Frontiers in Clinical Drug Research - Anti-Cancer Agents: Volume 8 E-Book
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- Herausgeber: Bentham Science Publishers
- Kategorie: Wissenschaft und neue Technologien
- Serie: Frontiers in Clinical Drug Research - Anti-Cancer Agents
- Sprache: Englisch
- Veröffentlichungsjahr: 2006
Frontiers in Clinical Drug Research - Anti-Cancer Agents is a book series intended for pharmaceutical scientists, postgraduate students and researchers seeking updated and critical information for developing clinical trials and devising research plans in anti-cancer research. Reviews in each volume are written by experts in medical oncology and clinical trials research and compile the latest information available on special topics of interest to oncology and pharmaceutical chemistry researchers. The eighth volume of the book features reviews on these topics:
- Key data management elements in clinical trials for oncological therapeutics
- Prospects for therapeutic targeting of microRNAs in brain tumors
- Breast cancer vaccines: current status and future approach
- Desmocollin-3 and cancer
- MDM2-p53 antagonists under clinical evaluation: a promising cancer targeted therapy for cancer patients harbouring wild-type tp53
- Towards targeted therapy: anticancer agents targeting cell organelle mitochondria
- Anticancer therapeutic strategies in gliomas: chemotherapy, immunotherapy, and molecularly targeted therapy in adults
Audience: Pharmaceutical Scientists, Medicinal Chemists, Clinical Oncologists, Researchers in Pre-clinical studies and clinical trials
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PREFACE
Frontiers in Clinical Drug Research - Anti-Cancer Agents presents the recent developments regarding various therapeutic approaches against different types of cancer. This volume is a valuable addition to the series, which serves as an important resource for pharmaceutical scientists, postgraduate students, and researchers seeking updated and critical information for developing clinical trials and devising research plans in anti-cancer research.
The seven chapters in this volume are written by eminent authorities in the field. Chapter 1, presented by Liu et al., gives an overview about the key data management elements in clinical trials for oncological therapeutics. Gareev and Beylerli in chapter 2 give an overview of the role that microRNAs play in various biological processes, including proliferation, differentiation, and apoptosis. Importantly, dysregulation of miRNAs is found to be involved in the pathogenesis of various human tumors, including brain tumors.
In chapter 3 of the volume, Yeniay et al., present vaccination strategies which are being used in current clinical trials. They also discuss the possible future directions for vaccine development against breast cancer. Khamar et al., in chapter 4 focus on desmocollin-3 (DSC3). Although this adhesion molecule is expressed in a variety of neoplasms, it can be used as a diagnostic biomarker for the identification of squamous non-small cell lung cancer (NSCLC) amongst undifferentiated and poorly differentiated NSCLC. It may be helpful in the selection of an appropriate therapy in patients with cancers.
Maryam Zanjirband in Chapter 5 reviews the role of TP53 as a tumour suppressor gene, targeting the interaction between p53 and MDM2 as a strategy for the treatment of malignancies and p53-MDM2 antagonists with emphasis on those that have been used in clinical trials. Manjunath and Choudhary in chapter 6 of the volume cover information about the mitochondrial functions in normal cells versus the functions in cancer cells and cancer stem cells. Anticancer therapy targeting mitochondrial proteins and processes is also elaborated. A catalogue of known mitochondrial mutations involved in cancer is presented. Immunotherapy using mutated mitochondrial proteins or peptides and immunometabolism as a target for cancer therapy is also discussed in this chapter. Finally, in last chapter of the book Hu et al., discussed and reviewed the therapeutic strategies currently available for treating gliomas in adult patients.
I hope that the readers will find these reviews valuable and thought-provoking so that they may trigger further research in the quest for new and novel therapies against cancers. I am grateful for the timely efforts made by the editorial personnel, especially Mr. Mahmood Alam (Editorial Director), Mr. Obaid Sadiq (in-charge Books Department) and Miss Asma Ahmed (Senior Manager Publications) at Bentham Science Publishers.
List of Contributors
Key Data Management Elements in Clinical Trials for Oncological Therapeutics
Daniel Liu1,*,Hualong Sun1,Yan Bo2,Joey Wang2Abstract
Clinical trial designs for anti-cancer agents are sophisticated due to the involvement of complex etiological and pharmaceutical mechanisms, multiple potential indications, emergent therapeutic techniques, clinical needs of long-run assessments and observations of primary endpoints, advanced assessment standards and techniques for disease status as well as various data capture approaches for anti-cancer agents.Also, poor subjects’ health conditions and concomitant therapeutics and medications result in significant challenges for data management in anti-cancer clinical trials. This chapter will overview and describe the main operational and processing elements in the standpoints of data management views, include global data management standards, good trial Case Report Form (CRF) design practice to support various trial design, key elements in data management for anti-cancer trials, management of Independent Data Monitoring Committees in oncological clinical trials, and risk-based data control and collaboration with relevant stakeholders in the management of oncological trials.
