Volume 18, Number 2, European Edition - February 2013
Challenges in Oncology: From Clinical Trials to Introducing New Drugs to the Clinic
Maureen E. Trudeaua, Ciara M. Kellyb, Lillian Smythb, Cathy Kellyb, Mark Lawlerc
aOdette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada; bMater Misericordiae University Hospital, Dublin, Ireland; cCentre for Cancer Research and Cell Biology, Queens University Belfast, Belfast, Northern Ireland, United Kingdom
Pan-European cooperative clinical trial initiatives and Europe-wide collaborative research efforts have significant potential for improving outcomes for cancer patients in Europe. While cancer clinical trials have underpinned significant advances, the current model of cancer drug discovery and delivery needs to be streamlined to ensure rapid access to new innovative drug therapy approaches for European cancer patients. In addition, the significant costs associated with cancer clinical trials must be addressed, particularly in this era of economic austerity. A further obstacle to providing optimal treatment for cancer patients has been the European Clinical Trials Directive. The recent publication by the European Commission of a “Proposal for a Regulation of the European Parliament and of the Council on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC” is welcomed and is currently the subject of widespread consultation and discussion. It is imperative that the new version of the Directive removes the obstacles that have curtailed clinical trial activity in Europe over the last decade. In addition, new approaches to improve the recruitment of patients to cancer clinical trials need to be developed and must include significant engagement with all potential stakeholders, including the cancer patients and their representatives. In the video accompanying this article, lead author Maureen Trudeau talks to European Perspectives and provides her insight on the challenges facing a clinical trials unit while identifying some potential solutions that will allow us to improve access to cancer clinical trials and provide an optimal standard of care to the cancer patient.
A greater understanding of disease biology and the development of new therapeutic approaches with increasing efficacy, has led to significant improvements in breast cancer care over the last decade . The process of introducing a new drug into the clinic can, however, be a complex process, from the perspective of clinical trial design and implementation, drug approval and reimbursement. While the current and future potential of targeted therapy is compelling, it must also be acknowledged that in the present economic climate, there is a critical need for consideration of cost-effectiveness, both in the trial setting and when the drug or therapeutic intervention is introduced as a standard of care. Tailoring of clinical trial design approaches may increase both efficacy and efficiency and also help reduce the economic costs to the Clinical Trials Unit (CTU). Maximising accrual to cancer clinical trials also needs to be prioritised, particularly among minority groups. Once the drug or therapeutic approach has been approved, the issue of cost remains a challenging one, with significant global variation in the reimbursement of publicly funded cancer drugs .
The Changing Face of Cancer Clinical Trials
New Models of Clinical Trial Design
The realisation that clinical trial design needs to evolve, in order to more effectively transition drugs from promising candidates to clinical entities and to reject drugs that do not demonstrate clinical efficacy, has been an important recent development. Crucial parameters such as study population size and accrual times for clinical trials are being reassessed. Increasingly, the model of large studies with long accrual times addressing a single question is being re-evaluated. Smaller, more refined early phase studies with shorter recruitment periods can inform more focused and effective Phase III trials, while adaptive clinical trial design and implementation can help underpin innovative studies that deliver measurable clinical benefit in a timely fashion .
Targeted drugs and companion diagnostics
In this era of personalized/stratified medicine, the co-development of new anticancer agents, in conjunction with predictive biomarkers/companion diagnostics, is increasingly relevant. Biomarker-driven clinical trials permit identification of the population most likely to respond to the drug, through molecular prescreening at early clinical trial stage , thereby minimising unnecessary toxicity and cost and potentially accelerating patient benefit. However, at a regulatory level, it is important that the drug and companion diagnostic are linked, both from an approval and a reimbursement perspective. This is now increasingly the case in the U.S., as demonstrated by the recent Food and Drug Administration (FDA) approval of the anaplastic lymphoma kinase (ALK) inhibitor crizotinib and the Vysis ALK Break Apart FISH Probe Kit companion diagnostic . In Europe, however, biomarkers and companion diagnostics are currently evaluated in a hybrid decentralised model involving independent European notified bodies and under the Directive on in vitro diagnostic medical devices (Directive 98/79/ EC). As a step in the right direction, the European Medicines Agency (EMA) has published a reflection paper on the co-development of pharmacogenomics biomarkers and therapeutic drugs . A mechanism to more closely align therapeutic drug and companion diagnostics would greatly enhance the process from a European perspective.
