International clinical trials: perspectives of clinical research coordinators

There are several different task roles among the co-medicals who are involved in international clinical trials (ICTs). In this review article, several issues related with ICTs from the view point of clinical research coordinators (CRCs) will be discussed. The discussions include interview results from eight CRCs of four institutions who have been involved in ICTs, current status of education for co-medicals in the field of ICTs, and future perspectives of ICTs from the CRC's view point. The following topics are especially focused in the discussion. 1) It is necessary to establish the infra-structure for free discussion among the ICT team so that opinions of co-medicals as the operation managers of the participating institutions can be openly shared and importantly taken into account. 2) It is also important for co-medicals to conduct research studies to clarify the problems in the current ICT support systems. 3) Lastly, the significance of early involvement of CRCs into the ICT protocol development must be emphasized, because the quality of protocols will be better improved by the practical insight of CRCs, and consequently, the accomplishment of the ICT, such as the speed and the data quality, may be accelerated.     

SEOM clinical guidelines for using molecular markers in clinical practice

Nowadays, treatment selection for most types of cancers is based on anatomical, histological and clinical criteria, which are defined by the selection criteria used in registration phase III trials. However, different cancers present distinct molecular features, so the current approach results in a lack of specificity of cancer therapy, which is associated with decreased efficacy and unnecessary toxicities and costs. Molecular diagnostics has proved able to predict the efficacy of selected targeted therapies. This allows the selection of specific treatments for different types of cancer, increasing their efficiency. Even though the number of treatments for solid tumours that can be selected based on molecular diagnostic tools is limited, much effort is being put into the identification of new biomarkers. This guideline reviews molecular diagnostic biomarkers that allow selection of specific therapies that have obtained regulatory approval as treatment of solid tumours.     

Modern clinical oncomorphology

The concept of present-day oncomorphology and the perspectives of its development are discussed. The role of morphological research in oncological clinic and trends in improvement of tumor diagnostic procedures are outlined. The review specifies the number of the studies and their objects. The importance of cytological diagnostic procedures and concurrent application of histo- and cytological methods is emphasized. Wide application of such modern diagnostic methods as electron microscopy, histochemical, immunomorphological and others is recommended. Procedures providing more quantitative information should be used on a wider scale.     

Comparative clinical trials

The therapeutic advantages of a newly developed cancer chemotherapy should be evaluated in comparison with the standard (or control) treatment. Therefore the comparative clinical trials should be designed so that the only differences observed among treatment groups are directly made by treatment program. This requires comparability of patients throughout the trial. The preferred method of evaluation is randomized controlled trials which can eliminate conscious or unconscious bias in assigning treatment. Before patients are randomized into the treatments of the trial, it is advisable to stratify patients according to known prognostic factors (stratified randomization) in an attempt to achieve equal distribution of these factors within each stratum. There are many difficulties with historical control study in the conduct of the comparative clinical trials, and its use may be acceptable only when randomized controlled trials are not feasible. The method of administration of anticancer drugs, patient eligibility, response parameters, toxicity of anticancer drugs, size and duration of the study, and advantages and disadvantages of multi-institution trials were also discussed within the framework of the comparative clinical trials.     

Net clinical benefit: Functional endpoints in brain tumor clinical trials

Primary brain tumors are associated with a poor prognosis and recognized impact on physical and neurologic function. In an effort to improve poor prognosis, novel therapeutic approaches have been pursued. The impact of therapy on function has not been fully evaluated in the past, with clinical trials focused on traditional survival endpoints. Therapies to date have been associated with incremental improvements in survival that may not have been associated with improvement in functional status. Methods for evaluating this impact include health-related quality of life symptom burden and evaluation of neurocognitive function. Each approach has associated benefits and limitations based on the type of treatment and the potential impact on functional status. An essential component of trial design evaluating functional endpoints is the development of clear hypotheses, specific aims, and predefined metrics of functional change related to each measure. This paper reviews these three approaches and discusses their potential use in evaluation of therapies for patients with primary brain tumors.     