1. INTRODUCTION
A tumor (neoplasm) is a new growth that results from abnormal gene expression and abnormal cell proliferation caused by changes in cell genetic materials (including mutation, amplification and/or loss and inactivation of tumor suppressor genes) due to various pathogenic factors. Tumor cells have a feature of uncontrolled autonomous growth or relatively autonomous growth, even when the oncogenic factors are ceasing. A malignant tumor has distinct characteristics with
the ability to infiltrate and metastasize, such as no capsule, unclear boundary, invasive growth to surrounding tissues, abnormal morphology, metabolism and rapid growth, immature differentiation of tumor cells and so on, and shows different levels of atypia with great harm to the human body. Malignant tumors often lead to eventual death from the destruction of essential functions of relevant organs or tissues due to recurrence and/or metastasis.
A traditional infrastructure in the clinical development of antitumor drugs is as follows:
Phase I clinical trials focus on drug-related safety, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activities;Phase II clinical trials are more focused on exploring the efficacy and safety of specific tumor therapy on cancer patients, such as assessment of objective response rate (ORR), tumor progression time (TTP), and disease progression-free (PFS) and so on;Phase III clinical trials are designed to confirm the clinical efficacy and safety of the trial drugs in comparison to the current standard of care or placebo. A common way of doing this is by comparing the outcomes of randomized, double blinded studies with the standard treatment of anti-tumor drugs to assess the overall survival of trial subjects.Unlike the intermittent administration of chemotherapy drugs, administration of immune-targeted drugs needs to be prolonged and continuous to achieve effective inhibition of targeted tumor cellular receptors [1]. The relevant specificities of those immuno-drugs are reflected in the inhibition of tumor cell growth or metastasis by targeting membrane receptors, components of cell signal transduction channels, cell cycle regulatory proteins and important proteins or factors involved in angiogenesis. Because of this, immune-targeted drugs require different clinical development methods from traditional cytotoxic drugs. For example, in the early stage, more attention is paid to the validation of drug mechanisms, including safety and tolerance between target and non-target effects, preliminary anti-tumor activities, and evidence of targeted biomarkers involvement in pharmacodynamic effectiveness. In the late stage, more focus is put on further confirmation of clinical efficacy (e.g., total survival, OS, etc.) and predictable biomarkers in the clinical antitumor outcomes, including those alternative endpoints (e.g., ORR, TTP, PFS, etc.). Given these matters, it is necessary for us to generalize strategies and methodologies of trial designs and data processing knowledge in clinical development of anti-tumor targeted drugs.
2. CDISC STANDARDS APPLICATIONS TO ONCOLOGY CLINICAL TRIALS
As time goes by, the importance of Clinical Data Interchange Standards Consortium (CDISC) standards grows. Especially after the FDA [2] and PMDA [3] began to endorse CDISC standards, the implementation of CDISC standards in clinical trials has become necessary. The CDISC foundational standards cover different areas, including non-clinical and clinical areas. In the CDISC essence, the most widely known standards are probably Clinical Data Acquisition Standards Harmonization (CDASH) [4], Study Data Tabulation Model (SDTM) [5] and Analysis Data Model (ADaM) [6]. These standards are now entrenched in the process of data collection, data organization and data analysis in clinical trials. Oncology studies, as a specific type of clinical trials, are also encouraged or required to be conducted under CDISC standards.
2.1. Data Collection Based on CDASH Standards in Oncology Studies
The major differences between oncology studies and other studies have been mentioned in other chapters in this book. CDISC realized that differences between the different types of studies might bring extra difficulties during the implementation of oncology studies. CDASH categorizes [7] data collection fields into three different types, i.e., Highly Recommended (HR), Recommended/Conditional (R/C) and Optional (O). HR means the data field should always be on the CRF, R/C indicates that the data field should be used on a CRF based on the condition described in the implementation notes column of the CDASH implementation guide (CDASHIG) while O indicates that the data field is optional to be used. As CDASH is used to provide instructions for generating a case report form, the categories above do not impose any rules that require a data field to be populated with a value. They are only intended to instruct which fields should be shown on the case report form.
