Innovation in oncology clinical trial design

Progress in and better understanding of cancer biology causes a shift in cancer drug development: away from the evaluation of drugs in large tumour histology defined patient populations towards targeted agents in increasingly heterogeneous molecularly defined subpopulations. This requires novel approaches in clinical trial design by academia and industry, and development of new assessment tools by regulatory authorities.Pharmaceutical industry is developing new targeted agents generating many clinical studies, including target combinations. This requires improved operational efficiency by development of innovative trial designs, strategies for early-stage decision making and early selection of candidate drugs with a high likelihood of success. In addition, patient awareness and ethical considerations necessitate that agents will be rapidly available to patients.Regulatory Authorities such as the European Medicine Agency and national agencies recognise that these changes require a different attitude towards benefit-risk analysis for drug approval. The gold standard of randomised confirmatory Phase III trials is not always ethical or feasible when developing drugs for treatment of small cancer populations. Alternative strategies comprise accelerated approval via conditional marketing approval, which can be granted in the EU based on small non-randomised Phase II trials.The paper describes innovative trial designs with their pros and cons and efforts of pharmaceutical industry and regulatory authorities to deal with the paradigm shift. Furthermore, all stakeholders should continue to share their experiences and discuss problems in order to understand the position and concerns of the other stakeholders to learn from each other and to progress the field of novel oncology clinical trial design.     

Clinical trial risk in leukemia: Biomarkers and trial design

This study analyzed the risk of clinical trial failure for leukemia drug development between January 1999 and January 2020. The specific leukemia subtypes of interest were acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML). Drug development was investigated using data obtained from https://www.clinicaltrials.gov and other publicly available databases. Drug compounds were excluded if they began phase I testing for the indication of interest before January 1999, if they were not industry sponsored, or if they treated secondary complications of the disease. Further analysis was conducted on biomarker usage, drug mechanisms of action, and line of treatment. Drugs were identified following our inclusion criteria for ALL (72), CLL (106), AML (159), and CML (47). The likelihood (cumulative pass rate), a drug would pass all phases of clinical testing and obtain Food and Drug Administration approval, was 18% (ALL), 10% (CLL), 7% (AML), and 12% (CML). Biomarker targeted therapies improved the success rates by three‐ and sevenfold, for ALL and AML, respectively. Enzyme inhibitors doubled the cumulative success rate for AML. First‐line therapy and kinase inhibitors both independently doubled the cumulative success rate for CLL. Oncologists enrolling patients in clinical trials can increase success rates by up to sevenfold by prioritizing participation in trials involving biomarker usage, while consideration of factors such as drug mechanism of action and line of therapy can further double the clinical trial success rate.     

Clinical trial design for target-based therapy

Anticancer drug discovery has shifted from an empiric random screening directed approach to a more rational and mechanistic, target-based approach, which reflects our rapidly expanding knowledge of the pathogenesis of a variety of forms of cancer at the molecular level, providing new targets for drug discovery and development. The clinical development of target-based anticancer drugs will require fundamental changes to the traditional clinical trial design and end points that have been used for conventional cytotoxic drugs. In the phase I and II settings, traditional end points (toxicity and response) may not be suitable for more selective, cytostatic target-based agents, and these end points may be replaced by biological or pharmacokinetic end points to define the optimal doses and the therapeutic effects of these drugs on their targets. For phase III trials, measurable clinical benefit will continue to be the primary end point. As our understanding of the complex pathways and networks controlling cell signaling, proliferation, and cell death expands, we must learn how and when to use agents to target specific steps in malignant transformation and proliferation, and we must adapt clinical trial design to test the clinical utility of this promising new class of anticancer drugs.     

Sem: a suitable statistical software adaptated for research in oncology

Many softwares have been adapted for medical use; they rarely enable conveniently both data management and statistics. A recent cooperative work ended up in a new software, Sem (Statistics Epidemiology Medicine), which allows data management of trials and, as well, statistical treatments on them. Very convenient, it can be used by non professional in statistics (biologists, doctors, researchers, data managers), since usually (excepted with multivariate models), the software performs by itself the most adequate test, after what complementary tests can be requested if needed. Sem data base manager (DBM) is not compatible with usual DBM: this constitutes a first protection against loss of privacy. Other shields (passwords, cryptage...) strengthen data security, all the more necessary today since Sem can be run on computers nets. Data organization enables multiplicity: forms can be duplicated by patient. Dates are treated in a special but transparent manner (sorting, date and delay calculations...). Sem communicates with common desktop softwares, often with a simple copy/paste. So, statistics can be easily performed on data stored in external calculation sheets, and slides by pasting graphs with a single mouse click (survival curves...). Already used over fifty places in different hospitals for daily work, this product, combining data management and statistics, appears to be a convenient and innovative solution.     