The impact of clinical practice guidelines and clinical trials on treatment decisions

With increasing numbers of clinical practice guidelines (CPGs) becoming available to guide physicians, it is important to understand how guidelines are developed. Of importance, is evaluation of the scientific evidence on which guidelines are based, indeed whether the guideline is evidence based or based on expert opinion alone. This report will review in general, guideline development. The impact of CPGs, including expected outcomes, as well as potential harms is discussed. Clinical trials, meta analyses and CPGs relevant to the treatment of lung cancer are reviewed.     

Response assessment in clinical trials: implications for sarcoma clinical trial design

Response assessment and design of clinical trials require careful consideration of many factors, especially as validated response criteria can ultimately lead to the approval of an anticancer agent. Current anatomic imaging criteria are difficult to apply for evaluation of certain types of tumors, including soft tissue sarcomas. The emergence of new molecular imaging techniques, such as 64-slice computed tomography scanners and dynamic contrast magnetic resonance imaging, provide complementary information to conventional anatomical imaging. Currently the U.S. National Cancer Institute and the U.S. Food and Drug Administration are aiming to revise existing response criteria based on the development of volumetric anatomic imaging for oncology. Reviewing existing and new approaches in the design of clinical trials will help to optimize the clinical development and evaluation of new therapies for sarcomas.     

A clinical trial for the Food and Drug Administration's clinical trial process

The U.S. Food and Drug Administration (FDA) is tasked with opposing goals which demand tradeoffs--the time and cost of clinical trials to assure safety and efficacy while also encouraging speedy drug advances and affordability. On top of that, there is no feedback mechanism to inform the FDA of the effectiveness of their tradeoff decisions. Dual Tracking is a proposed public policy field experiment that would provide needed feedback information. The proposal is rooted in the right of informed patients to choose among FDA-approved or new, experimental drugs still in clinical trials. All new drugs would continue along the FDA's clinical testing track. On a new track independent of the FDA (but only after successful FDA Phase I safety evaluations), drug development firms would have the option to legally contract with individual patients and their doctors to sell them a not-yet-FDA-approved drug. The contract would require ongoing Internet reporting in a specified format of all drug-related experiences. The results of the Dual Tracking process compared to the FDA's process would constitute the critical information now missing.     

Bisphosphonates: clinical experience

Bone is a preferred site of metastasis for many solid tumors, and the complications associated with bone metastases can result in significant skeletal morbidity including severe bone pain, pathologic fracture, spinal cord compression, and hypercalcemia of malignancy (HCM). Bisphosphonates are the current standard of care for preventing skeletal complications associated with bone metastases. Clinical trials investigating the benefit of bisphosphonate therapy have used a composite end point defined as a skeletal-related event (SRE) or bone event, which typically includes pathologic fracture, spinal cord compression, radiation or surgery to bone, and HCM. Bisphosphonates have been shown to significantly reduce the incidence of these events in patients with bone metastases. Zoledronic acid (Zometa; Novartis Pharmaceuticals Corp.; East Hanover, NJ), pamidronate (Aredia; Novartis Pharmaceuticals Corp.), clodronate (Bonefos; Anthra Pharmaceuticals; Princeton, NJ), and ibandronate (Bondronat; Hoffmann-La Roche Inc.; Nutley, NJ) all have demonstrated efficacy superior to that of placebo in patients with breast cancer. Zoledronic acid is the only bisphosphonate that has been compared directly with pamidronate, and it was shown by multiple event analysis to be significantly more effective at reducing the risk of an SRE. In patients with prostate cancer, clodronate, etidronate (Didronel; Procter and Gamble Pharmaceuticals, Inc.; Cincinnati, OH), and pamidronate have demonstrated transient palliation of bone pain. However, zoledronic acid is the only bisphosphonate to demonstrate both significant and sustained pain reduction and a significantly lower incidence and longer time to onset of SREs compared with placebo. Zoledronic acid is also the only bisphosphonate to demonstrate efficacy in patients with bone metastases from a variety of other solid tumors, including lung cancer and renal cell carcinoma. In conclusion, bisphosphonates effectively reduce skeletal complications in patients with bone metastases from breast cancer, and zoledronic acid has demonstrated the broadest clinical activity in patients with a wide variety of tumor types.     