Moreover, CDISC added some oncology specific domains in the data model including Disease Response and Clinical Classification (RS), Tumor/Lesion Identification (TU), Tumor/Lesion Results (TR), etc. to facilitate the building of the CRFs and data maps, and also developed a number of Therapeutic Area User Guides (TAUG) in the oncology therapeutic area. There are three domains in CDASH that might be important in oncology studies:
RS domain has in total 16 data fields in CDASH standards, including 5 common data fields also used in other domains (STUDYID, SITEID, SUBJID, VISIT, VISDAT). RS domain usually plays an important role in both showing the response data and the staging information of the tumor. The RS data fields made for oncology studies are: Response or Clinical Classification Evaluator (RSEVAL) is used for recording the evaluator of the assessment and is expected for oncology response criteria.Response or Clinical Classification Link ID (RSLNKID) is used for providing the link between the RS records and records from other domains where appropriate. Especially in oncology studies, the RSLNKID could be used to identify the identification of tumor. This data field is rarely used since the response of the subject might not be related to only one record and the response may sometimes be evaluated by investigators or independent reviewers.Response or Clinical Classification Link Group (RSLNKGRP) is similar to the RSLNKID but provides a link between groups of records. Sometimes, this group could be explicitly collected from a case report form, while usually, this information will be derived from a SDTM dataset from the pre-specified information of the case report form.RSTEST is used to record the type of response assessment, while the REORRES is used to record the response result.TU domain has in total 22 data fields and this domain is made for recording the identification of the tumor. Therefore, technically, TU domain should always be used for data collection in oncology studies, especially for the oncology study using RECIST evaluation criteria. The identification of the tumor is usually conducted at the baseline visit by using PET, MRI or CT method (recording in TUMETHOD). Quite a few data fields could be used for identifying the tumor, including TULNKID, TULNKGRP, TUEVAL and so on. Usually, the TULNKID will be used to collect the ID of the specific tumor. It is a highly recommended variable in CDASH, as otherwise it will be difficult to link the tumor with the response just based on the data collected.Data fields such as TULOC, TULAT and TUDIR are often used for recording the details of the tumor.TR domain contains 18 data fields and most of them are similar to the data fields in TU domain. Thus, the TU domain and TR domain are usually put together on one page and the names of these data fields are interchangeable (e.g., TULNKID, TRLNKID). The quantitative and qualitative assessments of each tumor for each time point should be recorded in this domain.Sometimes, it is tricky to distinguish TU and TR in data collection process and for the result collection, we usually just need to use TRORRES to record the original result of tumor assessment and only occasionally need to set the TUORRES data field.
As mentioned above, TU domain and TR domain will be often used together in the same case report form page while the RS domain will be used in a separate page so that the response result could be collected separately from each tumor/lesion for each assessment or visit. A typical illustration of a RS, TU/TR case report form can be found in Fig. (1) [8].
Fig. (1)) A typical illustration of a RS, TU/TR case report form.Aside from the above domains, domains such as Medical History (MH), Concomitant Medication (CM) and Subject Status (SS) are also useful when recording the initial diagnosis, medication/radiotherapy treatments and subject survival information.
Also, some specific data fields that are not in the above domains are also frequently used in oncology studies.
AETOXGR represents the “AE standard toxicity grade” and commonly has the question text of “What is the [NCI CTCAE/Name of scale (toxicity)”. Since CTCAE grade is often used in oncology studies, the data field is recommended to be used in AE domain in oncology studies.LBTOXGR represents the “Lab standard toxicity grade” and commonly has the question text of “What is the Toxicity Grade”. The lab data results might relate to the NCI CTCAE toxicity scale so it could be optionally used to catch such data. Although if the trial sponsor is not willing to collect the data from case report forms this might lead to extra attention to the SDTM mapping process.From the above information, we can also find that there are several typical edit checks that might be uniquely implemented in oncology studies.
Cross-check edit check for the consistency of the group of the tumor page and response page. For example, if there is no non-target tumor identified in the tumor page, then no data should be recorded in the non-target response field and vice versa.Cross-check edit check for evaluator where appropriate. If both the tumor page and response page have set the fields to record the evaluator information, then the consistency of these two fields should be checked.It is also quite common that we cannot implement the online edit check for the response criteria conformance. In this case, we might need to take an offline listing approach to manually check the data. In addition, medical monitoring staff could also be involved in the process of the generation of such offline listing since the medical expertise could be highly useful.
2.2. The SDTM Data Mapping Process of Oncology Clinical Trials
SDTM represents data standards for the submission of human clinical trial data tabulations to regulatory authorities such as the US FDA. The folder structure of the data submission for the US FDA can be seen in Fig. (2). The SDTM datasets should be placed under the tabulations->sdtm folder. Generally speaking, SDTM standards made the foundation of CDISC standards due to the highly standardized formats and detailed description of each variable. The SDTM is built around the concept of observations of collected about subjects who participated in a clinical study [9]. The origin of SDTM data can originate from case report forms, derivation of the data or assignment of external evaluator. Most likely, the data on case report forms will be transferred to SDTM datasets while few data fields that are solely set for data collection purpose will not be used in SDTM datasets.
Fig. (2)) The folder structure of the data submission for the US Food and Drug Administration (FDA).There are several classes of domains under SDTM: interventions, events, findings, special purpose and so on. Each class serves a typical purpose of data tabulation. The oncology specific SDTM domains were added to SDTM standards in SDTMIG v3.1.3. The oncology specific domains in SDTM standards are similar to those in CDASH standards, which are TU, TR, RS, etc.