Clinical pathways in oncology

The diagnosis-related-group/prospective-payment system (DRG/PPS) was introduced into the health care system of the United States in 1983. This system triggered the development and implementation of clinical pathways aimed at reducing the length and cost of hospitalization. In Japan, trial use of a Japanese version of DRG/PPS was initiated in November 1998 in 10 hospitals under the control of the Ministry of Health and Welfare, and full-scale implementation of the system is expected in the near future. Clinical pathways, therefore, are a current focus of attention, mainly because of their success in enhancing management efficiency in the U.S. However, in actual clinical settings where clinical pathways are used, several Japanese health care providers have come to realize that they are also useful in improving staff coordination, patient satisfaction, and patient care, rather than simply reducing the length of hospital stay and cost of health care. The introduction of clinical pathways requires that treatment of the disease in question be defined and standardized. The implementation of pathways for the treatment of cancer, however, might prove difficult because of the high frequency of variation. In our experience, the main reason for the use of clinical pathways is not to reduce the number of variant cases but to provide high-quality care through the promotion of a team approach to treatment and enhanced patient care. Therefore, even if there were frequent variances following surgery for cancer, those occurring in accordance with the pathophysiological state of the patient would not interfere with management by clinical pathways. Clinical pathways are advantageous because they allow patients to know their treatment schedule; to prepare for hospitalization procedures; to have a better perspective on discharge; to reduce anxiety regarding hospital admission, even if it is the first time; to communicate better with doctors, nurses, and other medical care staff, leading to greater trust; and to improve their ability for self-management. These features are all important for the improvement of patient care. Furthermore, clinical pathways may lead to a situation in which the cost of hospitalization can be predicted prior to admission, enabling patients to compare differences between several hospitals. From our experience with gastric cancer, breast cancer, and esophageal cancer management, we consider clinical pathways to be of great benefit in helping to reform the current medical care system in regard to the management of cancer patients as well as patients with other diseases.     

Molecular oncology and the neoadjuvant setting: the perfect blend for treatment personalization and clinical trial design

Breast cancer is a heterogeneous disease. Predictive molecular markers are crucial in patient management, but the only recommended predictive biomarkers are estrogen and progesterone receptors and HER2. There are many new targeted therapies, and although the target pathway expression is readily analyzed on conventional pathology, the dynamic response cannot be assessed and pathway expression is no guarantee it has a major driver role, even if mutated. Selecting therapies requires considering the patient, the molecular characteristics of the tumor, and the microenvironment of the tumor. Thus, the integration of molecular pathology, imaging, and early tumor biological response to therapy may provide evidence of drug activity and allow more rapid changes of therapy. The adaptive response of the tumor is a key resistance mechanism that can be assessed readily in the neoadjuvant setting. Although there are no markers that meet all surrogacy criteria, their use could provide crucial information on mechanisms of drug sensitivity/resistance. Validation of such markers requires a major emphasis on neoadjuvant trials to relate early-biomarker response to outcome.     

Clinical trial presentations, agency guidelines, and oncology practice: findings from the arimidex, tamoxifen, alone or in combination trial

PurposeOur objective was to explore the potential influence of agency guidelines/technology assessments regarding anastrozole use in clinical practice in the United States and European Union, based on findings related to the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial.Patients and MethodsWe examined temporal relationships among ATAC-related oral data presentations, peer-reviewed publications, regulatory agency approvals and agency guidelines/technology assessments to the patient days' use of anastrozole in the United States and European Union.ResultsAnastrozole usage increased at a relatively constant rate following oral presentations of ATAC results at oncology congresses and did not appear to be strongly influenced by publications or agency guidelines/technology assessments, which appeared to lag rather than lead clinical usage.ConclusionThe presentation of clinical trial data at large international congresses rapidly changed anastrozole use in clinical practice regardless of ongoing guideline recommendations. This observation raises the following question: Have clinicians adopted adjuvant anastrozole use prematurely? Or, is the level of evidence required by expert panels higher than that with which oncologists in clinical practice are comfortable?     

Clinical oncology in resource-limited settings

Infectious Agents and Cancer is introducing a new section of Clinical Oncology with the main objective of stimulating debate through articles published in the section. Infectious diseases have been the major causes of morbidity and mortality in human populations, and have dominated the medical approach to clinical and public health. Successful efforts to control mortality from acute infections have paved the way for chronic, mostly indolent, infections to become major causes of morbidity. Cancer, hitherto thought to be rare in resource-limited settings, is becoming a major contributor. The changes in mortality patterns are due, in part, to diseases linked to rapid changes in lifestyle, urbanization, and pollution. These diseases include many of the non-infection associated cancers. However, there is a dearth of information about the burden, pathogenesis, and therapeutic approaches about cancer in resource-limited countries. There are also substantial other challenges, including economic, infrastructure, technology, and personnel. The Journal advocates for interactive local–global (lo-bal) efforts to generate relevant knowledge about cancer burden, pathogenesis, and therapeutic approaches using a bottom-up approach to sharpen the focus on local and global relevance of research and clinical and public practice, particularly in resource-limited countries. The section on Clinical Oncology in Infectious Agents and Cancer will harness these “lo-bal” strategies to reduce substantially the time from concept, discovery, and development and implementation of locally and globally applicable diagnostic and therapeutic technologies.