While the current and future potential of targeted therapy is compelling, it must also be acknowledged that in the present economic climate, there is a critical need for consideration of cost-effectiveness, both in the trial setting andwhenthe drug or therapeutic intervention is introduced as a standard of care.
The Value of Patient Reported Outcomes (PROs)
Patient reported outcomes (PROs), which are prognostic for survival and help inform decision making, are increasingly being included as relevant end-point measures in study designs . Incorporating PROs into study endpoints, e.g. the well-recognized and widely used EORTC quality of life scale (EORTC QLQ-C30), can provide additional information regarding both the patient experience and help to revise clinical trial design. PROs are validated and reliable, unlike common toxicity criteria that are often measured in studies, and can lead to an increased appreciation of the patient experience that informs better decisions by all stakeholders in the clinical trials process (patients, health care providers, regulators, and payers).
Barriers to Accrual to Clinical Trials
Only 2-4% of newly diagnosed adult cancer patients are recruited to clinical trials. For breast cancer, accrual rates approach 3%. Barriers to clinical trial accrual include physician-associated barriers, protocol-or eligibility-associated barriers, patient-associated barriers and funding-associated barriers. Surveys suggest that over 50% of potentially eligible patients are not offered clinical trials due to the physician’s decision not to offer a clinical trial option . In addition, perceived poor performance status is also cited as a reason for lack of enrolment in a clinical trial. Encouraging physicians to regularly check the availability of new protocols (both early Phase and Phase III) and to critically review the details of eligibility should allow all potential patients that satisfy protocol criteria to be recruited to appropriate clinical trials. From a patient perspective, ethnic and racial minorities, older adults, residents in rural areas and individuals of low socioeconomic status are underrepresented among participants in cancer clinical trials. Barriers to accrual of under-represented populations can include mistrust of research and the medical system, perceived harm, cost, patient demographics, transportation, lack of education regarding clinical trials, time commitment, fear and family issues [8,9].
Both the international oncology community and individual clinical trials units (CTUs) need to address the issue of how to increase the accrual of underrepresented populations to cancer clinical trials. Education is a key priority, both for the physician and the prospective participant. Innovative approaches to improving clinical trial recruitment include education initiatives in the local community, in places of worship, in social/ sports clubs etc. Recruitment of celebrity ambassadors can also be effective. In Ireland, an initiative was recently launched to educate and increase awareness among the Irish public regarding the role and meaning of clinical trials in oncology. Culturally sensitive approaches in certain groups of patients will also be needed to encourage participation in clinical trials. A final barrier to clinical trial accrual is the worry from the potential participants, particularly in the U.S., in relation to insurance coverage for cancer clinical trials.
Reinvigorating Cancer Clinical Trials Networks
In 2007, following an internal review the previous year, an external review of the National Cancer Institute (NCI) Cooperative Group Program by the Institute of Medicine led to the publication of a series of recommendations , which informed the establishment of a new structure in 2012, the NCI National Clinical Trials Network (NCTN) . Key developments include the consolidation of nine adult-oriented disease cooperative groups to four, the development of a new evaluation and funding model and an increased emphasis on community site involvement in cancer clinical trials. In Europe, the European Organisation for Research and Treatment of Cancer (EORTC) launched a new initiative, the EORTC Network of Core Institutions (NOCI), aimed at promoting cooperation between the Translational Research and Clinical Research divisions of EORTC and the EORTC disease groups with a particular focus on translational clinical trials . In addition, an increased focus on international cooperation in academic cancer trial activity has the potential to significantly improve cancer treatment globally . All these approaches can help to reinvigorate the clinical trials process, maximise effectiveness and stimulate increased awareness and participation in clinical trials in oncology.