As mentioned, the TU domain is used to identify unique tumors. The identification of tumors is usually conducted from the baseline visit by different methods, such as CT, MRI or other methods specified in the protocol. For new, split, or merged lesions, the post-baseline data should also be included in the TU domain. In these cases, the proper use of TULNKID, TUGRPID would be critical. The result of the TU domain is often derived from pre-specified information from the case report form (e.g., target, non-target). A typical example of the TU domain is shown in Fig. (3).
Fig. (3)) A typical example of TU domain.Unlike CDASH while in SDTM the information of both TU and TR could be collected in one unique case report form, the TR domain still needs to be separated from the TU domain although the data record result from the TR domain is related to that from TU domain. All the assessment results of a tumor needs to be put into the TR domain, including the diameter, tumor state and so on. TRLNKID is often used to link records in the TR domain to an identification record in the TU domain. The corresponding data across the TU and TR domains needs a RELREC dataset to link the related data records. In addition, TRLNKGRP is often used to link records in the TR domain to a response assessment data record in the RS domain. The corresponding of data across the TR and RS domains needs a RELREC relationship to link the related data records. A typical example of the TR domain is shown in Fig. (4).
Fig. (4)) A typical example of the TR domain.The RS domain is used for clinical classifications, including oncology disease response criteria. The data in RS domain is not necessarily collected directly from the case report form. For example, the assessment name of each data record can be directly obtained from the criteria defined in protocol. An example of the RS domain is shown in Fig. (5).
Fig. (5)) An example of the RS domain.The RELREC domain is used to represent the relationship of the records among TU domain, TR domain and RS domain. An example of the RELREC domain is shown in Fig. (6).
Fig. (6)) An example of the RELREC domain.2.3. The Data Analysis of Oncology Clinical Trials by Implementing ADaM Datasets
The ADaM data model [6] defines the standards used for the generation of analysis datasets and associated metadata. While SDTM is developed for data tabulation, ADaM standards are designed for data derivation and analysis. Ideally, SDTM data can be easily transferred into the ADaM datasets to allow for easy traceability and the generation of data that is analysis-ready to facilitate the preparation of tables, figures and listings (TFLs).
Generally, ADaM includes the Subject-Level Analysis Dataset (ADSL) which mainly focuses on the data of describing subjects, analysis populations and treatment groups, including one record per subject and the Basic Data Structure (BDS) dataset which could contain one or more data records per subject, per analysis parameter or per analysis time point [6]. It is possible to derive extra analysis parameters if needed for any additional analysis requirement. ADaM standards provide the flexibility to add various kinds of derived data to meet analysis needs. The folder structure of Data submission for ADaM datasets to the US FDA can be found in Fig. (2).
For oncology studies, often disease characteristics used for stratification are included in the ADSL dataset. Data such as gene expression, status of mutation and other baseline information could be recorded in the ADSL dataset so that these data could be used as status flags in other ADaM datasets. ADSL is usually the first ADaM dataset to be created purely from SDTM datasets.
The analysis objectives of oncology studies usually include both time to event analysis and response analysis. Time to event endpoint usually needs to be analyzed based on the event time and response data. Typically one dataset is created for the event information and another dataset is created for the time to event response. For example, we could create an intermediate dataset called ADEVENT or ADDATES to record all events for each subject including all tumor assessment information, so that we can have a full picture of all possible events for each subject in that dataset. The intermediate dataset, ADEVENT, can be created based on ADSL and SDTM datasets and contains key date information to support the time to event analysis. Based on ADSL, ADEVENT and SDTM datasets, the ADTTE dataset is created to obtain the analysis endpoints for each subject, which means the PARAMCD variable in ADTTE could be PFS (progression free survival), OS (overall survival), EFS (event-free survival) and other time to event endpoints.
For the response analysis, an optional ADRESP dataset may be created for recording the response data for the oncology study. Best overall response (BOR) and objective response rate (ORR) are often calculated as the endpoints of oncology studies. The results of the assessment, such as complete response (CR) or partial response (PR), are commonly used in the response analysis.
2.4. The Developing Status of Therapeutic Area Data Standards User Guide
The Therapeutic Area Data Standards User Guide (TAUG) [10] is used to fully support the implementation of all the CDISC standards (CDASH, SDTM and ADaM) for certain types of studies. Because of differences between various types of tumors, CDISC has developed several TAUGs for oncology studies such as TAUG for lung cancer, breast cancer, and prostate cancer and so on.
