigational medicinal product dossier?
For many candidate chemotherapies, first-in-man studies are designed to identify the maximum tolerated dose and dosing schedule. Yet newer investigational targeted agents, such as monoclonal antibodies, signal transduction pathway inhibitors or antisense molecules may require optimal biological dose endpoints. Consequently, the research protocol will need to adequately define how to determine the recommended Phase II dose, and to describe new assays or procedures to measure biological endpoints as well as to capture traditional patient safety assessments.
In early stage oncology protocols, sponsors must account for the complex disease processes of patients with advanced cancer. These patients usually have comorbid conditions that require significant concomitant medication. Both these illnesses and treatments create side effects that frequently can obscure recognisable effects of the trial’s candidate medicine. The trial protocol and data management design should strive to make such disease and concomitant medications effects distinct from the tested therapy.
Ideally, the oncology trial team should have the tools to recognise and anticipate such disease manifestations, and consequently to distinguish adverse events due to a concomitant medication from unanticipated adverse events due to study drug. Such expertise creates trial efficiencies, with minimisation of data queries and greater sensitivity for detection of true safety signals.
Moreover, because Phase I oncology trials enroll patients with advanced disease, protocols must account for high mortality rates as well as the ready detection of relevant data trends, which always require prompt action to ensure patient safety and regulatory compliance.
In the EU, sponsors conduct most Phase I cancer studies via academic centres of excellence and as identified by collaborative organisations, such as Cancer Research UK, Southern Europe New Drug organization, Central European Society for Anticancer Drug Research, and the French National Federation of Cancer Centers.5
The baseline for any trial site is its competency and capability in enrolling appropriate patients, ability to offer Good Clinical Practice (GCP)facilities and procedures, and possession of available, qualified staff.
Ongoing, current relationships and experience with institutions, investigators and their staff help tremendously in choosing trial sites. While two potential investigative sites may have equivalent capabilities, a sponsor or the sponsor’s clinical research organisation (CRO) benefits from understanding where potential principal investigators (PIs) align strongly enough with the science of the candidate treatment to be prepared to be a champion for the trial over other trials which may be ongoing in the same institution, and to encourage patient enrollment.
While the approval of new drugs is the purview of the EMA, the approval of clinical trials is the purview of each EU member state’s regulatory authority. A sponsor with extensive EU-based early stage oncology trial experience, expertise and staffing can navigate these requirements and successfully manage the trial within one country or across borders.
However, before commencement of a trial a sponsor should develop familiarity with the standard operating procedures of each site, such as its institutional contracting procedures, scientific and ethics review body practices and document requirements and processes. Sponsors also must know and understand how local sites comply with national as well as institutional regulations to protect and care for human subjects (and their health information) in research.
The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use guidelines and GCP principals provide international recommendations to standardise the conduct of clinical trials across the EU, U.S. and Japan, but their use differs among researchers, institutions and countries. The EU Clinical Trials and GCP Directives provide a legal framework for trials that must be incorporated into each member state’s statutory system, and their interpretation may be intertwined with other legislation, such as the EU Data Protection Directive. Additionally, all trials, after national approvals, must be issued an EU Drug Regulating Authorities Clinical Trials number (EudraCT) from the EMA.
These EU and national requirements substantially impact the resources, including time and money, required to set up and conduct trials, particularly those that cross borders. If a sponsor has limited practical experience of such EU systems, a CRO can provide knowledge, skills and abilities for guidance on the most efficient path, and to plan both the trial approval and management, as well as risk mitigation.
A foundation for operational excellence includes using vetted, oncology trial-tested procedures and resources that will accelerate the implementation of the trial infrastructure. Templates and libraries
of standards will reduce drafting, review and finalisation cycles while improving quality, expediting dose-escalation decisions and minimizing trial delays. These efficiencies are especially beneficial
for small- to mid-sized sponsors that often are under pressure for expedited trial initiation to meet corporate funding milestones.
Operational excellence also involves proficient use of eClinical technologies, which facilitate 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 systems and safety databases.
The investment in EDC for early phase trials is no longer a deterrent in relation to paper methods. The ability of EDC to expedite real-time alignment of data with patient profiles, visits and cohort
assessments creates efficiencies and accuracy. Moreover, EDC affords on site or remote safety reviews by investigators and advisory boards and transparency into trial conduct.
Many Phase I oncology trials of any design permit continuous administration of drug doses as long as patients do not experience disease progression or an apparent therapeutic response. This dose-escalation protocol and patient consent/availability/site capacity will set the pace of patient accrual.
However, cohort management is not just the result of the availability of the next dose level. Assignments also stem from cohort vacancies created by patients who become ineligible or decide not to enroll, or from patient mortality. Therefore, accrual adjustments should be planned as part of the protocol to keep study enrollment on track from the first-patient/ first-visit onwards. With such a plan, the success in tracking and accruing participants then can be focused to simple, yet constant communication between the trial manager and on-site managers.
Sponsors are accountable for the quality of data and analyses, particularly regarding dosing and safety. Consequently, the protocol must include systems to verify the integrity of data and study procedures.
Quality data documentation and an oncology-experienced team that embraces integrated data review across multiple functional areas, and thus from differing perspectives, facilitates analyses that can expose viability or liabilities of the candidate therapy.
For example, thorough and current data can uncover toxicities that occur in a single site or in a subset of patients, which can be as revealing about the candidate treatment as those events that affect all study patients.
Increasingly, sponsors also seek documentation of patients’ quality of life and anecdotal efficacy information. For example, documenting patient-specific information such as duration of stable disease and time to disease progression for a Phase I investigational therapy has value to sponsors in the context of established treatments and in determination of specific indications to pursue for further drug development.
The average times to a clean data set, database lock and data analyses are quality checkpoints for trial management. But quality and reliability of data should never be compromised for speed. Planning, expertise and tools can guide the process with great efficiency. For example, early involvement of biostatisticians experienced in oncology can yield case report form designs that from the start capture appropriate data that can quickly and effectively be translated to statistical outputs for trial analysis.References
1 “The Global Use of Medicines: Outlook Through 2015,” Report by the IMS Institute for Healthcare Informatics. May 2011.
2 Performing Phase I Clinical Trials of Anticancer Agents: Perspectives from within the European Union and Japan,” Martin D.
Forster, et. al. Clin Cancer Resea 16(6) March 15, 2010 pp 1737-44.
3 “Majority of Clinical Trial Protocols Are Amended, But One-Third of Those Changes Are Avoidable,” News Release, Sept. 13, 2011,
Tufts Center for the Study of Drug Development.
4 “Protocol Amendments: a Costly Solution,” Kenneth A. Getz. Applied Clinical Trials. May 1, 2011.
5 “Performing Phase I Clinical Trials of Anticancer Agents: Perspectives from within the European Union and Japan,” Martin D.
Forster, et. al. Clin Cancer Resea 16(6) March 15, 2010 pp 1737-44.
Novella Clinical, Inc. is a full service contract research organisation specialising in early phase oncology trials. With dual headquarters in Stevenage, UK, and Research Triangle Park, N.C., Novella provides the experience and insight to bring medicines to market on time and on budget. For more information, visit www.novellaclinical.com
or contact us at +44 (0) 11438 221122.