Statistics in clinical trials

Statistical developments over the past several years are described in this review. Efforts in phase I studies have focused on efficient estimation of maximum tolerated dose. Issues investigated for phase II trials include incorporation of multiple endpoints and randomization. For phase III trials, methods to reduce time or use the sample size more efficiently have been investigated. However, design innovations come with costs, including possible increased risk of incorrect conclusions. Other recent challenging statistical developments in clinical trials relate to use of complementary outcomes such as quality of life and to associated biologic questions, including the emergence of the field of genomics.     

Sedation in clinical oncology

The clinical status of terminal cancer patients is very complex and is affected by several severe symptoms, of extended duration, changing with time and of multifactorial origin. When there are no reasonable cancer treatments specifically able to modify the natural history of the disease, symptom control acquires priority and favours the possible better adaptation to the general inexorable deterioration related to the neoplasic progression. Despite the important advances in Palliative Medicine, symptoms are frequently observed that are intolerable for the patient and which do not respond to usual palliative measures. This situation, characterised by rapid deterioration of the patient, very often heralds, implicitly or explicitly, approaching death. The intolerable nature and being refractory to treatment indicates to the health-care team, on many occasions, the need for sedation of the patient. The requirement for sedation of the cancer patient is a situation that does not allow for an attitude of doubt regarding maintenance of the patient in unnecessary suffering for more than a reasonable time. Given the undoubted clinical difficulty in its indication, it is important to have explored at an earlier stage all usual treatments possible and the grade of response, commensurate with the patient's values and desires. Sedation consists of the deliberate administration of drugs in minimum doses and combinations required not only to reduce the consciousness of the patients but also to achieve adequate alleviation of one or more refractory symptoms, and with the prior consent given by the patient explicitly, or implicitly or delegated. Sedation is accepted as ethically warranted when considering the imperative of palliation and its administration and, whenever contemplated, the arguments that justify them are clear recorded in the clinical history. It is not an easy decision for the physician since, traditionally, the training has been "for the fight to save life". Nevertheless, it seems necessary to make some preparations regarding these problems that have a central affect on the clinical oncologist in his daily function.     

Globalization of clinical trials

Based on reviews of the Japanese clinical trial situation in lung cancer, gastric cancer, prostate cancer and breast cancer, it was clear that much progress has been made in short time. There are considerable differences between Japan and the West and also differences between clinical areas in Japan. For regulatory purposes bridging studies have become increasingly important. Use of identical protocols are required for effective bridging. Participations in global phase III trials is the best way of achieving registration in Japan. For successful global trials in Japan it is important to include Japanese investigators in the preparation of the protocol and to recognise the challenges facing such a project. Clinical practice in diagnosis and treatment have many differences, thus it is recommended to have clear and detailed information in the protocol. Hard end points like survival are important since they are not biased by cultural differences. There are clear difficulties with HE or QOL outcomes. The emergence of focus on evidence based medicine is also happening in Japan and will help to harmonize documentation across the world. For large adjuvant or prevention cancer global trials are essential. To facilitate global studies further development of infrastructure is necessary in Japan. Use of electronic data capture web based communication etc. will help overcome communication difficulties. Other improvements that will make Japanese participation in global trials easier and better include establishment of clinical trial centre at each hospital, introduction of trial coordinators or study nurses and an improved collaboration with company staff. A critical issue that also need addressing is agreement of centre target recruitment. We need to introduce a new flexible system in Japan if participation in global trial is to be optimised. If we can address these issues Japanese investigators and collaborative groups should be able to initiate and lead global trials in the future.