The objectives of TAUGs are to provide an overview of certain cancer, indicate the subject and disease characteristics, and indicate the implementation method of CDASH, SDTM and ADaM standards for specific cancer. Usually, the TAUG includes diagrams of the diagnostic process, treatment process, and assessment process of certain type of tumor, which illustrates the whole process from the start of a subject participating in a study to the end of the subject withdrawing from the study. It is always good practice to run through the specific TAUG before implementing the study for a specific tumor.
3. Key perspectives of clinical data in clinical trial development of cancer drugs
According to the characteristics of tumor disease and antitumor drug therapy, different dosage limiting toxicity (DLT) and maximum tolerate dose (MTD) may be produced by different administration regimens in the clinical trial design. As long as the toxicity can be tolerated, the dose should be increased as much as possible to achieve the best efficacy. Therefore, at the early stage of clinical trials, different dose groups should be explored as much as possible to find the most effective and tolerable drug regimen. Based on the mechanism of action of the investigation medical product, an antitumor drug may be effective against multiple tumor types. Therefore, in early Phase I/II exploratory clinical trials, multiple tumor types may be appropriately selected for testing to find preliminary results of the drug's sensitivity to different tumor types. In phase III, confirmatory studies with large samples are conducted based on the preliminary results of tumor treatment observed in early clinical trials. As shown in Table 1, according to different stages, objectives, and tumor types of clinical trials, the selected primary endpoint is also different.
A surrogate endpoint (SE) is a substitute for measuring an outcome being studied in a clinical trial, and can be a biomarker, such as a laboratory measurement, radiographic image, physical sign, or other measures. The SE is not itself a direct measurement of clinical benefit but is known to predict clinical benefit.
Before an SE can be accepted in place of a clinical outcome, there must be extensive evidence showing that it can be relied upon to predict or correlate with clinical benefit. From a regulatory standpoint, there are several characteristics of SEs based on the level of clinical validation:
Validated SEs can be reliably assumed to predict a clinical outcome, and be accepted as evidence of clinical benefits to support regulatory approval.SEs can be used to support accelerated approval, but post-approval clinical trials are needed to show that these SEs can be relied upon to predict or correlate with clinical benefit.SEs are reasonably likely to predict a clinical benefit, and supported by strong mechanistic and/or epidemiologic rationale, but the amount of clinical data available is not sufficient to show that they are validated.Candidate SEs are still under evaluation for their ability to predict clinical benefits.Only types 1 and 2 are permitted to be used as evidential data to test new therapies and new indications for existing therapies. When an SE shows a beneficial effect through appropriate studies, its use may allow clinical trials to be conducted in smaller numbers of subjects over shorter periods of time, thereby speeding up drug development. In the clinical stage, clinical benefits for regular endpoint data include:
Overall survival (OS): defined as the time from the beginning of randomization to death from any cause. When clinical trials are designed adequately to assess survival of cancer therapy, the OS is usually the preferred endpoint, since it is assumed as a meaningful clinical benefit for trial subjects to have any small improvement in survival. The measurement bias is avoidable in the endpoint assessment due to the association with the date of death. This endpoint should be assessed periodically, either by direct contact with trial subjects at the time of therapeutic initiation or by talking to trial subjects via phone interview. Considered a time-dependent endpoint, OS should be evaluated in randomized control clinical trials rather than historical clinical studies, since different usages of medications, imaging techniques or supportive treatments might complicate assessment of historical studies. In the actual execution of clinical trials, sometimes the confirmation of death date for non-inpatient subjects is difficult to determine or the time of death has an independent causal relationship with the trial drugs. Also, implementation management of long-term trials might be difficult, and subsequent antitumor therapy might confuse the survival analysis. When trial subjects are lost from follow-up before the death was recorded, the last contacting record could be used as the survival time. When the subjects remain alive at the end of clinical trials, the last follow-up visit would be the survival time.Pathological complete remission (pCR): a direct measure of the anti-tumor activity for cancer drugs in neoadjuvant therapy. The criteria of pathologic complete response should be defined well in the protocol design in order to collect and analyze appropriate data of pCR. Unfavorable factors in the pCR outcomes are relatively subjective evaluation under a microscope. Thus, clear data requirements are critical to produce reliable results.Symptoms-relieved evidence: improvements in signs and symptoms, such as weight gain and pain, are often considered clinical benefits. Currently, regulatory authority may accept the symptoms-relieved evidence, or clinical improvements evaluated with PRO tools (e.g., QOL, HRQL, TTP, etc.), such as weight gain, decreased exudation, pain relief or reduction, etc., as the main effective endpoints in clinical trials. These tools may be used as efficacy evaluations in blinded, control and randomized trials with less imaging assessment to support regulatory claims. A non-blinded trial used with these tools is likely to induce subjective bias of evaluations. As an endpoint, it is imperative to distinguish improvements of tumor-related symptoms from the reduction or lack of drug toxicities.Objective Response Rate (ORR): a direct measure of the anti-tumor activity of cancer therapy in cancer lesions, but a surrogate measure in some lesions. The ORR measures the proportion of subjects whose tumors shrink to a certain size and remain there for a certain amount of time (mainly for solid tumors), including a complete response (CR) and a partial response (PR). According to the cancer therapeutic standards, a CR represents a complete disappearance of tumor for more than 1 month, and a PR suggests a reduction by 50% in the product of maximal diameter and maximal vertical diameter of tumor lesion, and no increase in other lesions for more than 1 month.This indicator is a common endpoint in phase II clinical trials or a single arm trial to provide directly attributable evidence of bioactivities of cancer drugs (Fig. 7). However, since a single arm trial might not fully reflect a time-event endpoint, such as survival period, PFS and TTP need to be done in a randomized control trial when the time-event endpoint is specified in a protocol. This data assessment can be performed based on image evaluations at certain frequent intervals, which may require an independent or central evaluation. In the setting of such data collections, external visits or testing requirements might be considered in the protocol. A definition of ORR should be clarified, such as CR+PR, or PR+VGPR+CR, as well as mitigation criteria of tumor lesions prior to trial initiation, including tumor location, response time, response volume, remission lasting period, CR or PR rate, etc. The time-event should be required for data recording as well. At the assessment, the best data selection may be exercised based on protocol definition, but sometimes there would be additional imaging data collection to determine cancer progresses.