Cost of Operating Clinical Trials Units
With the loss of infrastructural support due to decreasing hospital and government budgets, maintaining a CTU is challenging. Adhering to codes of good clinical practice and maintaining compliance with the Clinical Trials Directive (in Europe) has increased the workload of the CTU, with a corresponding effect on budget. Previously, a CTU was reimbursed at the outset of study initiation per patient enrolled. Nowadays, payment is staggered throughout the course of the patient’s time on clinical trial, with patient death or early withdrawal significantly affecting reimbursement despite the need to maintain follow-up data for these individuals. Although it is recognized that conducting research independently from pharmaceutical companies is important, reimbursement for co-operative group or investigator-led studies is often minimal. As a consequence, a CTU has to balance the budget with pharmaceutical company driven trials. However, as pharmaceutical companies are increasingly performing their studies in countries where these costs are minimal, the ability to balance the CTU budget in this manner will become more difficult. Compliance with trial protocol procedures can also be a financial burden for a CTU. One example is the requirement for RECIST defined restaging imaging reports. While RECIST is a very important and validated approach for assessing response, this criteria is not used routinely by radiology departments, which then seek funding to comply with this request.
Global Variation in Reimbursement of Cancer Drugs
The process of drug approval and funding differs between countries and is either locally or nationally determined. Recently, one of us (MT) has investigated inter-country variability in access to cancer drugs . In this study, 12 countries were selected that have both universal health care and a national or regional public drug reimbursement program. The number of indications reimbursed by public drug programs for 10 cancer drugs licensed after 1995 and chosen to reflect different tumour sites, mechanism of action and route of administration was assessed. The 10 cancer drugs selected were: bevacizumab, bortezomib, cetuximab, erlotinib, imatinib, pemetrexed, rituximab, sorafenib, sunitinib and trastuzumab. The United States’ Medicare program, which is not a form of universal health insurance, was also included in the analysis. Of the 13 countries studied, cost effectiveness analysis (CEA)/ Health Technology Assessment (HTA) was performed for 8 countries. The study showed that Finland, France, Germany, Sweden, and the U.S. Medicare program have the broadest access to publicly funded cancer drugs, while in Australia, Canada, England, New Zealand and Scotland there is more restricted access. These latter five countries each have a CEA/ HTA incorporated into the reimbursement process, and lack of cost effectiveness was the major reason for restricted access. Risk sharing agreements and special price negotiations with pharmaceutical companies were subsequently employed to improve patient access to cancer drugs.
Regulating Resource Allocation: The Need for Transparency and Effective Budget Management
There is no doubt that resource allocation decisions are difficult and need an ethical framework for legitimacy, fairness and transparency that incorporates the patient’s voice. One example of such is the pan-Canadian Oncology Drug Review (pCODR), an expert review committee with a deliberative framework based on accountability for reasonableness . It consists of a clinical guidance panel, which evaluates clinical benefit through evidence-based reports; an economic guidance panel, which provides economic evaluation; advocacy groups, which provide patient-based values; and a provincial advisory group, which evaluates adoption feasibility of the drug. Working within a fixed budget also requires more economic drug usage. The Odette Cancer Unit reduced wastage from $156,000 to $28,000 in one year by scheduling patients to receive the same drug on the same day and tracking all orders to identify any drugs that are not for direct reimbursement (a non-formulary request) for further discussion within the Department.
Clinical trials in oncology identifies new cancer drugs that have therapeutic efficacy. Improved clinical trial design and implementation are crucial to maximising the efficiency of the clinical trials process. Increased patient accrual widens access to cancer clinical trials for diverse patient groups, including underrepresented populations. Transitioning new drugs from clinical trials to the clinic setting raises many challenges, including access and resource issues. Highlighting these difficulties encourages the oncology community to develop innovative solutions, thus ensuring that the cancer patient has improved access to new drugs both on clinical trial and ultimately in the clinic.
Conception/Design: Maureen E. Trudeau, Ciara M. Kelly, Lillian Smyth, Cathy Kelly, Mark Lawler Collectionand/orassemblyofdata:Maureen E. Trudeau, Ciara M. Kelly, Lillian Smyth, Cathy Kelly, Mark Lawler
Manuscript writing: Maureen E. Trudeau, Lillian Smyth, Cathy Kelly, Mark Lawler
Final approval of manuscript: Maureen E. Trudeau, Lillian Smyth, Cathy Kelly, Mark Lawler
The authors indicated no financial relationships.
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Correspondence: Cathy Kelly, MD, MSc., Department of Medical Oncology, Mater Misericordiae University Hospital, Eccles St, Dublin 7 Telephone: 01 803 4447 E-mail: email@example.com. Received December 8, 2012; accepted for publication February 8, 2013. ©AlphaMed Press 1083-7159/2013/$20.00/0 http://dx.doi.org/10.1634/theoncologist.2013-0043