The image completion time should be captured in the CRF. In order to prevent data collection and analysis from unblinded risks, the image results may be required to be stored in a separate database from the clinical database. Reconciliation of the two databases (e.g., image collection and/or completion time) might be necessary prior to the database lock.
Improvement in tumor-related symptoms in conjunction with an improved ORR and adequate response duration has supported regular approval in several clinical settings. In summary, the pros and cons of these endpoints are listed in Table 2.
Fig. (7)) General consideration of clinical position for trial.4. Key Considerations of CRF Designs in Cancer Trials
Scientific results of clinical trials depend on collecting correct and quality data in the trials, which firstly and foremost relies on the quality of a relevant data collection tool. Case Report Forms (CRF) play a significant part in the clinical trial management process greatly impacting trial outcome success. Many factors can affect the design of CRF, including therapeutic field, drug type, trial stage, adoption of a paper or electronic data management system and so on. A difference in the therapeutic field is the main cause leading to diverse CRF designs. Because of the complexity of cancer disease itself, especially involvement of research endpoints as well as relevant indicators, data collection and management are becoming more complex in oncology than in clinical trials of other therapeutic fields.
As discussed previously, CDISC have been developing relevant Therapeutic Area Standards (TA) for clinical data, including those data standards related to breast, prostate, colorectal, and lung cancer published, and some are still being developed. Once these standards and procedures of data management are established at the initial stage of clinical trials, the quality and integrity of data mapping transformation may be ensured at the later stage of data production used for statistical analysis in compliance with Study Data Tabulation Model (SDTM) Data sets. Moreover, some specific country-level guidance documents, for example, relevant guidelines of evaluation of anticancer drugs for human use by European Medicines Agency (EMA) (2013), relevant technique requirements for clinical data of anti-tumor drugs for NDA submission by the United States Food and Drug Administration (FDA), are good reference sources for CRF developments [11, 12].
4.1. History of Tumor Therapy/Prior Treatment
Data from the subject’s treatment history is helpful to predict treatment outcomes and provide a baseline indicator prior to enrollment in the clinical trials. In inclusion and exclusion criteria, a protocol has to be established for a subject with previous therapies that may or may not interfere with the trial intervention assessments. Prior tumor therapy should be assessed based on therapeutic types, such as previous surgery, previous radiotherapy, and previous drug therapy and so on according to the protocol. This historical information generally includes therapy with drug type, drug name, dose, dosing frequency, initial date and end date, therapeutic outcome, preferred response, etc. The response evaluation should be referred to a categorical variable with codes based on tumor assessment criteria defined by medical definitions. In some scenarios, the CRF form may include detailed collection requirements of therapeutic data, such as chemotherapy regimen, chemotherapy period and so on. The history of the subject's cancer therapy can be designed as an independent form from a form of normal medical history in the CRF. Table 3 shows an example of the independent data form of cancer therapeutic histories collected in the CRF.
Table 4 demonstrates a history form of previous tumor surgery captured with surgery date, surgery name, surgery position, surgery purpose, surgery outcomes and so on.
Table 5 gives an example for a history form to capture key data from previous cancer radiotherapies, including radiotherapy position, intensity, cycles, initial and end date, prognosis post radiotherapy etc.
4.2. Tumor Diagnosis
The tumor diagnosis is generally divided into two steps:
Firstly qualitative diagnosis, i.e., assessment if tumor is malignant or not, and further determination of its histological type and differentiation degree;Secondly staging judgment, i.e., specification of cancer range and understanding of status of tumor invasion and metastasis, which lays the foundation for subsequent therapeutic measures post preliminary diagnosis.Due to different indications and/or tumor types defined by a protocol, a field type in CRF forms may be distinct, which reflects answer selection of histological classification, position, staging and degree of tumors, etc. The clinical guidelines stipulated by the National Comprehensive Cancer Network (NCCN) (www.nccn.org) have formulated certain categorical standards as follows, which is referred to in the field type settings in the CRF development of cancer trials as follows:
1.Histological type: Each kind of cancer has been classified into different subtype, e.g., lung cancer as small lung cancer, adenocarcinoma, squamous carcinoma, large cell carcinoma; breast cancer as preinvasive carcinoma and invasive carcinoma. Also, the field settings for every sub-type of cancer may be different due to changeable or inconsistent cancer naming, for example, adenocarcinoma or glandular carcinoma. When inclusion and exclusion criteria of a protocol are developed, the histological type must be clearly defined to be accurate in the field type setting of the CRF form. When there are multiple sub-types of a cancer, a few main sub-types can be selected as field types and the others for uncommon sub-types of carcinoma, unless the trial objective is targeted to those uncommon sub-types.2.Position: a field type of cancer position in the CRF form is designed for primary carcinoma. When inclusion and exclusion criteria are designed, the exact position of carcinoma should be clearly defined. For example, a position of esophagus carcinoma is assumed as epimere, midpiece or hypomere; colon cancers as epityphlon, cecum, ascending colon, right flexure, left flexure, descending colon, sigmoid flexure, rectum, etc.3.Staging: TNM staging is used in most tumor staging. Also, some specific staging criteria are seen in hematological malignances, such as Ann Arbor Staging Criteria for malignant lymphoma (Stage I, II, III1, III2 and IV); Rai Stage or Binet stage for chronic granulocytic leukemia, and further staging based on the cancer progression, such as chronic/stable phase, acceleration/proliferation phase, acute transformation phase.4.Differentiation degree: A common differentiation degree is including GX indetermination (unrated), G1 high differentiation, G2 moderate differentiation, G3 hypodifferentiation, G4 undifferentiation. Some tumor descriptions adopt other criteria, such as Scarff-Bloom-Richardson differentiation for invasive breast cancer; Gleason differentiation for prostatic cancer.Generally speaking, criteria of inclusion/exclusion and prognostic assessment in a protocol should clearly define the tumor status, such as pathological classification, clinical staging, cancer progression etc. Then, the CRF should collect relevant data including with diagnostic date, histological type, staging (e.g., TNM, clinical staging), differentiated degree, metastatic status and position etc. Based on the purpose of the protocol, other data may be captured, such as primary tumor position, a method of pathological diagnosis, biosampling source and date, recurrent or metastatic date, special functional scoring (e.g., Child-Push assess-ment of hepatic functions for liver cancer). Table 6 shows examples of CRF forms in clinical trials for a drug to treat esophageal squamous carcinoma (ESC).
4.3. Status Rating of Physical Performances
An important indicator of health status for cancer subjects is the evaluation of subjects’ physical performance state (PS) in clinical trials. Some clinical trials are also designed for subjects with a poor state of physical performance with an advanced cancer stage. Therefore, the status rating of physical performance is used to assess cancer subjects’ improvement of physical performance state from the baseline following trial drug therapy, and/or toleration to the trial drug therapy in clinical trials. A common evaluation tool for physical performance is the global Karnofsky rating form, which is used as the rate of toleration evaluation to chemotherapy, i.e., less than 40% suggests not being suitable for continuous chemotherapy due to drug toxicities. An additional physical performance scoring tool developed by Eastern Cooperative Oncology Group (also called the ECOG form) is extensively used in clinical trials to assess physical PS of cancer subjects and classifies PS by 6 levels (0-5 level) [13]. Usually, the ECOG level (e.g., 0-1 level) is listed as one of inclusion criteria in a protocol of clinical trials for cancer drugs. Table 7 lists an example of ECOG data collected in clinical trials.
4.4. Questionnaire of Quality of Life
A key to the treatment of malignant tumors is to make either clinical benefits (e.g., extended survival) or improvements of quality of life (QOL) for cancer patients, or both as much as possible. For the advanced cancer subjects participated in clinical trials, one of main objectives is to improve and maintain the quality of life. There are many types of QOL forms in the medical practices, which are assumed as part of patient reported outcome (PRO) tools. A series of QLQ forms developed by the European Organization for Research and Treatment Cancers (EORTC) is highly recommended to be used in clinical trials, of which QLQ-C30 is the one of the general rating models targeted to cancer patients. Some QLQ forms are specifically designed to be useful in special cancer types, such as QLQ for lung cancer, QLQ-B2R3 for breast cancer, etc. A protocol should define the QOL tool to be used in clinical trials and the field type and code of QOL items used in CRF forms should be mapped with the selection by protocol. An attention should be paid to the copyright of QOL tools. Before the QOL tool is applicable in clinical trials, permission from the owner of the QOL tools selected has to be obtained. Usually, the applicable QOL tool in clinical trials would not be allowed to change the item formats, including questionnaire types, replying selection order and coding, since these QOL tools are validated well in advance and any amendment of these tools will affect the tool applicability, including validity, reliability, precision, responsiveness, appropriateness, sensitivity, feasibility and so on.
Pain scale is another QOL tool mostly used for evaluations of assisting analgesic effects in clinical trials for cancer drugs. A few of common rating mechanisms include numeric rating scale (NRS), facial expression rating scale, and visual analogue scale (VAS). One of the currently recognized scaling tools for cancer pains is the brief pain inventory (BPI) with NRS mechanism which is composed of 7 questionnaires encompassing the subject’s daily activities, emotions, entertainments, social relationship, sleeping quality, working and walking. Other pain scales more commonly used include McNeill pain questionnaire (MPQ), Mc Miller pain questionnaire, global pain assessment scale (GPAS), and behavioral pain scale (BPS). Any pain scale selected by a protocol should be incorporated into the CRF forms according to data management of QOL principles. Moreover, some specific assessment questionnaires for targeted cancers and relevant symptoms reliefs may be considered, such as NSCLC-SAQ, MMRC dyspnea scale, KPS scale, EQ-5D-3L scale, EQ-5D-5L scale and so on. When a CRF with QOL is developed, CDISC data standards regarding QRS supplements should be applicable. With more involvement of electronic techniques in QOL tools, an electronic PRO (ePRO) system should be validated before it is put into the actual QOL data collections and processing, which is essential as per the GCP and regulations.
4.5. Body Weight
Compared with other drugs in clinical trials, data of subjects’ body weights should be continuously captured instead of only once at the screening stage. Fluctuation of body weights is closely associated with health status of cancer subjects. For example, a rapid decline of body weights suggests worsening of cancer progression. Moreover, some research has shown that the body mass index (BMI) with body weight value and muscle density affects the toleration to chemotherapy for cancer subjects [3-8]. In cancer trials, body weight/BMI is also related to drug dosing. Basic data of body weight in a CRF should be collected with a question for measuring, measure date and measure value.
4.6. Medical Diagnosis with Molecular Biology Techniques
With the development of basic clinical research, more and more targeted anti-tumor drugs play a specific and effective role against proto-oncogene mutations. These anti-tumor drugs have a specific proto-oncogene loci which target specific mutation sites in the tumor. Thus, screenings of gene mutations via molecular biological tests need to be collected in clinical trials. Table 8 gives an example of detection data for a NSCLC with mutations of the eml4-alk gene (not including mutation data of EGFR and k-ras loci) in the CRF form. The basic data to be collected includes sampling date, sample type, measuring method, measuring result etc. These data are helpful to verify, clean up and judge if relevant data are normalized or deviated from the protocol.
4.7. Biomarkers Measures
Tumor biomarkers are one of the most effective precision medical tools extensively used in the selection of targeted cancer subjects and the assessment of targeted drugs therapy for cancer subjects in clinical trials [9]. In brief, biomarkers are used as one of lab tests in clinical trials, which should capture biomarker name and type, test purpose, test date and method. Biomarker types and test items are set according to the protocol definitions. Generally, relevant data are captured based on settings of characteristics of cancer types defined in the protocol and categorical variables in the CRF. Table 9 demonstrates an example of biomarker data collection via CRF tool in a lung cancer trial.
4.8. Imaging Evaluations and Tumor Lesion Measurements
Imaging techniques are mainly used for measurements of solid tumor lesions, such as X-rays, CT scans, MRI, radioimmunography, PET/PET-CT, ultrasonic examinations, etc. A CRF form should be able to map relevant data collections from these technique applications. A trial project management plan (PMP) should stipulate how to handle data collections for unplanned evaluations outside standard scheduled evaluations and relevant source data recording and verifications. A statistical analytic plan (SAP) should be formulated for how to analyze the outcomes of both evaluations and measurements of cancer lesions, including management of missing and/or censoring data clinical trials.
When special evaluation tools are used in clinical trials, e.g., RECIST 1.1 etc., the basic data points to be collected in CRF forms should include each lesion number (for clear distinction of multiply tumors at the same part), lesion location, lesion type (e.g., primary, lymph nodes, or metastatic lesion, etc.), examination methods (e.g., scan CT, spiral CT, enhanced CT, MRI etc.), assessment results (e.g., the longest diameter of lesions, diameter sum of target lesions), examination date, etc. Table 10 lists an example of such lesion measurements by imaging evaluations.
